SOTALOL HYDROCHLORIDE tablet
For Healthcare Providers >

1. Patient Information
2. Manufactured In Czech Republic By:
3. Manufactured For:
4. It Is Important That When You Go Home, You Take The Exact Dose The Doctor Prescribed For You. At Any Time While You Are Taking Sotalol Hydrochloride Tablets (af), Watch For Signs That You May Be Getting This Different Type Of Abnormal Heartbeat And Call Your Doctor If They Occur. Call Your Doctor Right Away If You:
5. Also, Call Your Doctor Right Away If You Have Any Of The Following Conditions:
6. What Are Sotalol Hydrochloride Tablets, Usp (af)?
7. Who Should Not Take Sotalol Hydrochloride Tablets, Usp (af)?
8. Do Not Take Sotalol Hydrochloride Tablets (af) If You:
9. How Should I Take Sotalol Hydrochloride Tablets, Usp (af)?
10. What Should I Avoid While Taking Sotalol Hydrochloride Tablets, Usp (af)?
11. What Is The Most Important Information I Should Know About Sotalol Hydrochloride Tablets, Usp (af)?

Patient Information ⮝

Advise patients to contact their healthcare provider in the event of syncope, pre-syncopal symptoms or cardiac palpitations.

Advise patients that their electrolytes and ECG will be monitored during treatment[see Warnings and Precautions (5.1)].

Advise patients to contact their healthcare provider in the event of conditions that could lead to electrolyte changes such as severe diarrhea, unusual sweating, vomiting, less appetite than normal or excessive thirst[see Warnings and Precautions (5.1)].

Advise patients not to change the sotalol hydrochloride dose prescribed by their healthcare provider.

Advise patients that they should not miss a dose, but if they do miss a dose they should not double the next dose to compensate for the missed dose: they should take the next dose at the regularly scheduled time[see Dosage and Administration (2)].

Advise patients to not interrupt or discontinue sotalol hydrochloride without their physician s advice, that they should get their prescription for sotalol filled and refilled on time so they do not interrupt treatment[see Dosage and Administration (2)].

Advise patients to not start taking other medications without first discussing new medications with their healthcare provider.

Advise patients that they should avoid taking sotalol hydrochloride within two hours of taking antacids that contain aluminum oxide or magnesium hydroxide[see Drug Interactions (7.7)].

All brand names listed are the registered trademarks of their respective owners and are not trademarks of Teva Pharmaceuticals USA.

Manufactured In Czech Republic By: ⮝

TEVA CZECH INDUSTRIES s.r.o.

Opava-Komarov, Czech Republic

Manufactured For: ⮝

TEVA PHARMACEUTICALS USA, INC.

North Wales, PA 19454

Rev. M 6/2016

It Is Important That When You Go Home, You Take The Exact Dose The Doctor Prescribed For You. At Any Time While You Are Taking Sotalol Hydrochloride Tablets (af), Watch For Signs That You May Be Getting This Different Type Of Abnormal Heartbeat And Call Your Doctor If They Occur. Call Your Doctor Right Away If You: ⮝

• faint,
• become dizzy, or
• have fast heartbeats.

If you cannot reach your doctor, go to the nearest hospital emergency room. Take your sotalol hydrochloride tablets (AF) with you and show them to the doctor or nurse.

Also, Call Your Doctor Right Away If You Have Any Of The Following Conditions: ⮝

• severe diarrhea
• unusual sweating
• vomiting
• less appetite than normal, or
• more thirst than normal.

These are conditions that will make you more likely to get the different type of abnormal heartbeat.

If you take sotalol hydrochloride (AF) with certain other medicines, you will increase your chance of getting this different type of abnormal heartbeat. These medicines are listed below under"

What Are Sotalol Hydrochloride Tablets, Usp (af)? ⮝

Sotalol hydrochloride tablets (AF) is a medicine that is given to patients with atrial fibrillation (irregular heartbeats). Atrial fibrillation happens when certain parts of the heart (the chambers known as atria) beat too fast or irregularly. When this happens, your heart cannot pump blood through your body as well as it should. This may make you feel weak and tired, or get out of breath easily. You may get an uncomfortable feeling in your chest and "fluttering" or "palpitations". Atrial fibrillation can be changed back (converted) to normal heart rhythm by an electric shock or by using certain medicines. However, atrial fibrillation can return. Sotalol hydrochloride tablets (AF) may help your heart stay beating regularly for a longer period of time.

This information about sotalol hydrochloride tablets (AF) was developed to ensure that you and your doctor get the right information about your type of irregular heartbeats. Consult your doctor before you accept any other sotalol product that does not provide this patient information.

Who Should Not Take Sotalol Hydrochloride Tablets, Usp (af)? ⮝

Sotalol hydrochloride tablets (AF) are not for everyone with irregular heartbeats (atrial fibrillation). This is why you and your doctor need to discuss the benefits and risks of sotalol hydrochloride tablets (AF) and whether your symptoms are troublesome enough for you to start taking sotalol hydrochloride tablets (AF).

Do Not Take Sotalol Hydrochloride Tablets (af) If You: ⮝

• have serious kidney problems or are on kidney dialysis;
• have lung disease causing shortness of breath (such as asthma, chronic bronchitis or emphysema);
• have symptoms of heart failure (such as shortness of breath when you exercise or are physically active and swelling of the ankles or legs);
• have a very slow heart beat and do not have an implanted artificial pacemaker;

Taking certain other medicines with sotalol hydrochloride tablets (AF) can increase the chance that you will get the dangerous abnormal heartbeat discussed in"

How Should I Take Sotalol Hydrochloride Tablets, Usp (af)? ⮝

Your doctor will start you on sotalol hydrochloride (AF) in the hospital and will check your heart rhythm for the first 2 or more days of treatment. This will allow your doctor to find the right dose for you. Always take the exact amount your doctor prescribes. Never change your sotalol hydrochloride tablets (AF) dose unless your doctor tells you to. Your doctor will do regular tests to check that the amount you're taking is still right for you.

Keep taking your sotalol hydrochloride tablets (AF) until your doctor tells you to stop. Keep taking it even if you feel fine. However, never take an extra dose of sotalol hydrochloride tablets (AF) even if you do not feel well. When it is time to stop taking sotalol hydrochloride tablets (AF), your doctor will give you instructions on how to gradually reduce your dose over a period of 1 to 2 weeks.

You may take sotalol hydrochloride tablets (AF) with or without food. However, it is important to take sotalol hydrochloride tablets (AF) at the same time every day. This gives your heart a steady supply of the medicine. It might be helpful to take sotalol hydrochloride tablets (AF) at the same time as something you regularly do every day.

If you are taking an antacid containing aluminum or magnesium to treat heartburn or upset stomach wait at least 2 hours after your dose of sotalol hydrochloride tablets (AF) before you take the antacid.

Never try to make up for a missed dose of sotalol hydrochloride tablets (AF). You could increase your chance of getting the different type of abnormal heartbeat. If you miss taking a dose of sotalol hydrochloride tablets (AF), just take your normal amount at the next scheduled time.

If you take more sotalol hydrochloride tablets (AF) than you should have, call your doctor right away. If you cannot reach your doctor, go to the nearest hospital emergency room. Take your sotalol hydrochloride tablets (AF) with you to show to the doctor or nurse.

What Should I Avoid While Taking Sotalol Hydrochloride Tablets, Usp (af)? ⮝

Certain other medicines taken with sotalol hydrochloride tablets (AF) may increase the chance that you will get the dangerous abnormal heartbeat (

Sotalol hydrochloride tablets (AF) most serious side effect, a different type of dangerous abnormal heartbeat, is discussed in"

What Is The Most Important Information I Should Know About Sotalol Hydrochloride Tablets, Usp (af)? ⮝

". Dangerous abnormal heartbeats happen rarely. But they can be serious and, in rare instances, can even cause death.

Sotalol hydrochloride tablets (AF) most common side effects are tiredness, slow rate, shortness of breath, and dizziness. Sotalol hydrochloride tablets (AF) can also cause other side effects. If you are concerned about these or any other side effects, ask your doctor.

Important points about sotalol hydrochloride tablets, USP (AF)

Sotalol hydrochloride tablets (AF) can help you best if you take it as your doctor has prescribed it.

• Take your medicine every day as prescribed
• Do not miss doses or take extra doses
• Call your doctor right away if you feel new fast heartbeats with lightheadedness and fainting. These can be serious and in rare instances can even cause death.
• Do not take sotalol hydrochloride tablets (AF) if you have serious kidney problems, lung disease causing shortness of breath, symptoms of heart failure.
• Tell your doctor and pharmacist the name of all medications (prescription, non-prescription, and natural/herbal remedies) you are taking
• Do not start taking any other medicines without telling your doctor
• Go for all your regular checkups
• Get your refills on time
• Do not stop taking sotalol hydrochloride tablets (AF) until your doctor tells you to stop.

This leaflet provides a summary of information about sotalol hydrochloride tablets, USP (AF). Your doctor or pharmacist has a longer leaflet written for healthcare professionals that you can ask to read. Sotalol hydrochloride tablets, USP (AF) was prescribed for your particular condition. Do not use it for another condition or give it to others.

APOTEX INC.
SOTALOL HYDROCHLORIDE TABLETS, USP (AF)
80 mg, 120 mg and 160 mg

Manufactured byManufactured for
Apotex Inc. Apotex Corp.
Toronto, Ontario Weston, Florida
Canada M9L 1T9 33326

Revised: July 2015

Rev. 2

1. No Title 1572543116
2. No Title 1572547161
3. No Title 1572547620
4. No Title 1572548281
5. No Title 1572552285
6. No Title 1572552960
7. No Title 1572554084
8. No Title 1572555053
9. Highlights Of Prescribing Information
10. Indications And Usage
11. Dosage And Administration
12. Dosage Forms And Strengths
13. Contraindications
14. Warnings And Precautions
15. Adverse Reactions
16. Drug Interactions
17. Warning: Life Threatening Proarrhythmia
18. 1 Indications And Usage
19. 2 Dosage And Administration
20. 3 Dosage Forms And Strengths
21. 4 Contraindications
22. 5 Warnings And Precautions
23. 6 Adverse Reactions
24. 7 Drug Interactions
25. 8 Use In Specific Populations
26. 10 Overdosage
27. 11 Description
28. 12 Clinical Pharmacology
29. 13 Nonclinical Toxicology
30. 14 Clinical Studies
31. 16 How Supplied/storage And Handling
32. No Title 1572449580
33. Repackaging Information
34. Principal Display Panel - 80 Mg
35. No Title 1572451422
36. Description
37. Clinical Pharmacology
38. Warnings
39. Precautions
40. Overdosage
41. How Supplied
42. Sotalol Hydrochloride
43. Sotalol Hydrochloride Tablets, Usp 8265401/0116 Rx Only
44. Package/label Display Panel Carton 80 Mg
45. Package/label Display Panel Blister 80 Mg
46. See Full Prescribing Information For Complete Boxed Warning.
47. Sotalol 120mg Tablet
48. Principal Display Panel 80 Mg
49. Principal Display Panel 120 Mg
50. Principal Display Panel 160 Mg
51. Principal Display Panel 240 Mg
52. Principal Display Panel 80 Mg (af)
53. Principal Display Panel 120 Mg (af)
54. Principal Display Panel 160 Mg (af)
55. No Title 1572453155
56. Drug Interactions
57. No Title 1572454346
58. Sotalol Hcl 80mg Tablet
59. No Title 1572455193
60. Package/label Display Panel
61. No Title 1572455658
62. Principal Display Panel - 80 Mg Bottle Label
63. Warning: Life Threatening Proarrhythmia
64. 1 Indications And Usage
65. 2 Dosage And Administration
66. 3 Dosage Forms And Strengths
67. 4 Contraindications
68. 5 Warnings And Precautions
69. 6 Adverse Reactions
70. 7 Drug Interactions
71. 8 Use In Specific Populations
72. 10 Overdosage
73. 11 Description
74. 12 Clinical Pharmacology
75. 13 Nonclinical Toxicology
76. 14 Clinical Studies
77. 16 How Supplied/storage And Handling
78. No Title 1572457619

No Title 1572543116 ⮝

To minimize the risk of induced arrhythmia, patients initiated or re-initiated on sotalol hydrochloride tablets, USP should be placed for a minimum of three days (on their maintenance dose) in a facility that can provide cardiac resuscitation and continuous electrocardiographic monitoring. Creatinine clearance should be calculated prior to dosing. For detailed instructions regarding dose selection and special cautions for people with renal impairment, see DOSAGE AND ADMINISTRATION. 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 are 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.

No Title 1572547161 ⮝

To minimize the risk of induced arrhythmia, patients initiated or reinitiated on sotalol hydrochloride tablets should be placed for a minimum of three days (on their maintenance dose) in a facility that can provide cardiac resuscitation and continuous electrocardiographic monitoring. Creatinine clearance should be calculated prior to dosing. For detailed instructions regarding dose selection and special cautions for people with renal impairment, see DOSAGE AND ADMINISTRATION. 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 are 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.

No Title 1572547620 ⮝

To minimize the risk of induced arrhythmia, patients initiated or re-initiated on sotalol hydrochloride tablets, USP should be placed for a minimum of three days (on their maintenance dose) in a facility that can provide cardiac resuscitation and continuous electrocardiographic monitoring. Creatinine clearance should be calculated prior to dosing. For detailed instructions regarding dose selection and special cautions for people with renal impairment, see DOSAGE AND ADMINISTRATION. 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 are 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.

No Title 1572548281 ⮝

To minimize the risk of induced arrhythmia, patients initiated or reinitiated on sotalol hydrochloride tablets should be placed for a minimum of three days (on their maintenance dose) in a facility that can provide cardiac resuscitation and continuous electrocardiographic monitoring. Creatinine clearance should be calculated prior to dosing. For detailed instructions regarding dose selection and special cautions for people with renal impairment, see DOSAGE AND ADMINISTRATION. 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 are 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.

No Title 1572552285 ⮝

To minimize the risk of induced arrhythmia, patients initiated or reinitiated on sotalol hydrochloride tablets should be placed for a minimum of three days (on their maintenance dose) in a facility that can provide cardiac resuscitation and continuous electrocardiographic monitoring. Creatinine clearance should be calculated prior to dosing. For detailed instructions regarding dose selection and special cautions for people with renal impairment, see DOSAGE AND ADMINISTRATION. 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 are 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.

No Title 1572552960 ⮝

To minimize the risk of induced arrhythmia, patients initiated or re-initiated on sotalol hydrochloride tablets, USP should be placed for a minimum of three days (on their maintenance dose) in a facility that can provide cardiac resuscitation and continuous electrocardiographic monitoring. Creatinine clearance should be calculated prior to dosing. For detailed instructions regarding dose selection and special cautions for people with renal impairment, see DOSAGE AND ADMINISTRATION. 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 are 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.

No Title 1572554084 ⮝

To minimize the risk of induced arrhythmia, patients initiated or re-initiated on sotalol hydrochloride tablets (AF) should be placed for a minimum of three days (on their maintenance dose) in a facility that can provide cardiac resuscitation, continuous electrocardiographic monitoring and calculations of creatinine clearance. For detailed instructions regarding dose selection and special cautions for people with renal impairment, see DOSAGE AND ADMINISTRATION. Sotalol is also indicated for the treatment of documented life-threatening ventricular arrhythmias and is marketed under the brand name Betapace (sotalol hydrochloride). Sotalol hydrochloride tablets, however, must not be substituted for Betapace AF (sotalol hydrochloride tablets, USP (AF)) because of significant differences in labeling (i.e. patient package insert, dosing administration and safety information).

No Title 1572555053 ⮝

Manufactured for:
QUALITEST PHARMACEUTICALS
Huntsville, AL 35811

8182127
Rev 5/16
R6

Highlights Of Prescribing Information ⮝

These highlights do not include all the information needed to use SOTALOL HYDROCHLORIDE TABLETS safely and effectively. See full prescribing information for SOTALOL HYDROCHLORIDE TABLETS.

SOTALOL HYDROCHLORIDE tablets, for oral use Initial U.S. Approval: 1992

Indications And Usage ⮝

Sotalol hydrochloride is an antiarrhythmic indicated for:

• the treatment of life threatening ventricular arrhythmias (1.1)

• the maintenance of normal sinus rhythm in patients with atrial fibrillation or flutter (AFIB/AFL) (1.2)

Limitations of Use

• Avoid use in patients with asymptomatic ventricular premature contraction (1.1)

• Avoid use in patients with minimally symptomatic or easily reversible AFIB/AFL (1.2)

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)

Dosage Forms And Strengths ⮝

80 mg,120 mg ,160 mg and 240 mg tablets (3)

Contraindications ⮝

For the treatment of AFIB/AFL or ventricular arrhythmias

• Sinus bradycardia, 2nd or 3rd degree AV block, sick sinus syndrome (4)

• Congenital or acquired long QT syndrome, (4)

• Serum potassium <4 mEq/L (4)

• Cardiogenic shock, decompensated heart failure (4)

• Bronchial asthma or related bronchospastic conditions (4)

• Hypersensitivity to sotalol (4)

For the treatment of AFIB/AFL also contraindicated for:

• QT interval >450 ms (4)

• Creatine clearance <40 ml/min (4)

Warnings And Precautions ⮝

• QT prolongation, bradycardia, AV block, hypotension, worsening heart failure: Reduce dose or discontinue (5.1)

• Acute exacerbation of coronary artery disease upon cessation of therapy: Do not abruptly discontinue (5.5)

• Correct any electrolyte disturbances (5.1)

• May mask symptoms of hypoglycemia or worsen hyperglycemia in diabetic patients; monitor (5.7)

Adverse Reactions ⮝

The most common adverse reactions ( 2%) for sotalol hydrochloride tablets are: fatigue 4%, bradycardia (less than 50 bpm) 3%, dyspnea 3%, proarrhythmia 3%, asthenia 2%, and dizziness 2%. (6)

To report SUSPECTED ADVERSE REACTIONS, contact Qualitest Pharmaceuticals at 1-800-444-4011 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Drug Interactions ⮝

• Class I or III Antiarrhythmics or other drugs that prolong the QT interval: Avoid concomitant use (7.1)

• Digoxin, calcium channel blocker: increased risk of bradycardia, hypotension, heart failure (7.2)

• Dosage of insulin or antidiabetic drugs may need adjustment (7.5)

• Aluminum or magnesium-based antacids reduce sotalol exposure (7.7)

See 17 for PATIENT COUNSELING INFORMATION.

Revised: 5/2016

Warning: Life Threatening Proarrhythmia ⮝

To minimize the risk of drug-induced arrhythmia, initiate or reinitiate oral sotalol in a facility that can provide cardiac resuscitation and continuous electrocardiographic monitoring.

Sotalol can cause life threatening ventricular tachycardia associated with QT interval prolongation.

If the QT interval prolongs to 500 msec or greater, reduce the dose, lengthen the dosing interval, or discontinue the drug.

Calculate creatinine clearance to determine appropriate dosing [see Dosage and Administration (2.5)].

1 Indications And Usage ⮝

1.1 Life-Threatening Ventricular Arrhythmias

Sotalol is indicated for the treatment of life-threatening, documented ventricular arrhythmias, such as sustained ventricular tachycardia (VT).

Limitation of Use:

Sotalol may not enhance survival in patients with ventricular arrhythmias. Because of the proarrhythmic effects of sotalol, including a 1.5 to 2% rate of Torsade de Pointes (TdP) or new ventricular tachycardia/fibrillation (VT/VF) in patients with either non-sustained ventricular tachycardia (NSVT) or supraventricular arrhythmias (SVT), its use in patients with less severe arrhythmias, even if the patients are symptomatic, is generally not recommended. Avoid treatment of patients with asymptomatic ventricular premature contractions [see Warnings and Precautions (5.2).]

1.2 Delay in Recurrence of Atrial Fibrillation/Atrial Flutter (AFIB/AFL)

Sotalol is indicated for the maintenance of normal sinus rhythm (delay in time to recurrence of AFIB/AFL) in patients with symptomatic AFIB/AFL who are currently in sinus rhythm.

Limitation of Use:

Because sotalol can cause life-threatening ventricular arrhythmias, reserve its use for patients in whom AFIB/AFL is highly symptomatic. Patients with paroxysmal AFIB that is easily reversed (by Valsalva maneuver, for example) should usually not be given sotalol.

2 Dosage And Administration ⮝

2.1 General Safety Measures for Initiation of Oral Sotalol Therapy

Withdraw other antiarrhythmic therapy before starting sotalol and monitor carefully for a minimum of 2 to 3 plasma half-lives if the patient's clinical condition permits [see Drug Interactions (7)].

Hospitalize patients 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 (insert cross ref to renal dosing). Continually monitor patients with each uptitration in dose, until they reach steady state. Determine QTc 2 to 4 hours after every 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 (because of the long terminal elimination half- life of sotalol, dosing more than a two times a day is usually not necessary). Oral doses as high as 480-640 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 creatinine clearance < 40 ml/min or QTc >450 is contraindicated [see Contraindication (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)].

From pediatric pharmacokinetic data the following is recommended:

For initiation of treatment, 30 mg/m2 three times a day (90 mg/m2 total daily dose) is approximately equivalent to the initial 160 mg total daily dose for adults. Subsequent titration to a maximum of 60 mg/m2 (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 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/m2, 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/m2, 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/m2. Use similar calculations for dose titration.

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.

2.5 Dosage for Patients with Renal Impairment

Adults

Use of sotalol in any age group with decreased renal function should be at lower doses or increased intervals between doses. It will take much longer to reach steady-state with any dose and/or frequency of administration. Closely monitor heart rate and 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.

The initial dose of 80 mg and subsequent doses should be administered at the intervals listed in Table 1 or Table 2.

Table 1: Dosing Intervals for treatment of Ventricular Arrhythmias in renal impairment

Creatinine Clearance mL/min	Dosing Interval (hours)
> 60	12
30 59	24
10 29	36 48
< 10	Dose should be individualized

Table 2: Dosing Intervals for treatment of AFIB/AFL in renal impairment

Creatinine Clearance mL/min	Dosing Interval (hours)
> 60	12
40 59	24
<40	Contraindicated

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 tablets USP, 120 mg 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, care should be taken 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 HCl. 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.

3 Dosage Forms And Strengths ⮝

Sotalol hydrochloride tablets, USP are supplied as capsule-shaped, light-blue, scored tablets:

• 80 mg imprinted with 58/75 on one side and V on the reverse side

• 120 mg imprinted with 58/76 on one side and V on the reverse side

• 160 mg imprinted with 58/77 on one side and V on the reverse side

• 240 mg imprinted with 58/78 on one side and V on the reverse side

4 Contraindications ⮝

Sotalol hydrochloride is 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 is also contraindicated in patients with:

• Baseline QT interval >450 ms

• Creatinine clearance < 40 mL/min

5 Warnings And Precautions ⮝

5.1 QT Prolongation and Proarrhythmia

Sotalol 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 (2.1)].

Correct hypokalemia or hypomagnesemia prior to initiating sotalol, 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 (2.1)].

In general, do not use sotalol with other drugs known to cause QT prolongation [see Drug Interactions (7.1)].

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 up titration of sotalol because of its beta- blocking effects. Monitor for signs and symptoms of heart failure and discontinue treatment if symptoms occur.

5.5 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, particularly in patients with ischemic heart disease, gradually reduce the dosage over a period of 1 2 weeks, if possible, and monitor the patient. If angina markedly worsens or acute coronary ischemia develops, treat appropriately (consider use of an alternative beta blocker). Warn patients not to interrupt therapy without their physician s advice. Because coronary artery disease may be common, but unrecognized, in patients treated with sotalol, abrupt discontinuation 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 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 Masked Signs of Hypoglycemia in Diabetics

Beta blockers may mask tachycardia occurring with hypoglycemia, but other manifestations such as dizziness and sweating may not be significantly affected. 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.

6 Adverse Reactions ⮝

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Adverse reactions that are clearly related to sotalol are those which are typical of its Class II (beta-blocking) and Class III (cardiac action potential duration prolongation) effects and are dose related.

Ventricular Arrhythmias

Serious Adverse Reactions

In patients with a history of sustained ventricular tachycardia, the incidence of Torsade de Pointes during oral sotalol treatment was 4% and worsened VT was about 1%; in patients with other less serious ventricular arrhythmias the incidence of Torsade de Pointes was 1% and new or worsened VT was about 0.7%. Incidence of Torsade de Pointes arrhythmias in patients with VT/VF are shown in Table 3 below.

Table 3: Percent Incidence of Torsade de Pointes and Mean QTc Interval by Dose For Patients With Sustained VT/VF

Daily Dose (mg)	Torsade de Pointes Incidence	Mean QTc * (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 QTc Interval (msec)	Incidence of Torsade de Pointes	Change from in Baseline QTc (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)

( ) Number of patients assessed

Table 5: Incidence (%) of Common Adverse Reactions ( 2% in the Placebo group and less frequent than in the Sotalol Hydrochloride groups) in a Placebo-controlled Parallel-group Comparison Study of Patients with Ventricular Ectopy

Body System/Adverse Reaction (Preferred Term)	Placebo	Sotalol Hydrochloride Total Daily Dose
	N = 37 (%)	320 mg N = 38 (%)	640 mg N = 39 (%)
CARDIOVASCULAR
Chest Pain	5.4	7.9	15.4
Dyspnea	2.7	18.4	20.5
Palpitation	2.7	7.9	5.1
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/m2 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/m2 daily, was discontinued because of increased frequency of sinus pauses/bradycardia. Additional cardiovascular AEs were seen at the 90 and 210 mg/m2 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 QTc 525 msec were seen in 2 patients at the 210 mg/m2 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 hydrochloride -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 Hydrochloride (AF) groups) in Four Placebo-controlled Studies of Patients with AFIB/AFL

Body System/ Adverse Reaction (Preferred Term)	Placebo	Sotalol Hydrochloride (AF) Total Daily Dose
	N = 282 (%)	160-240 mg N = 153 (%)	>240-320 mg N = 122 (%)
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.

7 Drug Interactions ⮝

7.1 Antiarrhythmics and other QT Prolonging Drugs

Sotalol has not been studied with other drugs that prolong the QT interval such as antiarrhythmics, some phenothiazines, tricyclic antidepressants, certain oral macrolides and certain quinolone antibiotics. Discontinue Class I or Class III antiarrhythmic agents for at least three half-lives prior to dosing with sotalol. Class Ia antiarrhythmic drugs, such as disopyramide, quinidine and procainamide and other Class III drugs (for example, amiodarone) are not recommended as concomitant therapy with sotalol, because of their potential to prolong refractoriness [see Warnings and Precautions (5.2)]. There is only limited experience with the concomitant use of Class Ib or Ic antiarrhythmics. Additive Class II effects would also be anticipated with the use of other beta-blocking agents concomitantly with sotalol.

7.2 Digoxin

Proarrhythmic events were more common in sotalol treated patients also receiving digoxin; it is not clear whether this represents an interaction or is related to the presence of CHF, a known risk factor for proarrhythmia, in the patients receiving digoxin. Both digitalis glycosides and beta-blockers slow atrioventricular conduction and decrease heart rate. Concomitant use can increase the risk of bradycardia.

7.3 Calcium-Channel Blocking Drugs

Sotalol and calcium-blocking drugs can be expected to have additive effects on atrioventricular conduction or ventricular function. Monitor such patients for evidence of bradycardia and hypotension.

7.4 Catecholamine-Depleting Agents

Concomitant use of catecholamine-depleting drugs, such as reserpine and guanethidine, with a beta-blocker may produce an excessive reduction of resting sympathetic nervous tone. Monitor such patients for evidence of hypotension and/or marked bradycardia which may produce syncope.

7.5 Insulin and Oral Antidiabetics

Hyperglycemia may occur, and the dosage of insulin or antidiabetic drugs may require adjustment [see Warnings and Precautions 5.7)].

7.6 Clonidine

Concomitant use with sotalol increases the risk of bradycardia. Because beta-blockers may potentiate the rebound hypertension sometimes observed after clonidine discontinuation, withdraw sotalol several days before the gradual withdrawal of clonidine to reduce the risk of rebound hypertension.

7.7 Antacids

Avoid administration of oral sotalol within 2 hours of antacids containing aluminum oxide and magnesium hydroxide.

8 Use In Specific Populations ⮝

8.1 Pregnancy

Pregnancy Category B

There are no adequate and well-controlled studies in pregnant women. Sotalol has been shown to cross the placenta, and is found in amniotic fluid. In animal studies there was no increase in congenital anomalies, but an increase in early resorptions occurred at sotalol doses 18 times the maximum recommended human dose (MRHD, based on surface area). Animal reproductive studies are not always predictive of human response.

Reproduction studies in rats and rabbits during organogenesis at 9 and 7 times the MRHD (based on surface area), respectively, did not reveal any teratogenic potential associated with sotalol. In rabbits, a dose of sotalol 6 times the MRHD produced a slight increase in fetal death as well as maternal toxicity. This effect did not occur at sotalol dose 3 times the MRHD. In rats a sotalol dose 18 times the MRHD increased the number of early resorptions, while a dose 2.5 times the MRHD, produced no increase in early resorptions.

8.3 Nursing Mothers

Sotalol is excreted in the milk of laboratory animals and has been reported to be present in human milk. Discontinue nursing on sotalol.

8.4 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 (QTc interval and resting heart rate) and drug concentrations have been evaluated in children aged between 3 days and 12 years old [see Dosage and Administration (2.4) and Clinical Pharmacology (12.2)].

8.6 Renal Impairment

Sotalol is mainly eliminated via the kidneys. Dosing intervals should be adjusted based on creatinine clearance [see Dosage and Administration (2.5)].

10 Overdosage ⮝

Intentional or accidental overdosage with sotalol has resulted in death.

Symptoms and Treatment of Overdosage

The most common signs to be expected are bradycardia, congestive heart failure, hypotension, bronchospasm and hypoglycemia. In cases of massive intentional overdosage (2 16 grams) of sotalol the following clinical findings were seen: hypotension, bradycardia, cardiac asystole, prolongation of QT interval, Torsade de Pointes, ventricular tachycardia, and premature ventricular complexes. If overdosage occurs, therapy with sotalol should be discontinued and the patient observed closely. Because of the lack of protein binding, hemodialysis is useful for reducing sotalol plasma concentrations. Patients should be carefully observed until QT intervals are normalized and the heart rate returns to levels >50 bpm.

The occurrence of hypotension following an overdose may be associated with an initial slow drug elimination phase (half-life of 30 hours) thought to be due to a temporary reduction of renal function caused by the hypotension. In addition, if required, the following therapeutic measures are suggested:

Bradycardia or Cardiac Asystole: Atropine, another anticholinergic drug, a beta-adrenergic agonist or transvenous cardiac pacing.

Heart Block: (second and third degree) transvenous cardiac pacemaker.

Hypotension: (depending on associated factors) epinephrine rather than isoproterenol or norepinephrine may be useful.

Bronchospasm: Aminophylline or aerosol beta-2-receptor stimulant. Higher than normal doses of beta-2 receptor stimulants may be required.

Torsade de Pointes: DC cardioversion, transvenous cardiac pacing, epinephrine, magnesium sulfate.

11 Description ⮝

Sotalol hydrochloride tablets, USP, are an antiarrhythmic drug with Class II (beta-adrenoreceptor blocking) and Class III (cardiac action potential duration prolongation) properties. Sotalol hydrochloride tablets, USP are supplied as a light-blue, capsule-shaped tablet for oral administration. Sotalol hydrochloride is a white, crystalline solid with a molecular weight of 308.8. It is hydrophilic, soluble in water, propylene glycol and ethanol, but is only slightly soluble in chloroform. Chemically, sotalol hydrochloride is d,l-N-[4-[1-hydroxy-2-[(1-methylethyl) amino]ethyl]phenyl]methane-sulfonamide monohydrochloride. The molecular formula is C12H20N2O3 S HCl and is represented by the following structural formula:

Sotalol hydrochloride tablets, USP contain the following inactive ingredients: colloidal silicon dioxide, FD&C blue color #2 (aluminum lake, conc.), lactose monohydrate, magnesium stearate, microcrystalline cellulose, sodium starch glycolate, and stearic acid.

12 Clinical Pharmacology ⮝

12.1 Mechanism of Action

Sotalol has both beta-adrenoreceptor blocking (Vaughan Williams Class II) and cardiac action potential duration prolongation (Vaughan Williams Class III) antiarrhythmic properties. The two isomers of sotalol have similar Class III antiarrhythmic effects, while the l-isomer is responsible for virtually all of the beta-blocking activity. The beta-blocking effect of sotalol is non-cardioselective, half maximal at about 80 mg/day and maximal at doses between 320 and 640 mg/day. Sotalol does not have partial agonist or membrane stabilizing activity. Although significant beta-blockade occurs at oral doses as low as 25 mg, significant Class III effects are seen only at daily doses of 160 mg and above.

In children, a Class III electrophysiologic effect can be seen at daily doses of 210 mg/m2 body surface area (BSA). A reduction of the resting heart rate due to the beta-blocking effect of sotalol is observed at daily doses 90 mg/m2 in children.

12.2 Pharmacodynamics

Cardiac Electrophysiological Effects

Sotalol hydrochloride prolongs the plateau phase of the cardiac action potential in the isolated myocyte, as well as in isolated tissue preparations of ventricular or atrial muscle (Class III activity). In intact animals it slows heart rate, decreases AV nodal conduction and increases the refractory periods of atrial and ventricular muscle and conduction tissue.

In man, the Class II (beta-blockade) electrophysiological effects of sotalol are manifested by increased sinus cycle length (slowed heart rate), decreased AV nodal conduction and increased AV nodal refractoriness. The Class III electrophysiological effects in man include prolongation of the atrial and ventricular monophasic action potentials, and effective refractory period prolongation of atrial muscle, ventricular muscle, and atrio ventricular accessory pathways (where present) in both the anterograde and retrograde directions. With oral doses of 160 to 640 mg/day, the surface ECG shows dose-related mean increases of 40 100 msec in QT and 10 40 msec in QTc [See Warnings and Precautions (5.1)]. No significant alteration in QRS interval is observed.

In a small study (n=25) of patients with implanted defibrillators treated concurrently with sotalol, the average defibrillatory threshold was 6 joules (range 2 15 joules) compared to a mean of 16 joules for a nonrandomized comparative group primarily receiving amiodarone.

Twenty-five children in an unblinded, multicenter trial with SVT and/or ventricular tachyarrhythmias, aged between 3 days and 12 years (mostly neonates and infants), received an ascending titration regimen with daily doses of 30, 90 and 210 mg/m2 with dosing every 8 hours for a total 9 doses. During steady-state, the respective average increases above baseline of the QTc interval were 2, 14, and 29 msec at the 3 dose levels. The respective mean maximum increases above baseline of the QTc interval were 23, 36, and 55 msec at the 3 dose levels. The steady-state percent increases in the RR interval were 3, 9 and 12%. The smallest children (BSA<0.33 m2) showed a tendency for larger Class III effects ( QTc) and an increased frequency of prolongations of the QTc interval as compared with larger children (BSA 0.33 m2). The beta-blocking effects also tended to be greater in the smaller children (BSA <0.33 m2). Both the Class III and beta-blocking effects of sotalol were linearly related to the plasma concentrations.

Hemodynamics

In a study of systemic hemodynamic function measured invasively in 12 patients with a mean LV ejection fraction of 37% and ventricular tachycardia (9 sustained and 3 non-sustained), a median dose of 160 mg twice daily of sotalol produced a 28% reduction in heart rate and a 24% decrease in cardiac index at 2 hours post-dosing at steady-state. Concurrently, systemic vascular resistance and stroke volume showed nonsignificant increases of 25% and 8%, respectively. One patient was discontinued because of worsening congestive heart failure. Pulmonary capillary wedge pressure increased significantly from 6.4 mmHg to 11.8 mmHg in the 11 patients who completed the study. Mean arterial pressure, mean pulmonary artery pressure and stroke work index did not significantly change. Exercise and isoproterenol induced tachycardia are antagonized by sotalol , and total peripheral resistance increases by a small amount.

In hypertensive patients, sotalol produces significant reductions in both systolic and diastolic blood pressures. Although sotalol is usually well-tolerated hemodynamically, deterioration in cardiac performance may occur in patients with marginal cardiac compensation [see Warnings and Precautions (5.3)].

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 90 100%. After oral administration, peak plasma concentrations are reached in 2.5 to 4 hours, and steady-state plasma concentrations are attained within 2 3 days (that is, after 5 6 doses when administered twice daily). Over the dosage range 160 640 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/m2 of sotalol was administered in the single dose study and daily doses of 30, 90 and 210 mg/m2 were administered every 8 hours in the multi-dose study. After rapid absorption with peak levels occurring on average between 2 3 hours following administration, sotalol was eliminated with a mean half-life of 9.5 hours.

Steady-state was reached after 1 2 days. The average peak to trough concentration ratio was 2. BSA was the most important covariate and more relevant than age for the pharmacokinetics of sotalol. The smallest children (BSA<0.33m2) 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 , 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. Doses or dosing intervals should be adjusted 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 Cmax 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.

13 Nonclinical Toxicology ⮝

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No evidence of carcinogenic potential was observed in rats during a 24-month study at 137 275 mg/kg/day (approximately 30 times the maximum recommended human oral dose (MRHD) as mg/kg or 5 times the MRHD as mg/m2) or in mice, during a 24-month study at 4141 7122 mg/kg/day (approximately 450 750 times the MRHD as mg/kg or 36 63 times the MRHD as mg/m2).

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 18 times the MRHD as mg/m2) prior to mating, except for a small reduction in the number of offspring per litter.

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/m2), respectively, did not reveal any teratogenic potential associated with sotalol HCl. In rabbits, a high dose of sotalol HCl (160 mg/kg/day) at 16 times the MRHD as mg/kg (6 times the MRHD as mg/m2) produced a slight increase in fetal death, and maternal toxicity. Eight times the maximum dose (80 mg/kg/day or 3 times the MRHD as mg/m2) did not result in an increased incidence of fetal deaths. In rats, 1000 mg/kg/day sotalol HCl, 100 times the MRHD (18 times the MRHD as mg/m2), increased the number of early resorptions, while at 14 times the maximum dose (2.5 times the MRHD as mg/m2), no increase in early resorptions was noted. However, animal reproduction studies are not always predictive of human response.

14 Clinical Studies ⮝

14.1 Ventricular Arrhythmias

Sotalol hydrochloride has been studied in life-threatening and less severe arrhythmias. In patients with frequent premature ventricular complexes (VPC), Sotalol hydrochloride was significantly superior to placebo in reducing VPCs, paired VPCs and non-sustained ventricular tachycardia (NSVT); the response was dose-related through 640 mg/day with 80 85% of patients having at least a 75% reduction of VPCs. Sotalol hydrochloride was also superior, at the doses evaluated, to propranolol (40 80 mg TID) and similar to quinidine (200 400 mg QID) in reducing VPCs. In patients with life-threatening arrhythmias [sustained ventricular tachycardia/fibrillation (VT/VF)], sotalol hydrochloride was studied acutely [by suppression of programmed electrical stimulation (PES) induced VT and by suppression of Holter monitor evidence of sustained VT] and, in acute responders, chronically.

In a double-blind, randomized comparison of sotalol and procainamide given intravenously (total of 2 mg/kg sotalol vs. 19 mg/kg of procainamide over 90 minutes), sotalol suppressed PES induction in 30% of patients vs. 20% for procainamide (p=0.2).

In a randomized clinical trial [Electrophysiologic Study Versus Electrocardiographic Monitoring (ESVEM) Trial] comparing choice of antiarrhythmic therapy by PES suppression vs. Holter monitor selection (in each case followed by treadmill exercise testing) in patients with a history of sustained VT/VF who were also inducible by PES, the effectiveness acutely and chronically of sotalol hydrochloride was compared with that of 6 other drugs (procainamide, quinidine, mexiletine, propafenone, imipramine and pirmenol). Overall response, limited to first randomized drug, was 39% for sotalol and 30% for the pooled other drugs. Acute response rate for first drug randomized using suppression of PES induction was 36% for sotalol vs. a mean of 13% for the other drugs. Using the Holter monitoring endpoint (complete suppression of sustained VT, 90% suppression of NSVT, 80% suppression of VPC pairs, and at least 70% suppression of VPCs), sotalol yielded 41% response vs. 45% for the other drugs combined. Among responders placed on long-term therapy identified acutely as effective (by either PES or Holter), sotalol , when compared to the pool of other drugs, had the lowest two- year mortality (13% vs. 22%), the lowest two-year VT recurrence rate (30% vs. 60%), and the lowest withdrawal rate (38% vs. about 75 80%). The most commonly used doses of sotalol hydrochloride in this trial were 320 480 mg/day (66% of patients), with 16% receiving 240 mg/day or less and 18% receiving 640 mg or more.

It cannot be determined, however, in the absence of a controlled comparison of sotalol vs. no pharmacologic treatment (for example, in patients with implanted defibrillators) whether sotalol response causes improved survival or identifies a population with a good prognosis.

Sotalol hydrochloride has not been shown to enhance survival in patients with ventricular arrhythmias.

14.2 Clinical Studies in Supra-ventricular Arrhythmias

Sotalol hydrochloride (AF) has been studied in patients with symptomatic AFIB/AFL in two principal studies, one in patients with primarily paroxysmal AFIB/AFL, the other in patients with primarily chronic AFIB.

In one study, a U.S. multicenter, randomized, placebo-controlled, double-blind, dose-response trial of patients with symptomatic primarily paroxysmal AFIB/AFL, three fixed dose levels of sotalol hydrochloride (AF) (80 mg, 120 mg and 160 mg) twice daily and placebo were compared in 253 patients. In patients with reduced creatinine clearance (40-60 mL/min) the same doses were given once daily. Patients were excluded for the following reasons: QT >450 msec; creatinine clearance <40 mL/min; intolerance to beta-blockers; bradycardia- tachycardia syndrome in the absence of an implanted pacemaker; AFIB/AFL was asymptomatic or was associated with syncope, embolic CVA or TIA; acute myocardial infarction within the previous 2 months; congestive heart failure; bronchial asthma or other contraindications to beta-blocker therapy; receiving potassium losing diuretics without potassium replacement or without concurrent use of ACE-inhibitors; uncorrected hypokalemia (serum potassium <3.5 meq/L) or hypomagnesemia (serum magnesium <1.5 meq/L); received chronic oral amiodarone therapy for >1 month within previous 12 weeks; congenital or acquired long QT syndromes; history of Torsade de Pointes with other antiarrhythmic agents which increase the duration of ventricular repolarization; sinus rate <50 bpm during waking hours; unstable angina pectoris; receiving treatment with other drugs that prolong the QT interval; and AFIB/AFL associated with the Wolff-Parkinson- White (WPW) syndrome. If the QT interval increased to 520 msec (or JT 430 msec if QRS >100 msec) the drug was discontinued. The patient population in this trial was 64% male, and the mean age was 62 years. No structural heart disease was present in 43% of the patients. Doses were administered once daily in 20% of the patients because of reduced creatinine clearance.

Sotalol hydrochloride (AF) was shown to prolong the time to the first symptomatic, ECG-documented recurrence of AFIB/AFL, as well as to reduce the risk of such recurrence at both 6 and 12 months. The 120 mg dose was more effective than 80 mg, but 160 mg did not appear to have an added benefit. Note that these doses were given twice or once daily, depending on renal function. The results are shown in Figure 2, Table 7 and Table 8.

Table 7: Study 1 Patient Status at 12 Months

	Placebo	Sotalol Hydrochloride (AF) Dose
		80 mg	120 mg	160 mg
Randomized	69	59	63	62
On treatment in NSR at 12 months without recurrencea	23%	22%	29%	23%
Recurrenceab	67%	58%	49%	42%
D/C for AEs	6%	12%	18%	29%
a Symptomatic AFIB/AFL
b Efficacy endpoint of Study 1; study treatment stopped.

Note that columns do not add up to 100% due to discontinuations (D/C) for other reasons.

Table 8: Study 1 Median Time to Recurrence of Symptomatic AFIB/AFL and Relative Risk (vs. Placebo) at 12 Months

	Placebo n=69	Sotalol Hydrochloride (AF) Dose
		80 mg n=59	120 mg n=63	160 mg n=62
P-value vs. placebo		0.325	0.018	0.029
Relative Risk (RR) to placebo		0.81	0.59	0.59
Median time to recurrence (days)	27	106	229	175

Discontinuation because of adverse events was dose related.

In a second multicenter, randomized, placebo-controlled, double-blind study of 6 months duration in 232 patients with chronic AFIB, sotalol hydrochloride (AF) was titrated over a dose range from 80 mg/day to 320 mg/day. The patient population of this trial was 70% male with a mean age of 65 years. Structural heart disease was present in 49% of the patients. All patients had chronic AFIB for >2 weeks but <1 year at entry with a mean duration of 4.1 months. Patients were excluded if they had significant electrolyte imbalance, QTc >460 msec, QRS >140 msec, any degree of AV block or functioning pacemaker, uncompensated cardiac failure, asthma, significant renal disease (estimated creatinine clearance <50 mL/min), heart rate <50 bpm, myocardial infarction or open heart surgery in past 2 months, unstable angina, infective endocarditis, active pericarditis or myocarditis, 3 DC cardioversions in the past, medications that prolonged QT interval, and previous amiodarone treatment. After successful cardioversion patients were randomized to receive placebo (n=114) or sotalol hydrochloride (AF) (n=118), at a starting dose of 80 mg twice daily. If the initial dose was not tolerated it was decreased to 80 mg once daily, but if it was tolerated it was increased to 160 mg twice daily. During the maintenance period 67% of treated patients received a dose of 160 mg twice daily, and the remainder received doses of 80 mg once daily (17%) and 80 mg twice daily (16%).

Tables 9 and 10 show the results of the trial. There was a longer time to ECG-documented recurrence of AFIB and a reduced risk of recurrence at 6 months compared to placebo.

Table 9: Study 2 Patient Status at 6 Months

	Placebo n=114	Sotalol Hydrochloride (AF)n=118
On treatment in NSR at 6 months without recurrencea	29%	45%
Recurrenceab	67%	49%
D/C for AEs	3%	6%
Death	1%
a Symptomatic or asymptomatic AFIB/AFL
b Efficacy endpoint of Study 2; study treatment stopped.

Table 10: Study 2 Median Time to Recurrence of Symptomatic AFIB/AFL/Death and Relative Risk (vs. Placebo) at 6 Months

	Placebo n=114	Sotalol Hydrochloride (AF) n=118
P-value vs. placebo		0.002
Relative Risk (RR) to placebo		0.55
Median time to recurrence (days)	44	>180

14.3 Clinical Studies in Patients with Myocardial Infarction

In a large double-blind, placebo controlled secondary prevention (postinfarction) trial (n=1,456); sotalol hydrochloride was given as a non-titrated initial dose of 320 mg once daily. Sotalol hydrochloride did not produce a significant increase in survival (7.3% mortality on sotalol hydrochloride vs. 8.9% on placebo, p=0.3), but overall did not suggest an adverse effect on survival. There was, however, a suggestion of an early (i.e., first 10 days) excess mortality (3% on sotalol hydrochloride vs. 2% on placebo).

In a second small trial (n=17 randomized to sotalol hydrochloride) where sotalol hydrochloride was administered at high doses (for example, 320 mg twice daily) to high-risk post-infarction patients (ejection fraction <40% and either >10 VPC/hr or VT on Holter), there were 4 fatalities and 3 serious hemodynamic/electrical adverse events within two weeks of initiating sotalol hydrochloride.

16 How Supplied/storage And Handling ⮝

Sotalol hydrochloride tablets, USP; capsule-shaped bisected light-blue scored tablets, are available as follows:

80 mg strength imprinted 58/75 on one side and V on the reverse side available in the following

configurations:

Bottles of 100: NDC 0603-5769-21

Bottles of 500: NDC 0603-5769-28

120 mg strength imprinted 58/76 on one side and V on the reverse side available in the following

configurations:

Bottles of 100: NDC 0603-5770-21

Bottles of 300: NDC 0603-5770-25

160 mg strength imprinted 58/77 on one side and V on the reverse side available in the following

configurations:

Bottles of 100: NDC 0603-5771-21

240 mg strength imprinted 58/78 on one side and V on the reverse side available in the following

configurations:

Bottles of 100: NDC 0603-5772-21

Store at 20 to 25 C (68 to 77 F) [see USP Controlled Room Temperature].

No Title 1572449580 ⮝

Manufactured for:
QUALITEST PHARMACEUTICALS
Huntsville, AL 35811

8182127
Rev 5/16
R6

Repackaging Information ⮝

Please reference the How Supplied section listed above for a description of individual tablets. This drug product has been received by Aphena Pharma - TN in a manufacturer or distributor packaged configuration and repackaged in full compliance with all applicable cGMP regulations. The package configurations available from Aphena are listed below:

Count	80 mg
30	43353-616-30
90	43353-616-60

Store between 20 -25 C (68 -77 F). See USP Controlled Room Temperature. Dispense in a tight light-resistant container as defined by USP. Keep this and all drugs out of the reach of children.

Repackaged by:

Cookeville, TN 38506

20171120JH

Principal Display Panel - 80 Mg ⮝

NDC 43353-616 - Sotalol HCl 80 mg - Rx Only

SOTALOL HYDROCHLORIDE sotalol hydrochloride tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:43353-616(NDC:0603-5769) Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength SOTALOL HYDROCHLORIDE (UNII: HEC37C70XX) (SOTALOL - UNII:A6D97U294I) SOTALOL HYDROCHLORIDE 80 mg

Inactive Ingredients Ingredient Name Strength SILICON DIOXIDE (UNII: ETJ7Z6XBU4) FD&C BLUE NO. 2 (UNII: L06K8R7DQK) LACTOSE MONOHYDRATE (UNII: EWQ57Q8I5X) MAGNESIUM STEARATE (UNII: 70097M6I30) CELLULOSE, MICROCRYSTALLINE (UNII: OP1R32D61U) SODIUM STARCH GLYCOLATE TYPE A POTATO (UNII: 5856J3G2A2) STEARIC ACID (UNII: 4ELV7Z65AP)

Product Characteristics Color BLUE (Light blue) Score 2 pieces Shape OVAL (capsule-shaped) Size 12mm Flavor Imprint Code 5875;V Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:43353-616-30 30 in 1 BOTTLE, PLASTIC; Type 0: Not a Combination Product 03/10/2010 2 NDC:43353-616-60 90 in 1 BOTTLE, PLASTIC; Type 0: Not a Combination Product 03/10/2010

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA075563 11/07/2003

Labeler - Aphena Pharma Solutions - Tennessee, LLC (128385585)

Establishment
Name	Address	ID/FEI	Business Operations
Aphena Pharma Solutions - Tennessee, LLC		128385585	REPACK(43353-616)

Revised: 11/2017 Document Id: c68dff8e-c8ac-4ed4-8700-a70b920554a8 34391-3 Set id: 28ba5f2a-ed6b-49a7-8a11-2d811ce9d946 Version: 1 Effective Time: 20171120 Aphena Pharma Solutions - Tennessee, LLC

No Title 1572451422 ⮝

To minimize the risk of induced arrhythmia, patients initiated or reinitiated on sotalol hydrochloride tablets should be placed for a minimum of three days (on their maintenance dose) in a facility that can provide cardiac resuscitation and continuous electrocardiographic monitoring. Creatinine clearance should be calculated prior to dosing. For detailed instructions regarding dose selection and special cautions for people with renal impairment, see DOSAGE AND ADMINISTRATION. 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 are 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.

Description ⮝

Sotalol hydrochloride, is an antiarrhythmic drug with Class II (beta-adrenoreceptor blocking) and Class III (cardiac action potential duration prolongation) properties. It 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. 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 C12H20N2O3S HCl and is represented by the following structural formula:

Each tablet for oral administration, contains 80 mg, 120 mg or 160 mg of sotalol hydrochloride. In addition, each tablet also contains the following inactive ingredients: magnesium stearate and microcrystalline cellulose.

Clinical Pharmacology ⮝

Mechanism of Action

Sotalol hydrochloride has both beta-adrenoreceptor blocking (Vaughan Williams Class II) and cardiac action potential duration prolongation (Vaughan Williams Class III) antiarrhythmic properties. Sotalol hydrochloride is a racemic mixture of d- and l-sotalol. Both isomers have similar Class III antiarrhythmic effects, while the l-isomer is responsible for virtually all of the beta-blocking activity. The beta-blocking effect of sotalol is non-cardioselective, half maximal at about 80 mg/day and maximal at doses between 320 and 640 mg/day. Sotalol does not have partial agonist or membrane stabilizing activity. Although significant beta-blockade occurs at oral doses as low as 25 mg, significant Class III effects are seen only at daily doses of 160 mg and above.

In children, a Class III electrophysiological effect can be seen at daily doses of 210 mg/m2 body surface area (BSA). A reduction of the resting heart rate due to the beta-blocking effect of sotalol is observed at daily doses 90 mg/m2 in children.

Electrophysiology

Sotalol hydrochloride prolongs the plateau phase of the cardiac action potential in the isolated myocyte, as well as in isolated tissue preparations of ventricular or atrial muscle (Class III activity). In intact animals it slows heart rate, decreases AV nodal conduction and increases the refractory periods of atrial and ventricular muscle and conduction tissue.

In man, the Class II (beta-blockade) electrophysiological effects of sotalol are manifested by increased sinus cycle length (slowed heart rate), decreased AV nodal conduction and increased AV nodal refractoriness. The Class III electrophysiological effects in man include prolongation of the atrial and ventricular monophasic action potentials, and effective refractory period prolongation of atrial muscle, ventricular muscle, and atrio-ventricular accessory pathways (where present) in both the anterograde and retrograde directions. With oral doses of 160 to 640 mg/day, the surface ECG shows dose-related mean increases of 40 to 100 msec in QT and 10 to 40 msec in QTc. In a study of patients with atrial fibrillation (AFIB)/flutter (AFIB/AFL) receiving three different oral doses of sotalol hydrochloride (AF) given q12h (or q24h in patients with a reduced creatinine clearance), mean increases in QT intervals measured from 12-lead ECGs of 25 msec, 40 msec and 54 msec were found in the 80 mg, 120 mg, and 160 mg dose groups, respectively. (See WARNINGS for description of relationship between QTc and Torsade de Pointes type arrhythmias.) No significant alteration in QRS interval is observed.

In a small study (n=25) of patients with implanted defibrillators treated concurrently with sotalol, the average defibrillatory threshold was 6 joules (range 2 to 15 joules) compared to a mean of 16 joules for a non-randomized comparative group primarily receiving amiodarone.

In a dose-response trial comparing three dose levels of sotalol hydrochloride (AF), 80 mg, 120 mg, and 160 mg with placebo given q12h (or q24h in patients with a reduced renal creatinine clearance) for the prevention of recurrence of symptomatic atrial fibrillation (AFIB)/flutter (AFL), the mean ventricular rate during recurrence of AFIB/AFL was 125, 107, 110 and 99 beats/min in the placebo, 80 mg, 120 mg and 160 mg dose groups, respectively (p <0.017 for each sotalol dose group versus placebo). In another placebo controlled trial in which sotalol hydrochloride (AF) was titrated to a dose between 160 and 320 mg/day in patients with chronic AFIB, the mean ventricular rate during recurrence of AFIB was 107 and 84 beats/min in the placebo and sotalol hydrochloride (AF) groups, respectively (p <0.001).

Twenty-five children in an unblinded, multicenter trial with supraventricular (SVT) and/or ventricular (VT) tachyarrhythmias, aged between 3 days and 12 years (mostly neonates and infants), received an ascending titration regimen with daily doses of 30, 90 and 210 mg/m2 with dosing every 8 hours for a total of 9 doses. During steady-state, the respective average increases above baseline of the QTc interval, in msec (%), were 2(+1%), 14(+4%) and 29(+7%) msec at the 3 dose levels. The respective mean maximum increases above baseline of the QTc interval, in msec (%), were 23(+6%), 36(+9%) and 55(+14%) msec at the 3 dose levels. The steady-state percent increases in the RR interval were 3, 9 and 12%. The smallest children (BSA<0.33 m2) showed a tendency for larger Class III effects ( QTc) and an increased frequency of prolongations of the QTc interval as compared with the larger children (BSA 0.33 m2). The beta-blocking effects also tended to be greater in the smaller children (BSA<0.33 m2). Both the Class III and beta-blocking effects of sotalol were linearly related with the plasma concentrations.

Hemodynamics

In a study of systemic hemodynamic function measured invasively in 12 patients with a mean LV ejection fraction of 37% and ventricular tachycardia (9 sustained and 3 non-sustained), a median dose of 160 mg twice daily of sotalol produced a 28% reduction in heart rate and a 24% decrease in cardiac index at 2 hours post dosing at steady-state. Concurrently, systemic vascular resistance and stroke volume showed non-significant increases of 25% and 8%, respectively. Pulmonary capillary wedge pressure increased significantly from 6.4 mmHg to 11.8 mmHg in the 11 patients who completed the study. One patient was discontinued because of worsening congestive heart failure. Mean arterial pressure, mean pulmonary artery pressure and stroke work index did not significantly change. Exercise and isoproterenol induced tachycardia are antagonized by sotalol, and total peripheral resistance increases by a small amount.

In hypertensive patients, sotalol produces significant reductions in both systolic and diastolic blood pressures. Although sotalol is usually well-tolerated hemodynamically, caution should be exercised in patients with marginal cardiac compensation as deterioration in cardiac performance may occur. (See WARNINGS, Congestive Heart Failure.)

Clinical Studies

Prolongation of Time to Recurrence of Symptomatic Atrial Fibrillation/Flutter

Sotalol hydrochloride (AF) has been studied in patients with symptomatic AFIB/AFL in two principal studies, one in patients with primarily paroxysmal AFIB/AFL, the other in patients with primarily chronic AFIB.

In one study, a U.S. multicenter, randomized, placebo-controlled, double-blind, dose-response trial of patients with symptomatic primarily paroxysmal AFIB/AFL, three fixed dose levels of sotalol hydrochloride (AF) (80 mg, 120 mg and 160 mg) twice daily and placebo were compared in 253 patients. In patients with reduced creatinine clearance (40 to 60 mL/min) the same doses were given once daily. Patients were not randomized for the following reasons: QT >450 msec; creatinine clearance <40 mL/min; intolerance to beta-blockers; bradycardia-tachycardia syndrome in the absence of an implanted pacemaker; AFIB/AFL was asymptomatic or was associated with syncope, embolic CVA or TIA; acute myocardial infarction within the previous 2 months; congestive heart failure; bronchial asthma or other contraindications to beta-blocker therapy; receiving potassium losing diuretics without potassium replacement or without concurrent use of ACE-inhibitors; uncorrected hypokalemia (serum potassium <3.5 meq/L) or hypomagnesemia (serum magnesium <1.5 meq/L); received chronic oral amiodarone therapy for >1 month within previous 12 weeks; congenital or acquired long QT syndromes; history of Torsade de Pointes with other antiarrhythmic agents which increase the duration of ventricular repolarization; sinus rate <50 bpm during waking hours; unstable angina pectoris; receiving treatment with other drugs that prolong the QT interval; and AFIB/AFL associated with the Wolff-Parkinson-White (WPW) syndrome. If the QT interval increased to 520 msec (or JT 430 msec if QRS >100 msec) the drug was discontinued. The patient population in this trial was 64% male, and the mean age was 62 years. No structural heart disease was present in 43% of the patients. Doses were administered once daily in 20% of the patients because of reduced creatinine clearance.

Sotalol hydrochloride (AF) was shown to prolong the time to the first symptomatic, ECG-documented recurrence of AFIB/AFL, as well as to reduce the risk of such recurrence at both 6 and 12 months. The 120 mg dose was more effective than 80 mg, but 160 mg did not appear to have an added benefit. Note that these doses were given twice or once daily, depending on renal function. The results are shown in Figure 1 and Tables 1 and 2.

Figure 1
Study 1 Time to First ECG-Documented Recurrence of Symptomatic AFIB/AFL Since Randomization

Table 1
Study 1 - Patient Status at 12 Months

	Placebo	Sotalol Hydrochloride (AF) Dose
		80 mg	120 mg	160 mg
Randomized	69	59	63	62
On treatment in NSR at 12 months without recurrencea	23%	22%	29%	23%
Recurrencea,b	67%	58%	49%	42%
D/C for AEs	6%	12%	18%	29%

a Symptomatic AFIB/AFL

b Efficacy endpoint of Study 1: study treatment stopped

Please note that columns do not add up to 100% due to discontinuations (D/C) for "other" reasons.

Table 2
Study 1 - Median Time to Recurrence of Symptomatic AFIB/AFL and Relative Risk (vs. Placebo) at 12 Months

	Placebo	Sotalol Hydrochloride (AF) Dose
		80 mg	120 mg	160 mg
p-value vs placebo		p=0.325	p=0.018	p=0.029
Relative Risk (RR) to placebo		0.81	0.59	0.59
Median time to recurrence(days)	27	106	229	175

Discontinuation because of adverse events was dose related.

In a second multicenter, randomized, placebo-controlled, double-blind study of 6 months duration in 232 patients with chronic AFIB, sotalol hydrochloride (AF) was titrated over a dose range from 80 mg/day to 320 mg/day. The patient population of this trial was 70% male with a mean age of 65 years. Structural heart disease was present in 49% of the patients. All patients had chronic AFIB for >2 weeks but <1 year at entry with a mean duration of 4.1 months. Patients were excluded if they had significant electrolyte imbalance, QTc >460 msec, QRS >140 msec, any degree of AV block or functioning pacemaker, uncompensated cardiac failure, asthma, significant renal disease (estimated creatinine clearance <50 mL/min), heart rate <50 bpm, myocardial infarction or open heart surgery in past 2 months, unstable angina, infective endocarditis, active pericarditis or myocarditis, 3 DC cardioversions in the past, medications that prolonged QT interval, and previous amiodarone treatment. After successful cardioversion patients were randomized to receive placebo (n=114) or sotalol hydrochloride (AF) (n=118), at a starting dose of 80 mg twice daily. If the initial dose was not tolerated it was decreased to 80 mg once daily, but if it was tolerated it was increased to 160 mg twice daily. During the maintenance period 67% of treated patients received a dose of 160 mg twice daily, and the remainder received doses of 80 mg once daily (17%) and 80 mg twice daily (16%).

Figure 2 and Tables 3 and 4 show the results of the trial. There was a longer time to ECG-documented recurrence of AFIB and a reduced risk of recurrence at 6 months compared to placebo.

Figure 2:
Study 2 Time to First ECG Documented recurrence of Symptomatic AFIB/AFL/Death since Randomization

Table 3:
Study 2 - Patient Status at 6 Months

Randomized	Sotalol Hydrochloride (AF)	Placebo
	118	114
On treatment in NSR at 6 months without recurrencea	45%	29%
Recurrencea,b	49%	67%
D/C for AEs	6%	3%
Death		1%

a Symptomatic or asymptomatic AFIB/AFL

b Efficacy endpoint of Study 2; study treatment stopped

Table 4
Study 2 - Median Time to Recurrence of Symptomatic AFIB/AFL/Death and Relative Risk (vs. Placebo) at 6 Months

p-value vs placebo	Sotalol Hydrochloride (AF)	Placebo
	p=0.002
Relative Risk (RR) to placebo	0.55
Median time to recurrence (days)	>180	44

Safety in Patients with Structural Heart Disease

In a multicenter double-blind randomized study reported by D. Julian et al, the effect of sotalol 320 mg once daily was compared with that of placebo in 1456 patients (randomized 3:2, sotalol to placebo) surviving an acute myocardial infarction (MI). Treatment was started 5 to 14 days after infarction. Patients were followed for 12 months. The mortality rate was 7.3% in the sotalol group and 8.9% in the placebo group, not a statistically significant difference. Although the results do not show evidence of a benefit of sotalol in this population, they do not show an added risk in post MI patients receiving sotalol.

Pharmacokinetics

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 (i.e., 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. Distribution occurs to a central (plasma) and to a peripheral compartment, with a mean elimination half-life of 12 hours. Dosing every 12 hours results in trough plasma concentrations, which are approximately one-half of those at peak.

Sotalol does not bind to plasma proteins and is not metabolized. Sotalol shows very little intersubject variability in plasma levels. The pharmacokinetics of the d and l enantiomers of sotalol are essentially identical. Sotalol crosses the blood brain barrier poorly. Excretion is predominantly via the kidney in the unchanged form, and therefore lower doses are necessary in conditions of renal impairment (see DOSAGE AND ADMINISTRATION). Age per se does not significantly alter the pharmacokinetics of sotalol, but impaired renal function in geriatric patients can increase the terminal elimination half-life, resulting in increased drug accumulation. The absorption of sotalol was reduced by approximately 20% compared to fasting when it was administered with a standard meal. Since sotalol is not subject to first-pass metabolism, patients with hepatic impairment show no alteration in clearance of sotalol.

The combined analysis of two unblinded, multicenter trials (a single dose 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/m2 of sotalol was administered in the single dose study and daily doses of 30, 90 and 210 mg/m2 were administered q8h 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. BSA was the most important covariate and more relevant than age for the pharmacokinetics of sotalol. The smallest children (BSA<0.33 m2) 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%.

Warnings ⮝

Ventricular Arrhythmia

Sotalol (AF) can cause serious ventricular arrhythmias, primarily Torsade de Pointes (TdP) type ventricular tachycardia, a polymorphic ventricular tachycardia associated with QT interval prolongation. QT interval prolongation is directly related to the dose of sotalol (AF). Factors such as reduced creatinine clearance, gender (female) and larger doses increase the risk of TdP. The risk of TdP can be reduced by adjustment of the sotalol (AF) dose according to creatinine clearance and by monitoring the ECG for excessive increases in the QT interval.

Treatment with sotalol (AF) must therefore be started only in patients observed for a minimum of three days on their maintenance dose in a facility that can provide electrocardiographic monitoring and in the presence of personnel trained in the management of serious ventricular arrhythmias. Calculation of the creatinine clearance must precede administration of the first dose of sotalol (AF). For detailed instructions regarding dose selection, see DOSAGE AND ADMINISTRATION.

Proarrhythmia in Atrial Fibrillation/Atrial Flutter Patients

In eight controlled trials of patients with AFIB/AFL and other supraventricular arrhythmias (N=659) there were four cases of Torsade de Pointes reported (0.6%) during the controlled phase of treatment with sotalol (AF). The incidence of Torsade de Pointes was significantly lower in those patients receiving total daily doses of 320 mg or less (0.3%), as summarized in Table 5 below. Both patients who had Torsade de Pointes in the group receiving >320 mg/day were receiving 640 mg/day. In the group receiving 320 mg daily, one case of TdP occurred at a daily dose of 320 mg on day 4 of treatment and one case occurred on a daily dose of 160 mg on day 1 of treatment.

Table 5 Incidence of Torsade de Pointes in Controlled Trials of AFIB and Other Supraventricular Arrhythmias

	Sotalol Hydrochloride (AF) (Daily Dose)
	Any Dose (N=659)	>320 mg/day (N=62)	320 mg/day (N=597)	240 mg/day (N=340)	Placebo (N=358)
	n(%)	n(%)	n(%)	n(%)	n(%)
Torsade de Pointes	4(0.6%)	2(3.2%)	2(0.3%)	1(0.3%)	0

Prolongation of the QT interval is dose related, increasing from baseline an average of 25, 40, and 50 msec in the 80, 120, and 160 mg groups, respectively, in the clinical dose-response study. In this clinical trial sotalol (AF) treatment was not initiated if the QT interval was greater than 450 msec and during therapy the dose was reduced or discontinued if the QT interval was 520 msec.

Experience in patients with ventricular arrhythmias is also pertinent to the risk of Torsade de Pointes in patients with AFIB/AFL (see below).

Proarrhythmia in Ventricular Arrhythmia Patients

[see Sotalol Hydrochloride Package Insert]

In patients with a history of sustained ventricular tachycardia, the incidence of Torsade de Pointes during sotalol treatment was 4% and worsened VT in about 1%; in patients with other less serious ventricular arrhythmias the incidence of Torsade de Pointes was 1% and new or worsened VT in about 0.7%. 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.

Torsade de Pointes arrhythmias in patients with VT/VF were dose related, as was the prolongation of QT (QTc) interval, as shown in Table 6 below.

Table 6
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* (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 7 below relates the incidence of Torsade de Pointes to on-therapy QTc and change in QTc from baseline. 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 7
Relationship Between QTc Interval Prolongation and Torsade de Pointes

On-Therapy QTC Interval (msec)	Incidence of Torsade de Pointes	Change in QTC Interval From Baseline (msec)	Incidence of Torsade de Pointes
less than 500	1.3% (1787)	less than 65	1.6% (1516)
500 to 525	3.4% (236)	65 to 80	3.2% (158)
525 to 550	5.6% (125)	80 to 100	4.1% (146)
>550	10.8% (157)	100 to 130	5.2% (115)
		>130	7.1% (99)

( ) Number of patients assessed

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 QTc interval 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 ventricular arrhythmia 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.

Use with Drugs that Prolong QT Interval and Antiarrhythmic Agents

The use of sotalol (AF) in conjunction with other drugs that prolong the QT interval has not been studied and is not recommended. Such drugs include many antiarrhythmics, some phenothiazines, bepridil, tricyclic antidepressants, and certain oral macrolides. Class I or Class III antiarrhythmic agents should be withheld for at least three half-lives prior to dosing with sotalol (AF). In clinical trials, sotalol (AF) was not administered to patients previously treated with oral amiodarone for >1 month in the previous three months. 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 (AF), because of their potential to prolong refractoriness (see WARNINGS). There is only limited experience with the concomitant use of Class Ib or Ic antiarrhythmics.

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 heart failure controlled by digitalis and/or diuretics, sotalol (AF) 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 a pooled data base of four placebo-controlled AFIB/AFL and PSVT studies, new or worsening CHF occurred during therapy with sotalol (AF) in 5 (1.2%) of 415 patients. In these studies patients with uncontrolled heart failure were excluded (i.e., NYHA Functional Classes III or IV). In other premarketing sotalol 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 life-table 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 (AF) 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.

Bradycardia/Heart Block

The incidence of bradycardia (as determined by the investigators) in the supraventricular arrhythmia population treated with sotalol (AF) (N = 415) was 13%, and led to discontinuation in 2.4% of patients. Bradycardia itself increases the risk of Torsade de Pointes.

Recent Acute MI

Sotalol has been used in a controlled trial following an acute myocardial infarction without evidence of increased mortality (see Safety in Patients with Structural Heart Disease). Although specific studies of its use in treating atrial arrhythmias after infarction have not been conducted, the usual precautions regarding heart failure, avoidance of hypokalemia, bradycardia or prolonged QT interval apply.

The following warnings are related to the beta-blocking activity of sotalol AF.

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 (AF), 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 (AF) 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 (AF), 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 (AF) is to be administered, to use the smallest effective dose, so that inhibition of bronchodilation produced by endogenous or exogenous catecholamine stimulation of beta2 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 (AF) should be given with caution since beta-blockade may mask some important premonitory signs of acute hypoglycemia; e.g., tachycardia.

Sick Sinus Syndrome

Sotalol (AF) 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. In patients with AFIB and sinus node dysfunction, the risk of Torsade de Pointes with sotalol (AF) therapy is increased, especially after cardioversion. Bradycardia following cardioversion in these patients is associated with QTc interval prolongation which is augmented due to the reverse use dependence of the Class III effects of sotalol (AF). Patients with AFIB/AFL associated with the sick sinus syndrome may be treated with sotalol (AF) if they have an implanted pacemaker for control of bradycardia symptoms.

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. The beta-blocking effects of sotalol (AF) may be useful in controlling heart rate in AFIB associated with thyrotoxicosis but no study has been conducted to evaluate this.

Precautions ⮝

Renal Impairment

Sotalol hydrochloride (AF) is eliminated principally 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 hydrochloride (AF). Guidance for dosing in conditions of renal impairment can be found under DOSAGE AND ADMINISTRATION.

Information for Patients

Please refer to the patient package insert.

Prior to initiation of sotalol (AF) therapy, the patient should be advised to read the patient package insert and reread it each time therapy is renewed. The patient should be fully instructed on the need for compliance with the recommended dosing of sotalol (AF), the potential interactions with drugs that prolong the QT interval and other antiarrhythmics, and the need for periodic monitoring of QT and renal function to minimize the risk of serious abnormal rhythms.

Medications and Supplements

Assessment of patients' medication history should include all over-counter, prescription and herbal/natural preparations with emphasis on preparations that may affect the pharmacodynamics of sotalol (AF) such as other cardiac antiarrhythmic drugs, some phenothiazines, bepridil, tricyclic antidepressants and oral macrolides (see WARNINGS, Use With Drugs That Prolong QT Interval and Antiarrhythmic Agents). Patients should be instructed to notify their health care providers of any change in over-the-counter, prescription or supplement use. If a patient is hospitalized or is prescribed a new medication for any condition, the patient must inform the health care provider of ongoing sotalol (AF) therapy. Patients should also check with their health care provider and/or pharmacist prior to taking a new over-the-counter medicine.

Electrolyte Imbalance

If patients experience symptoms that may be associated with altered electrolyte balance, such as excessive or prolonged diarrhea, sweating, or vomiting, or loss of appetite or thirst, these conditions should be immediately reported to their health care provider.

Dosing Schedule

Patients should be instructed NOT to double the next dose if a dose is missed. The next dose should be taken at the usual time.

Overdosage ⮝

Intentional or accidental overdosage with sotalol has rarely resulted in death.

Symptoms and Treatment of Overdosage

The most common signs to be expected are bradycardia, congestive heart failure, hypotension, bronchospasm and hypoglycemia. In cases of massive intentional overdosage (2 to 16 grams) of sotalol the following clinical findings were seen: hypotension, bradycardia, cardiac asystole, prolongation of QT interval, Torsade de Pointes, ventricular tachycardia, and premature ventricular complexes. If overdosage occurs, therapy with sotalol (AF) should be discontinued and the patient observed closely. Because of the lack of protein binding, hemodialysis is useful for reducing sotalol plasma concentrations. Patients should be carefully observed until QT intervals are normalized and the heart rate returns to levels >50 bpm. The occurrence of hypotension following an overdose may be associated with an initial slow drug elimination phase (half life of 30 hours) thought to be due to a temporary reduction of renal function caused by the hypotension. In addition, if required, the following therapeutic measures are suggested:

Bradycardia or Cardiac Asystole: Atropine, another anticholinergic drug, a beta-adrenergic agonist or transvenous cardiac pacing.

Heart Block: (second and third degree) transvenous cardiac pacemaker.

Hypotension: (depending on associated factors) epinephrine rather than isoproterenol or norepinephrine may be useful.

Bronchospasm: Aminophylline or aerosol beta-2-receptor stimulant.

Torsade de Pointes: DC cardioversion, transvenous cardiac pacing, epinephrine, magnesium sulfate.

How Supplied ⮝

Sotalol hydrochloride tablets, USP (AF) 80 mg are available for oral administration as white to off-white, capsule shaped, scored tablets, imprinted "APO" on one side and "AF" bisect "80" on the other side; supplied in bottles of 100 (NDC 60505-0222-1) and bottles of 1,000 (NDC 60505-0222-2).

Sotalol hydrochloride tablets, USP (AF) 120 mg are available for oral administration as white to off-white, capsule shaped, scored tablets, imprinted "APO" on one side and "AF" bisect "120" on the other side; supplied in bottles of 100 (NDC 60505-0223-1) and bottles of 1,000 (NDC 60505-0223-2).

Sotalol hydrochloride tablets, USP (AF) 160 mg are available for oral administration as white to off-white, capsule shaped, scored tablets, imprinted "APO" on one side and "AF" bisect "160" on the other side; supplied in bottles of 100 (NDC 60505-0224-1) and bottles of 1,000 (NDC 60505-0224-2).

Store at 20 to 25 C (68 to 77 F) [see USP Controlled Room Temperature]. Dispense in a tight, light-resistant container [see USP].

APOTEX INC.
SOTALOL HYDROCHLORIDE TABLETS, USP (AF)
80 mg, 120 mg and 160 mg

Manufactured by Manufactured for
Apotex Inc. Apotex Corp.
Toronto, Ontario Weston, Florida
Canada M9L 1T9 33326

Revised: July 2015

Rev. 2

Sotalol Hydrochloride ⮝

SOTALOL HYDROCHLORIDE sotalol hydrochloride tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:50090-1299(NDC:60505-0080) Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength SOTALOL HYDROCHLORIDE (UNII: HEC37C70XX) (SOTALOL - UNII:A6D97U294I) SOTALOL HYDROCHLORIDE 80 mg

Inactive Ingredients Ingredient Name Strength MAGNESIUM STEARATE (UNII: 70097M6I30) MICROCRYSTALLINE CELLULOSE (UNII: OP1R32D61U)

Product Characteristics Color WHITE Score 2 pieces Shape OVAL (capsule shaped) Size 10mm Flavor Imprint Code APO;SO;80 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:50090-1299-0 60 in 1 BOTTLE; Type 0: Not a Combination Product 11/28/2014

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA076140 02/01/2003

Labeler - A-S Medication Solutions (830016429)

Establishment
Name	Address	ID/FEI	Business Operations
A-S Medication Solutions		830016429	RELABEL(50090-1299) , REPACK(50090-1299)

Revised: 11/2017 Document Id: 6bb80cc3-5fdd-4863-acb9-f392d98d1c9b 34391-3 Set id: 7cb4879f-31e7-4862-bc0c-d439e592d81c Version: 5 Effective Time: 20171117 A-S Medication Solutions

Sotalol Hydrochloride Tablets, Usp 8265401/0116 Rx Only  ⮝

To minimize the risk of induced arrhythmia, patients initiated or reinitiated on sotalol hydrochloride tablets should be placed for a minimum of three days (on their maintenance dose) in a facility that can provide cardiac resuscitation and continuous electrocardiographic monitoring. Creatinine clearance should be calculated prior to dosing. For detailed instructions regarding dose selection and special cautions for people with renal impairment, see DOSAGE AND ADMINISTRATION. 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 are 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.

Package/label Display Panel Carton 80 Mg ⮝

NDC 68084- 654-01

Sotalol Hydrochloride
Tablets, USP

80 mg

100 Tablets (10 x 10) Rx Only

Each Tablet Contains:
Sotalol hydrochloride ....................................................... 80 mg

Usual Dosage: See package insert for full prescribing
information.

Store at 20 to 25 C (68 to 77 F); excursions permitted
between 15 to 30 C (59 to 86 F) [see USP Controlled Room
Temperature].

Keep this and all drugs out of reach of children.

FOR YOUR PROTECTION: Do not use if blister is torn or
broken.

The drug product contained in this package is from
NDC # 60505-0080, Apotex Corp.

Packaged and Distributed by:
American Health Packaging
Columbus, Ohio 43217

065401
0265401/0519

Package/label Display Panel Blister 80 Mg ⮝

Sotalol Hydrochloride
Tablet, USP

80 mg

SOTALOL HYDROCHLORIDE sotalol hydrochloride tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:68084-654(NDC:60505-0080) Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength SOTALOL HYDROCHLORIDE (UNII: HEC37C70XX) (SOTALOL - UNII:A6D97U294I) SOTALOL HYDROCHLORIDE 80 mg

Inactive Ingredients Ingredient Name Strength MAGNESIUM STEARATE (UNII: 70097M6I30) CELLULOSE, MICROCRYSTALLINE (UNII: OP1R32D61U)

Product Characteristics Color white Score 2 pieces Shape OVAL (capsule shaped) Size 10mm Flavor Imprint Code APO;SO;80 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:68084-654-01 100 in 1 BOX, UNIT-DOSE 03/11/2014 1 NDC:68084-654-11 1 in 1 BLISTER PACK; Type 0: Not a Combination Product

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA076140 03/11/2014

Labeler - American Health Packaging (929561009)

Establishment
Name	Address	ID/FEI	Business Operations
American Health Packaging		929561009	repack(68084-654)

Revised: 5/2019 Document Id: 8a0b8e74-cb25-6772-e053-2a95a90a186b 34391-3 Set id: 4614480b-b36e-4dbd-9fc0-d083890d297d Version: 3 Effective Time: 20190529 American Health Packaging

See Full Prescribing Information For Complete Boxed Warning. ⮝

• Sotalol hydrochloride/ Sotalol hydrochloride AF can cause life threatening ventricular tachycardia associated with QT interval prolongation.
• If the QT interval prolongs to 500 msec or greater, reduce the dose, lengthen the dosing interval, or discontinue the drug.
• Initiate or reinitiate in a facility that can provide cardiac resuscitation and continuous electrocardiographic monitoring.
• Adjust the dosing interval based on creatinine clearance.

Sotalol 120mg Tablet ⮝

SOTALOL HYDROCHLORIDE sotalol hydrochloride tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:71335-1125(NDC:60505-0159) Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength SOTALOL HYDROCHLORIDE (UNII: HEC37C70XX) (SOTALOL - UNII:A6D97U294I) SOTALOL HYDROCHLORIDE 120 mg

Inactive Ingredients Ingredient Name Strength Magnesium Stearate (UNII: 70097M6I30) MICROCRYSTALLINE CELLULOSE (UNII: OP1R32D61U)

Product Characteristics Color WHITE Score 2 pieces Shape OVAL (capsule shaped) Size 11mm Flavor Imprint Code APO;SOT;120 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:71335-1125-1 60 in 1 BOTTLE; Type 0: Not a Combination Product 03/08/2019 2 NDC:71335-1125-2 30 in 1 BOTTLE; Type 0: Not a Combination Product 03/08/2019

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA076140 02/01/2003

Labeler - Bryant Ranch Prepack (171714327)

Establishment
Name	Address	ID/FEI	Business Operations
Bryant Ranch Prepack		171714327	REPACK(71335-1125) , RELABEL(71335-1125)

Revised: 6/2019 Document Id: 1644ed5d-60e2-4145-8c47-a32fef4afbb2 34391-3 Set id: 27c73b70-99e8-40e8-8aa9-36d3addd3bb4 Version: 1 Effective Time: 20190611 Bryant Ranch Prepack

Principal Display Panel 80 Mg  ⮝

Representative sample of labeling (see HOW SUPPLIED section for complete listing):

APOTEX CORP. NDC 60505-0080-0

Sotalol Hydrochloride Tablets, USP

80 mg 100 Tablets

Rx

Principal Display Panel 120 Mg  ⮝

Representative sample of labeling (see HOW SUPPLIED section for complete listing):

APOTEX CORP. NDC 60505-0159-0

Sotalol Hydrochloride Tablets, USP

120 mg 100 tablets

Rx

Principal Display Panel 160 Mg ⮝

Representative sample of labeling (see HOW SUPPLIED section for complete listing):

APOTEX CORP. 60505-0081-0

Sotalol Hydrochloride Tablets, USP

160 mg 100 Tablets

Rx

Principal Display Panel 240 Mg ⮝

Representative sample of labeling (see HOW SUPPLIED section for complete listing):

APOTEX CORP. 60505-0082-0

Sotalol Hydrochloride Tablets, USP

240 mg 100 Tablets

Rx

Principal Display Panel 80 Mg (af)  ⮝

Representative sample of labeling (see HOW SUPPLIED section for complete listing):

APOTEX CORP. NDC 60505-0222-1

SOTALOL HYDROCHLORIDE TABLETS, USP (AF)

80 mg 100 Tablets

Rx only

Principal Display Panel 120 Mg (af) ⮝

Representative sample of labeling (see HOW SUPPLIED section for complete listing):

APOTEX CORP. NDC 60505-0223-1

SOTALOL HYDROCHLORIDE TABLETS, USP (AF)

120 mg 100 Tablets

Rx only

Principal Display Panel 160 Mg (af) ⮝

Representative sample of labeling (see HOW SUPPLIED section for complete listing):

APOTEX CORP. NDC 60505-0224-1

SOTALOL HYDROCHLORIDE TABLETS, USP (AF)

160 mg 100 Tablets

Rx only

SOTALOL HYDROCHLORIDE sotalol hydrochloride tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:60505-0080 Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength Sotalol Hydrochloride (UNII: HEC37C70XX) (Sotalol - UNII:A6D97U294I) Sotalol Hydrochloride 80 mg

Inactive Ingredients Ingredient Name Strength Magnesium Stearate (UNII: 70097M6I30) Cellulose, Microcrystalline (UNII: OP1R32D61U)

Product Characteristics Color WHITE Score 2 pieces Shape OVAL (capsule shaped) Size 10mm Flavor Imprint Code APO;SO;80 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:60505-0080-0 100 in 1 BOTTLE; Type 0: Not a Combination Product 02/01/2003 2 NDC:60505-0080-1 1000 in 1 BOTTLE; Type 0: Not a Combination Product 02/01/2003

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA076140 02/01/2003

SOTALOL HYDROCHLORIDE sotalol hydrochloride tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:60505-0159 Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength Sotalol Hydrochloride (UNII: HEC37C70XX) (Sotalol - UNII:A6D97U294I) Sotalol Hydrochloride 120 mg

Inactive Ingredients Ingredient Name Strength Magnesium Stearate (UNII: 70097M6I30) Cellulose, Microcrystalline (UNII: OP1R32D61U)

Product Characteristics Color WHITE Score 2 pieces Shape OVAL (capsule shaped) Size 11mm Flavor Imprint Code APO;SOT;120 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:60505-0159-0 100 in 1 BOTTLE; Type 0: Not a Combination Product 02/01/2003 2 NDC:60505-0159-1 1000 in 1 BOTTLE; Type 0: Not a Combination Product 02/01/2003

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA076140 02/01/2003

SOTALOL HYDROCHLORIDE sotalol hydrochloride tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:60505-0081 Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength Sotalol Hydrochloride (UNII: HEC37C70XX) (Sotalol - UNII:A6D97U294I) Sotalol Hydrochloride 160 mg

Inactive Ingredients Ingredient Name Strength Magnesium Stearate (UNII: 70097M6I30) Cellulose, Microcrystalline (UNII: OP1R32D61U)

Product Characteristics Color WHITE Score 2 pieces Shape OVAL (capsule shaped) Size 13mm Flavor Imprint Code APO;SOT;160 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:60505-0081-0 100 in 1 BOTTLE; Type 0: Not a Combination Product 02/01/2003 2 NDC:60505-0081-1 1000 in 1 BOTTLE; Type 0: Not a Combination Product 02/01/2003

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA076140 02/01/2003

SOTALOL HYDROCHLORIDE sotalol hydrochloride tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:60505-0082 Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength Sotalol Hydrochloride (UNII: HEC37C70XX) (Sotalol - UNII:A6D97U294I) Sotalol Hydrochloride 240 mg

Inactive Ingredients Ingredient Name Strength Magnesium Stearate (UNII: 70097M6I30) Cellulose, Microcrystalline (UNII: OP1R32D61U)

Product Characteristics Color WHITE Score 2 pieces Shape OVAL (capsule shaped) Size 14mm Flavor Imprint Code APO;SOT;240 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:60505-0082-0 100 in 1 BOTTLE; Type 0: Not a Combination Product 02/01/2003 2 NDC:60505-0082-1 1000 in 1 BOTTLE; Type 0: Not a Combination Product 02/01/2003

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA076140 02/01/2003

SOTALOL HYDROCHLORIDE sotalol hydrochloride tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:60505-0222 Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength Sotalol Hydrochloride (UNII: HEC37C70XX) (Sotalol - UNII:A6D97U294I) Sotalol Hydrochloride 80 mg

Inactive Ingredients Ingredient Name Strength Magnesium Stearate (UNII: 70097M6I30) Cellulose, Microcrystalline (UNII: OP1R32D61U)

Product Characteristics Color WHITE Score 2 pieces Shape OVAL (capsule shaped) Size 10mm Flavor Imprint Code APO;AF;80 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:60505-0222-1 100 in 1 BOTTLE, PLASTIC; Type 0: Not a Combination Product 09/09/2003 2 NDC:60505-0222-2 1000 in 1 BOTTLE, PLASTIC; Type 0: Not a Combination Product 09/09/2003

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA076214 09/09/2003

SOTALOL HYDROCHLORIDE sotalol hydrochloride tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:60505-0223 Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength Sotalol Hydrochloride (UNII: HEC37C70XX) (Sotalol - UNII:A6D97U294I) Sotalol Hydrochloride 120 mg

Inactive Ingredients Ingredient Name Strength Magnesium Stearate (UNII: 70097M6I30) Cellulose, Microcrystalline (UNII: OP1R32D61U)

Product Characteristics Color WHITE Score 2 pieces Shape OVAL (capsule shaped) Size 11mm Flavor Imprint Code APO;AF;120 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:60505-0223-1 100 in 1 BOTTLE, PLASTIC; Type 0: Not a Combination Product 09/09/2003 2 NDC:60505-0223-2 1000 in 1 BOTTLE, PLASTIC; Type 0: Not a Combination Product 09/09/2003

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA076214 09/09/2003

SOTALOL HYDROCHLORIDE sotalol hydrochloride tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:60505-0224 Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength Sotalol Hydrochloride (UNII: HEC37C70XX) (Sotalol - UNII:A6D97U294I) Sotalol Hydrochloride 160 mg

Inactive Ingredients Ingredient Name Strength Magnesium Stearate (UNII: 70097M6I30) Cellulose, Microcrystalline (UNII: OP1R32D61U)

Product Characteristics Color WHITE Score 2 pieces Shape OVAL (capsule shaped) Size 13mm Flavor Imprint Code APO;AF;160 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:60505-0224-1 100 in 1 BOTTLE, PLASTIC; Type 0: Not a Combination Product 09/09/2003 2 NDC:60505-0224-2 1000 in 1 BOTTLE, PLASTIC; Type 0: Not a Combination Product 09/09/2003

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA076214 09/09/2003

Labeler - Apotex Corp. (845263701)

Registrant - Apotex Inc. (209429182)

Establishment
Name	Address	ID/FEI	Business Operations
Apotex Inc.		205576023	manufacture(60505-0080, 60505-0159, 60505-0081, 60505-0082, 60505-0223, 60505-0224, 60505-0222)

Establishment
Name	Address	ID/FEI	Business Operations
Moehs Catalana SL		460021629	api manufacture(60505-0080, 60505-0159, 60505-0081, 60505-0082, 60505-0222, 60505-0223, 60505-0224)

Revised: 11/2018 Document Id: b4b17a17-0e2a-adab-06eb-25298d7f7fdc 34391-3 Set id: 1a56c82e-7ecd-43b0-2899-f89e47adf7db Version: 11 Effective Time: 20181128 Apotex Corp.

No Title 1572453155 ⮝

To minimize the risk of induced arrhythmia, patients initiated or re-initiated on sotalol hydrochloride tablets (AF) should be placed for a minimum of three days (on their maintenance dose) in a facility that can provide cardiac resuscitation, continuous electrocardiographic monitoring and calculations of creatinine clearance. For detailed instructions regarding dose selection and special cautions for people with renal impairment, see DOSAGE AND ADMINISTRATION. Sotalol is also indicated for the treatment of documented life-threatening ventricular arrhythmias and is marketed under the brand name Betapace (sotalol hydrochloride). Sotalol hydrochloride tablets, however, must not be substituted for Betapace AF (sotalol hydrochloride tablets, USP (AF)) because of significant differences in labeling (i.e. patient package insert, dosing administration and safety information).

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 Cmax 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/m2) 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/m2).

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/m2) 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/m2), 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/m2) 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/m2) 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/m2), increased the number of early resorptions, while at 14 times the maximum dose (2.5 times the MRHD as mg/m2), 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 (QTc interval and resting heart rate) and drug concentrations have been evaluated in children aged between 3 days and 12 years old (see CLINICAL PHARMACOLOGY).

No Title 1572454346 ⮝

To minimize the risk of induced arrhythmia, patients initiated or reinitiated on sotalol hydrochloride tablets should be placed for a minimum of three days (on their maintenance dose) in a facility that can provide cardiac resuscitation and continuous electrocardiographic monitoring. Creatinine clearance should be calculated prior to dosing. For detailed instructions regarding dose selection and special cautions for people with renal impairment, see DOSAGE AND ADMINISTRATION. 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 are 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.

Sotalol Hcl 80mg Tablet ⮝

SOTALOL HYDROCHLORIDE sotalol hydrochloride tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:71335-0260(NDC:60505-0080) Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength SOTALOL HYDROCHLORIDE (UNII: HEC37C70XX) (SOTALOL - UNII:A6D97U294I) SOTALOL HYDROCHLORIDE 80 mg

Inactive Ingredients Ingredient Name Strength MAGNESIUM STEARATE (UNII: 70097M6I30) MICROCRYSTALLINE CELLULOSE (UNII: OP1R32D61U)

Product Characteristics Color WHITE Score 2 pieces Shape OVAL (capsule shaped) Size 10mm Flavor Imprint Code APO;SO;80 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:71335-0260-1 60 in 1 BOTTLE; Type 0: Not a Combination Product 02/22/2016 2 NDC:71335-0260-2 30 in 1 BOTTLE; Type 0: Not a Combination Product 02/22/2016 3 NDC:71335-0260-3 100 in 1 BOTTLE; Type 0: Not a Combination Product 02/22/2016

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA076140 02/01/2003

Labeler - Bryant Ranch Prepack (171714327)

Establishment
Name	Address	ID/FEI	Business Operations
Bryant Ranch Prepack		171714327	REPACK(71335-0260) , RELABEL(71335-0260)

Revised: 9/2018 Document Id: a2cf9507-9c00-4027-a47b-64c3c76edffd 34391-3 Set id: 876214ba-59c4-4acc-a8ad-c6bc91837de8 Version: 3 Effective Time: 20180908 Bryant Ranch Prepack

No Title 1572455193 ⮝

To minimize the risk of induced arrhythmia, patients initiated or reinitiated on sotalol hydrochloride tablets should be placed for a minimum of three days (on their maintenance dose) in a facility that can provide cardiac resuscitation and continuous electrocardiographic monitoring. Creatinine clearance should be calculated prior to dosing. For detailed instructions regarding dose selection and special cautions for people with renal impairment, see DOSAGE AND ADMINISTRATION. 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 are 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.

Package/label Display Panel  ⮝

Sotalol Hydrochloride Tablets, USP

80 mg

10 Tablets

SOTALOL HYDROCHLORIDE sotalol hydrochloride tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:55154-8179(NDC:68084-654) Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength SOTALOL HYDROCHLORIDE (UNII: HEC37C70XX) (SOTALOL - UNII:A6D97U294I) SOTALOL HYDROCHLORIDE 80 mg

Inactive Ingredients Ingredient Name Strength MAGNESIUM STEARATE (UNII: 70097M6I30) MICROCRYSTALLINE CELLULOSE (UNII: OP1R32D61U)

Product Characteristics Color white Score 2 pieces Shape OVAL (capsule shaped) Size 10mm Flavor Imprint Code APO;SO;80 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:55154-8179-0 10 in 1 BAG 03/11/2014 1 1 in 1 BLISTER PACK; Type 0: Not a Combination Product

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA076140 03/11/2014

Labeler - Cardinal Health (603638201)

Revised: 7/2019 Document Id: 4f5902e1-9f9f-4c6b-817d-2efbb5e28061 34391-3 Set id: 4f5902e1-9f9f-4c6b-817d-2efbb5e28061 Version: 1 Effective Time: 20190726 Cardinal Health

No Title 1572455658 ⮝

To minimize the risk of induced arrhythmia, patients initiated or re-initiated on sotalol hydrochloride tablets, USP should be placed for a minimum of three days (on their maintenance dose) in a facility that can provide cardiac resuscitation and continuous electrocardiographic monitoring. Creatinine clearance should be calculated prior to dosing. For detailed instructions regarding dose selection and special cautions for people with renal impairment, see DOSAGE AND ADMINISTRATION. 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 are 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.

Principal Display Panel - 80 Mg Bottle Label ⮝

Representative sample of labeling (see HOW SUPPLIED section for complete listing):

NDC 53217-0011-90

Sotalol Hydrochloride Tablets, USP

80 mg

Rx

90 count bottle

SOTALOL HYDROCHLORIDE sotalol hydrochloride tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:53217-011(NDC:60505-0080) Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength SOTALOL HYDROCHLORIDE (UNII: HEC37C70XX) (SOTALOL - UNII:A6D97U294I) SOTALOL HYDROCHLORIDE 80 mg

Inactive Ingredients Ingredient Name Strength MAGNESIUM STEARATE (UNII: 70097M6I30) CELLULOSE, MICROCRYSTALLINE (UNII: OP1R32D61U)

Product Characteristics Color WHITE Score 2 pieces Shape OVAL (capsule shaped) Size 10mm Flavor Imprint Code APO;SO;80 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:53217-011-90 90 in 1 BOTTLE, PLASTIC

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA076140 02/01/2003

Labeler - Aidarex Pharmaceuticals LLC (801503249)

Revised: 10/2013 Document Id: 909139f0-c2f9-4004-a245-b38cf54c4869 34391-3 Set id: 6481858a-353e-4b2a-af48-6c5d13ee0b2a Version: 1 Effective Time: 20131003 Aidarex Pharmaceuticals LLC

Warning: Life Threatening Proarrhythmia  ⮝

To minimize the risk of drug-induced arrhythmia, initiate or reinitiate oral sotalol in a facility that can provide cardiac resuscitation and continuous electrocardiographic monitoring.

Sotalol can cause life threatening ventricular tachycardia associated with QT interval prolongation.

If the QT interval prolongs to 500 msec or greater, reduce the dose, lengthen the dosing interval, or discontinue the drug.

Calculate creatinine clearance to determine appropriate dosing [see Dosage and Administration (2.5)].

1 Indications And Usage  ⮝

1.1 Life-Threatening Ventricular Arrhythmias

Sotalol hydrochloride tablets are indicated for the treatment of life-threatening, documented ventricular arrhythmias, such as sustained ventricular tachycardia (VT).

Limitation of Use:

Sotalol hydrochloride tablets may not enhance survival in patients with ventricular arrhythmias. Because of the proarrhythmic effects of sotalol hydrochloride tablets, including a 1.5 to 2% rate of Torsade de Pointes (TdP) or new ventricular tachycardia/fibrillation (VT/VF) in patients with either non-sustained ventricular tachycardia (NSVT) or supraventricular arrhythmias (SVT), its use in patients with less severe arrhythmias, even if the patients are symptomatic, is generally not recommended. Avoid treatment of patients with asymptomatic ventricular premature contractions [see Warnings and Precautions (5.2)].

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 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  ⮝

2.1 General Safety Measures for Initiation of Oral Sotalol Therapy

Withdraw other antiarrhythmic therapy before starting sotalol hydrochloride tablets and monitor carefully for a minimum of 2 to 3 plasma half-lives if the patient's clinical condition permits [see Drug Interactions (7)].

Hospitalize patients 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 (insert cross ref to renal dosing). Continually monitor patients with each uptitration in dose, until they reach steady state. Determine QTc 2 to 4 hours after every 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 (because of the long terminal elimination half-life of sotalol, dosing more than a two times a day is usually not necessary). 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 creatinine clearance < 40 ml/min or QTc >450 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)].

From pediatric pharmacokinetic data the following is recommended:

For initiation of treatment, 30 mg/m2 three times a day (90 mg/m2 total daily dose) is approximately equivalent to the initial 160 mg total daily dose for adults. Subsequent titration to a maximum of 60 mg/m2 (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 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/m2, 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/m2, 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/m2. Use similar calculations for dose titration.

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.

2.5 Dosage for Patients with Renal Impairment

Adults

Use of sotalol in any age group with decreased renal function should be at lower doses or increased intervals between doses. It will take much longer to reach steady-state with any dose and/or frequency of administration. Closely monitor heart rate and 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.

The initial dose of 80 mg and subsequent doses should be administered at the intervals listed in Table 1 or Table 2.

Table 1: Dosing Intervals for treatment of Ventricular Arrhythmias in renal impairment

Creatinine Clearance mL/min	Dosing Interval (hours)
> 60	12
30 to 59	24
10 to 29	36 to 48
< 10	Dose should be individualized

Table 2: Dosing Intervals for treatment of AFIB/AFL in renal impairment

Creatinine Clearance mL/min	Dosing Interval (hours)
> 60	12
40 to 59	24
<40	Contraindicated

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, care should be taken 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.

3 Dosage Forms And Strengths  ⮝

Sotalol hydrochloride tablets USP, 80 mg are available as light blue, oval-shaped tablets that are scored on one side and debossed with the numbers 93 and 61 on each side of the score, and plain on the other side.

Sotalol hydrochloride tablets USP, 120 mg are available as light blue, oval-shaped tablets that are scored on one side and debossed with the numbers 93 and 1060 on each side of the score, and plain on the other side.

Sotalol hydrochloride tablets USP, 160 mg are available as light blue, oval-shaped tablets that are scored on one side and debossed with the numbers 93 and 62 on each side of the score, and plain on the other side.

Sotalol hydrochloride tablets USP, 240 mg are available as light blue, oval-shaped tablets that are scored on one side and debossed with the numbers 93 and 63 on each side of the score, and plain on the other side.

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 ms

Creatinine clearance <40 mL/min

5 Warnings And Precautions  ⮝

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 (2.1)].

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 (2.1)].

In general, do not use sotalol with other drugs known to cause QT prolongation [see Drug Interactions (7.1)].

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 (consider use of an alternative beta blocker). Warn patients not to interrupt therapy without their physician s advice. Because coronary artery disease may be common, but unrecognized, in patients treated with sotalol, abrupt discontinuation 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 Masked Signs of Hypoglycemia in Diabetics

Beta blockers may mask tachycardia occurring with hypoglycemia, but other manifestations such as dizziness and sweating may not be significantly affected. 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.

6 Adverse Reactions  ⮝

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Adverse reactions that are clearly related to sotalol are those which are typical of its Class II (beta-blocking) and Class III (cardiac action potential duration prolongation) effects and are dose related.

Ventricular Arrhythmias

Serious Adverse Reactions

In patients with a history of sustained ventricular tachycardia, the incidence of Torsade de Pointes during oral sotalol treatment was 4% and worsened VT was about 1%; in patients with other less serious ventricular arrhythmias the incidence of Torsade de Pointes was 1% and new or worsened VT was about 0.7%. Incidence of Torsade de Pointes arrhythmias in patients with VT/VF are shown in Table 3 below.

Table 3: Percent Incidence of Torsade de Pointes and Mean QTc Interval by Dose For Patients With Sustained VT/VF

* highest on-therapy value
Daily Dose (mg)	Torsade de Pointes Incidence	Mean QTc* (msec)
80	0 (69)	463 (17)
160	0.5 (832)	467 (181)
320	1.6 (835)	473 (344)
480	4.4 (459)	483 (234)
640	3.7 (324)	490 (185)
>640	5.8 (103)	512 (62)
( ) Number of patients assessed

Table 4 below relates the incidence of Torsade de Pointes to on-therapy 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 QTc Interval (msec)	Incidence of Torsade de Pointes	Change from Baseline in QTc (msec)	Incidence of Torsade de Pointes
<500	1.3% (1787)	<65	1.6% (1516)
500 to 525	3.4% (236)	65 to 80	3.2% (158)
525 to 550	5.6% (125)	80 to 100	4.1% (146)
>550	10.8% (157)	100 to 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 hydrochloride groups) in a Placebo-controlled Parallel-group Comparison Study of Patients with Ventricular Ectopy

Body System/Adverse Reaction (Preferred Term)	Placebo	Sotalol hydrochloride Total Daily Dose
	N = 37 (%)	320 mg N = 38 (%)	640 mg N = 39 (%)
CARDIOVASCULAR
Chest Pain	5.4	7.9	15.4
Dyspnea	2.7	18.4	20.5
Palpitation	2.7	7.9	5.1
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/m2 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/m2 daily, was discontinued because of increased frequency of sinus pauses/bradycardia. Additional cardiovascular AEs were seen at the 90 and 210 mg/m2 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 QTc 525 msec were seen in 2 patients at the 210 mg/m2 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 hydrochloride-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 hydrochloride (AF) groups) in Four Placebo-controlled Studies of Patients with AFIB/AFL

Body System/Adverse Reaction (Preferred Term)	Placebo	Sotalol hydrochloride (AF) Total Daily Dose
	N = 282 (%)	160 to 240 mg N = 153 (%)	> 240 to 320 mg N = 122 (%)
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.

7 Drug Interactions  ⮝

7.1 Antiarrhythmics and other QT Prolonging Drugs

Sotalol has not been studied with other drugs that prolong the QT interval such as antiarrhythmics, some phenothiazines, tricyclic antidepressants, certain oral macrolides and certain quinolone antibiotics. Discontinue Class I or Class III antiarrhythmic agents for at least three half-lives prior to dosing with sotalol. Class Ia antiarrhythmic drugs, such as disopyramide, quinidine and procainamide and other Class III drugs (for example, amiodarone) are not recommended as concomitant therapy with sotalol hydrochloride, because of their potential to prolong refractoriness [see Warnings and Precautions (5.2)]. There is only limited experience with the concomitant use of Class Ib or Ic antiarrhythmics. Additive Class II effects would also be anticipated with the use of other beta-blocking agents concomitantly with sotalol hydrochloride.

7.2 Digoxin

Proarrhythmic events were more common in sotalol treated patients also receiving digoxin; it is not clear whether this represents an interaction or is related to the presence of CHF, a known risk factor for proarrhythmia, in the patients receiving digoxin. Both digitalis glycosides and beta-blockers slow atrioventricular conduction and decrease heart rate. Concomitant use can increase the risk of bradycardia.

7.3 Calcium-Channel Blocking Drugs

Sotalol and calcium-blocking drugs can be expected to have additive effects on atrioventricular conduction or ventricular function. Monitor such patients for evidence of bradycardia and hypotension.

7.4 Catecholamine-Depleting Agents

Concomitant use of catecholamine-depleting drugs, such as reserpine and guanethidine, with a beta-blocker may produce an excessive reduction of resting sympathetic nervous tone. Monitor such patients for evidence of hypotension and/or marked bradycardia which may produce syncope.

7.5 Insulin and Oral Antidiabetics

Hyperglycemia may occur, and the dosage of insulin or antidiabetic drugs may require adjustment [see Warnings and Precautions 5.7)].

7.6 Clonidine

Concomitant use with sotalol increases the risk of bradycardia. Because beta-blockers may potentiate the rebound hypertension sometimes observed after clonidine discontinuation, withdraw sotalol several days before the gradual withdrawal of clonidine to reduce the risk of rebound hypertension.

7.7 Antacids

Avoid administration of oral sotalol within 2 hours of antacids containing aluminum oxide and magnesium hydroxide.

8 Use In Specific Populations  ⮝

8.1 Pregnancy

Pregnancy Category B

There are no adequate and well-controlled studies in pregnant women. Sotalol has been shown to cross the placenta, and is found in amniotic fluid. In animal studies there was no increase in congenital anomalies, but an increase in early resorptions occurred at sotalol doses 18 times the maximum recommended human dose (MRHD, based on surface area). Animal reproductive studies are not always predictive of human response.

Reproduction studies in rats and rabbits during organogenesis at 9 and 7 times the MRHD (based on surface area), respectively, did not reveal any teratogenic potential associated with sotalol. In rabbits, a dose of sotalol 6 times the MRHD produced a slight increase in fetal death as well as maternal toxicity. This effect did not occur at sotalol dose 3 times the MRHD. In rats a sotalol dose 18 times the MRHD increased the number of early resorptions, while a dose 2.5 times the MRHD, produced no increase in early resorptions.

8.3 Nursing Mothers

Sotalol is excreted in the milk of laboratory animals and has been reported to be present in human milk. Discontinue nursing on sotalol hydrochloride.

8.4 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 (QTc interval and resting heart rate) and drug concentrations have been evaluated in children aged between 3 days and 12 years old [see Dosage and Administration (2.4) and Clinical Pharmacology (12.2)].

8.6 Renal Impairment

Sotalol is mainly eliminated via the kidneys. Dosing intervals should be adjusted based on creatinine clearance [see Dosage and Administration (2.5)].

10 Overdosage  ⮝

Intentional or accidental overdosage with sotalol has resulted in death.

Symptoms and Treatment of Overdosage

The most common signs to be expected are bradycardia, congestive heart failure, hypotension, bronchospasm and hypoglycemia. In cases of massive intentional overdosage (2 to 16 grams) of sotalol the following clinical findings were seen: hypotension, bradycardia, cardiac asystole, prolongation of QT interval, Torsade de Pointes, ventricular tachycardia, and premature ventricular complexes. If overdosage occurs, therapy with sotalol should be discontinued and the patient observed closely. Because of the lack of protein binding, hemodialysis is useful for reducing sotalol plasma concentrations. Patients should be carefully observed until QT intervals are normalized and the heart rate returns to levels >50 bpm.

The occurrence of hypotension following an overdose may be associated with an initial slow drug elimination phase (half-life of 30 hours) thought to be due to a temporary reduction of renal function caused by the hypotension. In addition, if required, the following therapeutic measures are suggested:

Bradycardia or Cardiac Asystole: Atropine, another anticholinergic drug, a beta-adrenergic agonist or transvenous cardiac pacing.

Heart Block: (second and third degree) transvenous cardiac pacemaker.

Hypotension: (depending on associated factors) epinephrine rather than isoproterenol or norepinephrine may be useful.

Bronchospasm: Aminophylline or aerosol beta-2-receptor stimulant. Higher than normal doses of beta-2 receptor stimulants may be required.

Torsade de Pointes: DC cardioversion, transvenous cardiac pacing, epinephrine, magnesium sulfate.

11 Description  ⮝

Sotalol hydrochloride tablets USP contains sotalol hydrochloride, USP an antiarrhythmic drug with Class II (beta-adrenoreceptor blocking) and Class III (cardiac action potential duration prolongation) properties Sotalol hydrochloride tablets USP are supplied as a light blue, oval-shaped tablet for oral administration. Sotalol hydrochloride, USP is a white, crystalline solid with a molecular weight of 308.8. It is hydrophilic, soluble in water, propylene glycol and ethanol, but is only slightly soluble in chloroform. Chemically, sotalol hydrochloride, USP is d,l-N-[4-[1-hydroxy-2-[(1-methylethyl) amino]ethyl]phenyl]methane-sulfonamide monohydrochloride. The molecular formula is C12H20N2O3 S HCl and is represented by the following structural formula:

Sotalol hydrochloride tablets USP contain the following inactive ingredients: corn starch, lactose monohydrate, magnesium stearate, povidone, and FD&C Blue No. 2.

12 Clinical Pharmacology  ⮝

12.1 Mechanism of Action

Sotalol has both beta-adrenoreceptor blocking (Vaughan Williams Class II) and cardiac action potential duration prolongation (Vaughan Williams Class III) antiarrhythmic properties. The two isomers of sotalol have similar Class III antiarrhythmic effects, while the l-isomer is responsible for virtually all of the beta-blocking activity. The beta-blocking effect of sotalol is non-cardioselective, half maximal at about 80 mg/day and maximal at doses between 320 and 640 mg/day. Sotalol does not have partial agonist or membrane stabilizing activity. Although significant beta-blockade occurs at oral doses as low as 25 mg, significant Class III effects are seen only at daily doses of 160 mg and above.

In children, a Class III electrophysiologic effect can be seen at daily doses of 210 mg/m2 body surface area (BSA). A reduction of the resting heart rate due to the beta-blocking effect of sotalol is observed at daily doses 90 mg/m2 in children.

12.2 Pharmacodynamics

Cardiac Electrophysiological Effects

Sotalol hydrochloride prolongs the plateau phase of the cardiac action potential in the isolated myocyte, as well as in isolated tissue preparations of ventricular or atrial muscle (Class III activity). In intact animals it slows heart rate, decreases AV nodal conduction and increases the refractory periods of atrial and ventricular muscle and conduction tissue.

In man, the Class II (beta-blockade) electrophysiological effects of sotalol are manifested by increased sinus cycle length (slowed heart rate), decreased AV nodal conduction and increased AV nodal refractoriness. The Class III electrophysiological effects in man include prolongation of the atrial and ventricular monophasic action potentials, and effective refractory period prolongation of atrial muscle, ventricular muscle, and atrio-ventricular accessory pathways (where present) in both the anterograde and retrograde directions. With oral doses of 160 to 640 mg/day, the surface ECG shows dose-related mean increases of 40 to 100 msec in QT and 10 to 40 msec in QTc [see Warnings and Precautions (5.1)]. No significant alteration in QRS interval is observed.

In a small study (n=25) of patients with implanted defibrillators treated concurrently with sotalol hydrochloride, the average defibrillatory threshold was 6 joules (range 2 to 15 joules) compared to a mean of 16 joules for a nonrandomized comparative group primarily receiving amiodarone.

Twenty-five children in an unblinded, multicenter trial with SVT and/or ventricular tachyarrhythmias, aged between 3 days and 12 years (mostly neonates and infants), received an ascending titration regimen with daily doses of 30, 90 and 210 mg/m2 with dosing every 8 hours for a total 9 doses. During steady-state, the respective average increases above baseline of the QTc interval were 2, 14, and 29 msec at the 3 dose levels. The respective mean maximum increases above baseline of the QTc interval were 23, 36, and 55 msec at the 3 dose levels. The steady-state percent increases in the RR interval were 3, 9 and 12%. The smallest children (BSA<0.33 m2) showed a tendency for larger Class III effects ( QTc) and an increased frequency of prolongations of the QTc interval as compared with larger children (BSA 0.33 m2). The beta-blocking effects also tended to be greater in the smaller children (BSA <0.33 m2). Both the Class III and beta-blocking effects of sotalol were linearly related to the plasma concentrations.

Hemodynamics

In a study of systemic hemodynamic function measured invasively in 12 patients with a mean LV ejection fraction of 37% and ventricular tachycardia (9 sustained and 3 non-sustained), a median dose of 160 mg twice daily of sotalol hydrochloride produced a 28% reduction in heart rate and a 24% decrease in cardiac index at 2 hours post-dosing at steady-state. Concurrently, systemic vascular resistance and stroke volume showed nonsignificant increases of 25% and 8%, respectively. One patient was discontinued because of worsening congestive heart failure. Pulmonary capillary wedge pressure increased significantly from 6.4 mmHg to 11.8 mmHg in the 11 patients who completed the study. Mean arterial pressure, mean pulmonary artery pressure and stroke work index did not significantly change. Exercise and isoproterenol induced tachycardia are antagonized by sotalol hydrochloride, and total peripheral resistance increases by a small amount.

In hypertensive patients, sotalol produces significant reductions in both systolic and diastolic blood pressures. Although sotalol is usually well-tolerated hemodynamically, deterioration in cardiac performance may occur in patients with marginal cardiac compensation [see Warnings and Precautions (5.3)].

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/m2 of sotalol was administered in the single dose study and daily doses of 30, 90 and 210 mg/m2 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. BSA was the most important covariate and more relevant than age for the pharmacokinetics of sotalol. The smallest children (BSA<0.33m2) 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. Doses or dosing intervals should be adjusted 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 Cmax 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.

13 Nonclinical Toxicology  ⮝

13.1 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/m2) 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/m2).

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 18 times the MRHD as mg/m2) prior to mating, except for a small reduction in the number of offspring per litter.

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/m2), respectively, did not reveal any teratogenic potential associated with sotalol HCl. In rabbits, a high dose of sotalol HCl (160 mg/kg/day) at 16 times the MRHD as mg/kg (6 times the MRHD as mg/m2) produced a slight increase in fetal death, and maternal toxicity. Eight times the maximum dose (80 mg/kg/day or 3 times the MRHD as mg/m2) did not result in an increased incidence of fetal deaths. In rats, 1000 mg/kg/day sotalol HCl, 100 times the MRHD (18 times the MRHD as mg/m2), increased the number of early resorptions, while at 14 times the maximum dose (2.5 times the MRHD as mg/m2), no increase in early resorptions was noted. However, animal reproduction studies are not always predictive of human response.

14 Clinical Studies  ⮝

14.1 Ventricular Arrhythmias

Sotalol hydrochloride has been studied in life-threatening and less severe arrhythmias. In patients with frequent premature ventricular complexes (VPC), sotalol hydrochloride was significantly superior to placebo in reducing VPCs, paired VPCs and non-sustained ventricular tachycardia (NSVT); the response was dose-related through 640 mg/day with 80 to 85% of patients having at least a 75% reduction of VPCs. Sotalol hydrochloride was also superior, at the doses evaluated, to propranolol (40 to 80 mg TID) and similar to quinidine (200 to 400 mg QID) in reducing VPCs. In patients with life-threatening arrhythmias [sustained ventricular tachycardia/fibrillation (VT/VF)], sotalol hydrochloride was studied acutely [by suppression of programmed electrical stimulation (PES) induced VT and by suppression of Holter monitor evidence of sustained VT] and, in acute responders, chronically.

In a double-blind, randomized comparison of sotalol hydrochloride and procainamide given intravenously (total of 2 mg/kg sotalol hydrochloride vs. 19 mg/kg of procainamide over 90 minutes), sotalol hydrochloride suppressed PES induction in 30% of patients vs. 20% for procainamide (p=0.2).

In a randomized clinical trial [Electrophysiologic Study Versus Electrocardiographic Monitoring (ESVEM) Trial] comparing choice of antiarrhythmic therapy by PES suppression vs. Holter monitor selection (in each case followed by treadmill exercise testing) in patients with a history of sustained VT/VF who were also inducible by PES, the effectiveness acutely and chronically of sotalol hydrochloride was compared with that of 6 other drugs (procainamide, quinidine, mexiletine, propafenone, imipramine and pirmenol). Overall response, limited to first randomized drug, was 39% for sotalol hydrochloride and 30% for the pooled other drugs. Acute response rate for first drug randomized using suppression of PES induction was 36% for sotalol hydrochloride vs. a mean of 13% for the other drugs. Using the Holter monitoring endpoint (complete suppression of sustained VT, 90% suppression of NSVT, 80% suppression of VPC pairs, and at least 70% suppression of VPCs), sotalol hydrochloride yielded 41% response vs. 45% for the other drugs combined. Among responders placed on long-term therapy identified acutely as effective (by either PES or Holter), sotalol hydrochloride, when compared to the pool of other drugs, had the lowest two-year mortality (13% vs. 22%), the lowest two-year VT recurrence rate (30% vs. 60%), and the lowest withdrawal rate (38% vs. about 75 to 80%). The most commonly used doses of sotalol hydrochloride in this trial were 320 to 480 mg/day (66% of patients), with 16% receiving 240 mg/day or less and 18% receiving 640 mg or more.

It cannot be determined, however, in the absence of a controlled comparison of sotalol hydrochloride vs. no pharmacologic treatment (for example, in patients with implanted defibrillators) whether sotalol hydrochloride response causes improved survival or identifies a population with a good prognosis.

Sotalol hydrochloride has not been shown to enhance survival in patients with ventricular arrhythmias.

14.2 Clinical Studies in Supra-ventricular Arrhythmias

Sotalol hydrochloride (AF) has been studied in patients with symptomatic AFIB/AFL in two principal studies, one in patients with primarily paroxysmal AFIB/AFL, the other in patients with primarily chronic AFIB.

In one study, a U.S. multicenter, randomized, placebo-controlled, double-blind, dose-response trial of patients with symptomatic primarily paroxysmal AFIB/AFL, three fixed dose levels of sotalol hydrochloride (AF) (80 mg, 120 mg and 160 mg) twice daily and placebo were compared in 253 patients. In patients with reduced creatinine clearance (40 to 60 mL/min) the same doses were given once daily. Patients were excluded for the following reasons: QT >450 msec; creatinine clearance <40 mL/min; intolerance to beta-blockers; bradycardia-tachycardia syndrome in the absence of an implanted pacemaker; AFIB/AFL was asymptomatic or was associated with syncope, embolic CVA or TIA; acute myocardial infarction within the previous 2 months; congestive heart failure; bronchial asthma or other contraindications to beta-blocker therapy; receiving potassium losing diuretics without potassium replacement or without concurrent use of ACE-inhibitors; uncorrected hypokalemia (serum potassium <3.5 meq/L) or hypomagnesemia (serum magnesium <1.5 meq/L); received chronic oral amiodarone therapy for >1 month within previous 12 weeks; congenital or acquired long QT syndromes; history of Torsade de Pointes with other antiarrhythmic agents which increase the duration of ventricular repolarization; sinus rate <50 bpm during waking hours; unstable angina pectoris; receiving treatment with other drugs that prolong the QT interval; and AFIB/AFL associated with the Wolff-Parkinson-White (WPW) syndrome. If the QT interval increased to 520 msec (or JT 430 msec if QRS >100 msec) the drug was discontinued. The patient population in this trial was 64% male, and the mean age was 62 years. No structural heart disease was present in 43% of the patients. Doses were administered once daily in 20% of the patients because of reduced creatinine clearance.

Sotalol hydrochloride (AF) was shown to prolong the time to the first symptomatic, ECG-documented recurrence of AFIB/AFL, as well as to reduce the risk of such recurrence at both 6 and 12 months. The 120 mg dose was more effective than 80 mg, but 160 mg did not appear to have an added benefit. Note that these doses were given twice or once daily, depending on renal function. The results are shown in Figure 2, Table 7 and Table 8.

Figure 2: Study 1 Time to First ECG-Documented Recurrence of Symptomatic AFIB/AFL Since Randomization

Table 7: Study 1 Patient Status at 12 Months

* Symptomatic AFIB/AFL Efficacy endpoint of Study 1; study treatment stopped.
	Placebo		Sotalol hydrochloride (AF) Dose
	80 mg		120 mg		160 mg
Randomized	69	59		63		62
On treatment in NSR at 12 months without recurrence*	23%	22%		29%		23%
Recurrence*	67%	58%		49%		42%
D/C for AEs	6%	12%		18%		29%

Note that columns do not add up to 100% due to discontinuations (D/C) for other reasons.

Table 8: Study 1 Median Time to Recurrence of Symptomatic AFIB/AFL and Relative Risk (vs. Placebo) at 12 Months

	Placebo n=69	Sotalol hydrochloride (AF) Dose
		80 mg n=59	120 mg n=63	160 mg n=62
P-value vs. placebo		0.325	0.018	0.029
Relative Risk (RR) to placebo		0.81	0.59	0.59
Median time to recurrence (days)	27	106	229	175

Discontinuation because of adverse events was dose related.

In a second multicenter, randomized, placebo-controlled, double-blind study of 6 months duration in 232 patients with chronic AFIB, sotalol hydrochloride (AF) was titrated over a dose range from 80 mg/day to 320 mg/day. The patient population of this trial was 70% male with a mean age of 65 years. Structural heart disease was present in 49% of the patients. All patients had chronic AFIB for >2 weeks but <1 year at entry with a mean duration of 4.1 months. Patients were excluded if they had significant electrolyte imbalance, QTc >460 msec, QRS >140 msec, any degree of AV block or functioning pacemaker, uncompensated cardiac failure, asthma, significant renal disease (estimated creatinine clearance <50 mL/min), heart rate <50 bpm, myocardial infarction or open heart surgery in past 2 months, unstable angina, infective endocarditis, active pericarditis or myocarditis, 3 DC cardioversions in the past, medications that prolonged QT interval, and previous amiodarone treatment. After successful cardioversion patients were randomized to receive placebo (n=114) or sotalol hydrochloride (AF) (n=118), at a starting dose of 80 mg twice daily. If the initial dose was not tolerated it was decreased to 80 mg once daily, but if it was tolerated it was increased to 160 mg twice daily. During the maintenance period 67% of treated patients received a dose of 160 mg twice daily, and the remainder received doses of 80 mg once daily (17%) and 80 mg twice daily (16%).

Tables 9 and 10 show the results of the trial. There was a longer time to ECG-documented recurrence of AFIB and a reduced risk of recurrence at 6 months compared to placebo.

Table 9: Study 2 Patient Status at 6 Months

* Symptomatic or asymptomatic AFIB/AFL Efficacy endpoint of Study 2; study treatment stopped.
		Placebo n=114	Sotalol hydrochloride (AF) n=118
On treatment in NSR at 6 months without recurrence*	29%		45%
Recurrence*	67%		49%
D/C for AEs	3%		6%
Death	1%

Table 10: Study 2 Median Time to Recurrence of Symptomatic AFIB/AFL/Death and Relative Risk (vs. Placebo) at 6 Months

		Placebo n=114	Sotalol hydrochloride (AF) n=118
P-value vs. placebo			0.002
Relative Risk (RR) to placebo			0.55
Median time to recurrence (days)	44		>180

Figure 3: Study 2 Time to First ECG-Documented Recurrence of Symptomatic AFIB/AFL/Death Since Randomization

14.3 Clinical Studies in Patients with Myocardial Infarction

In a large double-blind, placebo controlled secondary prevention (postinfarction) trial (n=1,456); sotalol hydrochloride was given as a non-titrated initial dose of 320 mg once daily. Sotalol hydrochloride did not produce a significant increase in survival (7.3% mortality on sotalol hydrochloride vs. 8.9% on placebo, p=0.3), but overall did not suggest an adverse effect on survival. There was, however, a suggestion of an early (i.e., first 10 days) excess mortality (3% on sotalol hydrochloride vs. 2% on placebo).

In a second small trial (n=17 randomized to sotalol hydrochloride) where sotalol hydrochloride was administered at high doses (for example, 320 mg twice daily) to high-risk post-infarction patients (ejection fraction <40% and either >10 VPC/hr or VT on Holter), there were 4 fatalities and 3 serious hemodynamic/electrical adverse events within two weeks of initiating sotalol hydrochloride.

16 How Supplied/storage And Handling  ⮝

Product: 71335-0860

NDC: 71335-0860-1 60 TABLET in a BOTTLE

NDC: 71335-0860-2 30 TABLET in a BOTTLE

NDC: 71335-0860-3 100 TABLET in a BOTTLE

No Title 1572457619 ⮝

To minimize the risk of induced arrhythmia, patients initiated or re-initiated on sotalol hydrochloride tablets, USP should be placed for a minimum of three days (on their maintenance dose) in a facility that can provide cardiac resuscitation and continuous electrocardiographic monitoring. Creatinine clearance should be calculated prior to dosing. For detailed instructions regarding dose selection and special cautions for people with renal impairment, see DOSAGE AND ADMINISTRATION. 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 are 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.