SORINE- sotalol hydrochloride tablet
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Patient Information

• Advise patients to contact their health care provider in the event of syncope, pre-syncopal symptoms or cardiac palpitations.
• Advise patients that their electrolytes and ECG will be monitored during treatment[seeWarnings 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[seeWarnings and Precautions (5.1)].
• Advise patients not to change the SORINE 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[seeDosage and Administration (2)].
• Advise patients to not interrupt or discontinue SORINE tablets without their physician's advice, that they should get their prescription for sotalol filled and refilled on time so they do not interrupt treatment[seeDosage and Administration (2)].
• Advise patients to not start taking other medications without first discussing new medications with their healthcare provider.
• Advice patients that they should avoid taking SORINE tablets within two hours of taking antacids that contain aluminum oxide or magnesium hydroxide[seeDrug Interactions (7.7)].

Manufactured by
UPSHER-SMITH LABORATORIES, LLC
Maple Grove, MN 55369

Revised 0617

1. No Title 1572548512
2. Highlights Of Prescribing Information
3. Warning: Life-threatening Proarrhythmia
4. See Full Prescribing Information For Complete Boxed Warning.
5. Dosage Forms And Strengths
6. Warnings And Precautions
7. Drug Interactions
8. 1 Indications And Usage
9. 2 Dosage And Administration
10. 3 Dosage Forms And Strengths
11. 4 Contraindications
12. 5 Warnings And Precautions
13. 6 Adverse Reactions
14. 7 Drug Interactions
15. 8 Use In Specific Populations
16. 10 Overdosage
17. 11 Description
18. 12 Clinical Pharmacology
19. 13 Nonclinical Toxicology
20. 14 Clinical Studies
21. 16 How Supplied/storage And Handling
22. Principal Display Panel - 80 Mg Tablet Bottle Label
23. Principal Display Panel - 120 Mg Tablet Bottle Label
24. Principal Display Panel - 160 Mg Tablet Bottle Label
25. Principal Display Panel - 240 Mg Tablet Bottle Label
26. No Title 1572448228
27. Description
28. Clinical Pharmacology
29. Indications And Usage
30. Contraindications
31. Warnings
32. Precautions
33. Adverse Reactions
34. Overdosage
35. Dosage And Administration
36. How Supplied
37. Package/label Display Panel

No Title 1572548512 ⮝

To minimize the risk of induced arrhythmia, patients initiated or reinitiated on Sorine 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 . This product is not approved for the AFIB/AFL indication and should not be substituted for Betapace AF because only Betapace AF is distributed with a patient package insert that is appropriate for patients with AFIB/AFL.

Rx only

Highlights Of Prescribing Information ⮝

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

SORINE (sotalol hydrochloride) tablets, for oral use
Initial U.S. Approval: 1992

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)].

See Full Prescribing Information For Complete Boxed Warning. ⮝

• SORINE (sotalol hydrochloride) tablets 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.

Dosage Forms And Strengths ⮝

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

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)

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: 6/2017

1 Indications And Usage ⮝

1.1 Life-Threatening Ventricular Arrhythmias

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

Limitation of Use:

SORINE (sotalol hydrochloride) tablets may not enhance survival in patients with ventricular arrhythmias. Because of the proarrhythmic effects of SORINE (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)

SORINE (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 SORINE (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 SORINE (sotalol hydrochloride) tablets.

2 Dosage And Administration ⮝

2.1 General Safety Measures for Initiation of Oral Sotalol Therapy

Withdraw other antiarrhythmic therapy before starting SORINE (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 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 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 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 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) SORINE (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 ⮝

SORINE (sotalol hydrochloride tablets, USP) are supplied as white capsule-shaped, scored tablets:

• 80 mg tablets are imprinted "US" to the left and "12" to the right of the score and "80" on the unscored side.
• 120 mg tablets are imprinted "US" to the left and "13" to the right of the score and "120" on the unscored side.
• 160 mg tablets are imprinted "US" to the left and "14" to the right of the score and "160" on the unscored side.
• 240 mg tablets are imprinted "US" to the left and "15" to the right of the score and "240" on the unscored side.

4 Contraindications ⮝

SORINE (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, SORINE (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

SORINE (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 SORINE (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%.

SORINE (sotalol hydrochloride) tablets are 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 SORINE, 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 SORINE tablets are 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)
( ) Number of patients assessed
* highest on-therapy value
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)

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
( ) Number of patients assessed
<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)

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 AV 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, 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 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 groups) in Four Placebo-controlled Studies of Patients with AFIB/AFL

Body System/ Adverse Reaction (Preferred Term)	Placebo	Sotalol Hydrochloride 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 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 SORINE.

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 ⮝

SORINE contains sotalol hydrochloride, USP an antiarrhythmic drug with Class II (beta-adrenoreceptor blocking) and Class III (cardiac action potential duration prolongation) properties. SORINE (sotalol hydrochloride, USP) is supplied as a white, capsule-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:

SORINE Tablets contain the following inactive ingredients: microcrystalline cellulose, lactose monohydrate, corn starch, stearic acid, magnesium stearate and silicon dioxide.

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 atrioventricular 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 <0.33 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%.

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 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, 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 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.

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 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 (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 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

	Placebo	Sotalol Hydrochloride Dose
		80 mg	120 mg	160 mg
Note that columns do not add up to 100% due to discontinuations (D/C) for "other" reasons.
* Symptomatic AFIB/AFL Efficacy endpoint of Study 1; study treatment stopped.
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%

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 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 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 (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 n=118
* Symptomatic or asymptomatic AFIB/AFL Efficacy endpoint of Study 2; study treatment stopped.
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 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 ⮝

SORINE (sotalol hydrochloride tablets, USP) 80 mg, 120 mg, 160 mg and 240 mg are white, capsule-shaped, scored tablets supplied as follows:

80 mg tablets are imprinted "US" to the left and "12" to the right of the score and "80" on the unscored side. They are available as follows:

	Bottles of 100 tablets	NDC 0245-0012-11
	Cartons of 100 unit-dose tablets	NDC 0245-0012-01

120 mg tablets are imprinted "US" to the left and "13" to the right of the score and "120" on the unscored side. They are available as follows:

	Bottles of 100 tablets	NDC 0245-0013-11
	Cartons of 100 unit-dose tablets	NDC 0245-0013-01

160 mg tablets are imprinted "US" to the left and "14" to the right of the score and "160" on the unscored side. They are available as follows:

	Bottles of 100 tablets	NDC 0245-0014-11
	Cartons of 100 unit-dose tablets	NDC 0245-0014-01

240 mg tablets are imprinted "US" to the left and "15" to the right of the score and "240" on the unscored side. They are available as follows:

	Bottles of 100 tablets	NDC 0245-0015-11
	Cartons of 100 unit-dose tablets	NDC 0245-0015-01

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

Dispense in a tight, light-resistant container as defined in the USP.

Principal Display Panel - 80 Mg Tablet Bottle Label ⮝

NDC 0245-0012-11

SORINE
(Sotalol Hydrochloride
Tablets, USP)

80 mg

100 Tablets
Rx only

UPSHER-SMITH

Principal Display Panel - 120 Mg Tablet Bottle Label ⮝

NDC 0245-0013-11

SORINE
(Sotalol Hydrochloride
Tablets, USP)

120 mg

100 Tablets
Rx only

UPSHER-SMITH

Principal Display Panel - 160 Mg Tablet Bottle Label ⮝

NDC 0245-0014-11

SORINE
(Sotalol Hydrochloride
Tablets, USP)

160 mg

100 Tablets
Rx only

UPSHER-SMITH

Principal Display Panel - 240 Mg Tablet Bottle Label ⮝

NDC 0245-0015-11

SORINE
(Sotalol Hydrochloride
Tablets, USP)

240 mg

100 Tablets
Rx only

UPSHER-SMITH

SORINE sotalol hydrochloride tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0245-0012 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 Microcrystalline Cellulose (UNII: OP1R32D61U) lactose monohydrate (UNII: EWQ57Q8I5X) starch, corn (UNII: O8232NY3SJ) stearic acid (UNII: 4ELV7Z65AP) magnesium stearate (UNII: 70097M6I30) silicon dioxide (UNII: ETJ7Z6XBU4)

Product Characteristics Color WHITE Score 2 pieces Shape OVAL Size 12mm Flavor Imprint Code US;12;80 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:0245-0012-11 100 in 1 BOTTLE; Type 0: Not a Combination Product 02/15/2011 2 NDC:0245-0012-01 100 in 1 CARTON 02/15/2011 2 NDC:0245-0012-89 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 ANDA075500 02/15/2011

SORINE sotalol hydrochloride tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0245-0013 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 Microcrystalline Cellulose (UNII: OP1R32D61U) lactose monohydrate (UNII: EWQ57Q8I5X) starch, corn (UNII: O8232NY3SJ) stearic acid (UNII: 4ELV7Z65AP) magnesium stearate (UNII: 70097M6I30) silicon dioxide (UNII: ETJ7Z6XBU4)

Product Characteristics Color WHITE Score 2 pieces Shape OVAL Size 14mm Flavor Imprint Code US;13;120 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:0245-0013-11 100 in 1 BOTTLE; Type 0: Not a Combination Product 02/15/2011 2 NDC:0245-0013-01 100 in 1 CARTON 02/15/2011 2 NDC:0245-0013-89 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 ANDA075500 02/15/2011

SORINE sotalol hydrochloride tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0245-0014 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 Microcrystalline Cellulose (UNII: OP1R32D61U) lactose monohydrate (UNII: EWQ57Q8I5X) starch, corn (UNII: O8232NY3SJ) stearic acid (UNII: 4ELV7Z65AP) magnesium stearate (UNII: 70097M6I30) silicon dioxide (UNII: ETJ7Z6XBU4)

Product Characteristics Color WHITE Score 2 pieces Shape OVAL Size 15mm Flavor Imprint Code US;14;160 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:0245-0014-11 100 in 1 BOTTLE; Type 0: Not a Combination Product 02/15/2011 2 NDC:0245-0014-01 100 in 1 CARTON 02/15/2011 2 NDC:0245-0014-89 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 ANDA075500 02/15/2011

SORINE sotalol hydrochloride tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0245-0015 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 Microcrystalline Cellulose (UNII: OP1R32D61U) lactose monohydrate (UNII: EWQ57Q8I5X) starch, corn (UNII: O8232NY3SJ) stearic acid (UNII: 4ELV7Z65AP) magnesium stearate (UNII: 70097M6I30) silicon dioxide (UNII: ETJ7Z6XBU4)

Product Characteristics Color WHITE Score 2 pieces Shape OVAL Size 18mm Flavor Imprint Code US;15;240 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:0245-0015-11 100 in 1 BOTTLE; Type 0: Not a Combination Product 02/15/2011 2 NDC:0245-0015-01 100 in 1 CARTON 02/15/2011 2 NDC:0245-0015-89 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 ANDA075500 02/15/2011

Labeler - Upsher-Smith Laboratories, Inc. (047251004)

Establishment
Name	Address	ID/FEI	Business Operations
Upsher-Smith Laboratories, Inc.		079111820	MANUFACTURE(0245-0012, 0245-0013, 0245-0014, 0245-0015) , LABEL(0245-0012, 0245-0013, 0245-0014, 0245-0015) , PACK(0245-0012, 0245-0013, 0245-0014, 0245-0015)

Establishment
Name	Address	ID/FEI	Business Operations
Upsher-Smith Laboratories, Inc.		047251004	ANALYSIS(0245-0012, 0245-0013, 0245-0014, 0245-0015)

Revised: 6/2017 Document Id: ccbb0602-b626-46b5-8780-9e47d30beae1 34391-3 Set id: 6ee6e904-a8e2-41d4-8261-67103ecfa605 Version: 6 Effective Time: 20170630 Upsher-Smith Laboratories, Inc.

No Title 1572448228 ⮝

To minimize the risk of induced arrhythmia, patients initiated or reinitiated on Sorine 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 . This product is not approved for the AFIB/AFL indication and should not be substituted for Betapace AF because only Betapace AF is distributed with a patient package insert that is appropriate for patients with AFIB/AFL.

Rx only

Description ⮝

Sorine (Sotalol Hydrochloride Tablets, USP) are an antiarrhythmic drug with Class II (beta-adrenoreceptor blocking) and Class III (cardiac action potential duration prolongation) properties. It is supplied as a white, capsule-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 C12H20N2O3S HCl and is represented by the following structural formula:

Sorine Tablets contain the following inactive ingredients: microcrystalline cellulose, lactose monohydrate, corn starch, stearic acid, magnesium stearate and silicon dioxide.

Clinical Pharmacology ⮝

Mechanism of Action: Sotalol hydrochloride has both betaadrenoreceptor 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 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.

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 40-100 msec in QT and 10-40 msec in QTc. (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 2-15 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 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 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<0.33m2 ) 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 0.33m2). The beta-blocking effects also tended to be greater in the smaller children (BSA<0.33m2). 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 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. 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 hydrochloride produces significant reductions in both systolic and diastolic blood pressures. Although sotalol hydrochloride 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: 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 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 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 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 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 vs. no pharmacologic treatment (e.g., in patients with implanted defibrillators) whether sotalol response causes improved survival or identifies a population with a good prognosis.

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 did not produce a significant increase in survival (7.3% mortality on sotalol 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 vs. 2% on placebo). In a second small trial (n=17 randomized to sotalol) where sotalol was administered at high doses (e.g., 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.

Pharmacokinetics: In healthy subjects, the oral bioavailability of sotalol hydrochloride 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 2-3 days (i.e., after 5-6 doses when administered twice daily). Over the dosage range 160-640 mg/day sotalol hydrochloride 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 hydrochloride does not bind to plasma proteins and is not metabolized. Sotalol hydrochloride shows very little intersubject variability in plasma levels. The pharmacokinetics of the d and l enantiomers of sotalol are essentially identical. Sotalol hydrochloride 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 hydrochloride was reduced by approximately 20% compared to fasting when it was administered with a standard meal. Since sotalol hydrochloride 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 q 8h 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%.

Indications And Usage ⮝

SORINE (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)

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)
• Creatinine clearance <40 mL/min (4)

Warnings ⮝

Mortality: The National Heart, Lung, and Blood Institute's Cardiac Arrhythmia Suppression Trial I (CAST I) was a long-term, multi-center, double-blind study in patients with asymptomatic, non-life-threatening ventricular arrhythmias, 1 to 103 weeks after acute myocardial infarction. Patients in CAST I were randomized to receive placebo or individually optimized doses of encainide, flecainide, or moricizine. The Cardiac Arrhythmia Suppression Trial II (CAST II) was similar, except that the recruited patients had had their index infarction 4 to 90 days before randomization, patients with left ventricular ejection fractions greater than 40% were not admitted, and the randomized regimens were limited to placebo and moricizine.

CAST I was discontinued after an average time-on-treatment of 10 months, and CAST II was discontinued after an average time-on-treatment of 18 months. As compared to placebo treatment, all three active therapies were associated with increases in short-term (14-day) mortality, and encainide and flecainide were associated with significant increases in longer-term mortality as well. The longer-term mortality rate associated with moricizine treatment could not be statistically distinguished from that associated with placebo.

The applicability of these results to other populations (e.g., those without recent myocardial infarction) and to other than Class I antiarrhythmic agents is uncertain. Sotalol hydrochloride is devoid of Class I effects, and in a large (n=1,456) controlled trial in patients with a recent myocardial infarction, who did not necessarily have ventricular arrhythmias, sotalol did not produce increased mortality at doses up to 320 mg/day (see Clinical Studies). On the other hand, in the large post infarction study using a non-titrated initial dose of 320 mg once daily and in a second small randomized trial in high-risk post-infarction patients treated with high doses (320 mg BID), there have been suggestions of an excess of early sudden deaths.

Proarrhythmia: Like other antiarrhythmic agents, sotalol can provoke new or worsened ventricular arrhythmias in some patients, including sustained ventricular tachycardia or ventricular fibrillation, with potentially fatal consequences. Because of its effect on cardiac repolarization (QTc interval prolongation), Torsade de Pointes, a polymorphic ventricular tachycardia with prolongation of the QT interval and a shifting electrical axis is the most common form of proarrhythmia associated with sotalol, occurring in about 4% of high risk (history of sustained VT/VF) patients. The risk of Torsade de Pointes progressively increases with prolongation of the QT interval, and is worsened also by reduction in heart rate and reduction in serum potassium (See Electrolyte Disturbances).

Because of the variable temporal recurrence of arrhythmias, it is not always possible to distinguish between a new or aggravated arrhythmic event and the patient's underlying rhythm disorder. (Note, however, that Torsade de Pointes is usually a drug-induced arrhythmia in people with an initially normal QTc.) Thus, the incidence of drug-related events cannot be precisely determined, so that the occurrence rates provided must be considered approximations. Note also that drug-induced arrhythmias may often not be identified, particularly if they occur long after starting the drug, due to less frequent monitoring. It is clear from the NIH-sponsored CAST (see WARNINGS: Mortality) that some antiarrhythmic drugs can cause increased sudden death mortality, presumably due to new arrhythmias or asystole, that do not appear early in treatment but that represent a sustained increased risk.

Overall in clinical trials with sotalol, 4.3% of 3257 patients experienced a new or worsened ventricular arrhythmia. Of this 4.3%, there was new or worsened sustained ventricular tachycardia in approximately 1% of patients and Torsade de Pointes in 2.4%. Additionally, in approximately 1% of patients, deaths were considered possibly drug-related; such cases, although difficult to evaluate, may have been associated with proarrhythmic events. In patients with a history of sustained ventricular tachycardia, the incidence of Torsade de Pointes was 4% and worsened VT in about 1%; in patients with other, less serious, ventricular arrhythmias and supraventricular arrhythmias, the incidence of Torsade de Pointes was 1% and 1.4%, respectively.

Torsade de Pointes arrhythmias were dose related, as is the prolongation of QT (QTc) interval, as shown in the table below.

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

( ) Number of patients assessed
*highest on-therapy value
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)

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 (see table below) and history of cardiomegaly or congestive heart failure. Patients with sustained ventricular tachycardia and a history of congestive heart failure appear to have the highest risk for serious proarrhythmia (7%). Of the patients experiencing Torsade de Pointes, approximately two-thirds spontaneously reverted to their baseline rhythm. The others were either converted electrically (D/C cardioversion or overdrive pacing) or treated with other drugs (see OVERDOSAGE). It is not possible to determine whether some sudden deaths represented episodes of Torsade de Pointes, but in some instances sudden death did follow a documented episode of Torsade de Pointes. Although sotalol therapy was discontinued in most patients experiencing Torsade de Pointes, 17% were continued on a lower dose.

Nonetheless, Sorine (Sotalol Hydrochloride Tablets) should be used with particular caution if the QTc is greater than 500 msec on-therapy and serious consideration should be given to reducing the dose or discontinuing therapy when the QTc exceeds 550 msec. Due to the multiple risk factors associated with Torsade de Pointes, however, caution should be exercised regardless of the QTc interval. The table 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.

Relationship Between QTc Interval Prolongation and Torsade de Pointes

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

Proarrhythmic events must be anticipated not only on initiating therapy, but with every upward dose adjustment. Proarrhythmic events most often occur within 7 days of initiating therapy or of an increase in dose; 75% of serious proarrhythmias (Torsade de Pointes and worsened VT) occurred within 7 days of initiating sotalol therapy, while 60% of such events occurred within 3 days of initiation or a dosage change. Initiating therapy at 80 mg BID with gradual upward dose titration and appropriate evaluations for efficacy (e.g., PES or Holter) and safety (e.g., QT interval, heart rate and electrolytes) prior to dose escalation, should reduce the risk of proarrhythmia. Avoiding excessive accumulation of sotalol in patients with diminished renal function, by appropriate dose reduction, should also reduce the risk of proarrhythmia (see DOSAGE AND ADMINISTRATION).

Congestive Heart Failure: Sympathetic stimulation is necessary in supporting circulatory function in congestive heart failure, and beta-blockade carries the potential hazard of further depressing myocardial contractility and precipitating more severe failure. In patients who have congestive heart failure controlled by digitalis and/or diuretics, Sorine should be administered cautiously. Both digitalis and sotalol slow AV conduction. As with all beta-blockers, caution is advised when initiating therapy in patients with any evidence of left ventricular dysfunction. In premarketing studies, new or worsened congestive heart failure (CHF) occurred in 3.3% (n=3257) of patients and led to discontinuation in approximately 1% of patients receiving sotalol. The incidence was higher in patients presenting with sustained ventricular tachycardia/fibrillation (4.6%, n=1363), or a prior history of heart failure (7.3%, n=696). Based on a lifetable analysis, the one-year incidence of new or worsened CHF was 3% in patients without a prior history and 10% in patients with a prior history of CHF. NYHA Classification was also closely associated to the incidence of new or worsened heart failure while receiving sotalol (1.8% in 1395 Class I patients, 4.9% in 1254 Class II patients and 6.1% in 278 Class III or IV patients).

Electrolyte Disturbances: Sorine should not be used in patients with hypokalemia or hypomagnesemia prior to correction of imbalance, as these conditions can exaggerate the degree of QT prolongation, and increase the potential for Torsade de Pointes. Special attention should be given to electrolyte and acid-base balance in patients experiencing severe or prolonged diarrhea or patients receiving concomitant diuretic drugs.

Conduction Disturbances: Excessive prolongation of the QT interval (>550 msec) can promote serious arrhythmias and should be avoided (see Proarrhythmia above). Sinus bradycardia (heart rate less than 50 bpm) occurred in 13% of patients receiving sotalol in clinical trials, and led to discontinuation in about 3% of patients. Bradycardia itself increases the risk of Torsade de Pointes. Sinus pause, sinus arrest and sinus node dysfunction occur in less than 1% of patients. The incidence of 2nd- or 3rd-degree AV block is approximately 1%.

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

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

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 Sorine , particularly in patients with ischemic heart disease, to carefully monitor the patient and consider the temporary use of an alternate betablocker if appropriate. If possible, the dosage of Sorine 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 Sorine , 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 Sorine (Sotalol Hydrochloride) Tablets are to be administered, to use the smallest effective dose, so that inhibition of bronchodilation produced by endogenous or exogenous catecholamine stimulation of beta 2 receptors may be minimized.

Anaphylaxis: While taking beta-blockers, patients with a history of anaphylactic reaction to a variety of allergens may have a more severe reaction on repeated challenge, either accidental, diagnostic or therapeutic. Such patients may be unresponsive to the usual doses of epinephrine used to treat the allergic reaction.

Major Surgery: Chronically administered beta-blocking therapy should not be routinely withdrawn prior to major surgery; however, the impaired ability of the heart to respond to reflex adrenergic stimuli may augment the risks of general anesthesia and surgical procedures.

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

Sick Sinus Syndrome: Sorine should be used only with extreme caution in patients with sick sinus syndrome associated with symptomatic arrhythmias, because it may cause sinus bradycardia, sinus pauses or sinus arrest.

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

Precautions ⮝

Renal Impairment: Sotalol hydrochloride is mainly eliminated via the kidneys through glomerular filtration and to a small degree by tubular secretion. There is a direct relationship between renal function, as measured by serum creatinine or creatinine clearance, and the elimination rate of sotalol. Guidance for dosing in conditions of renal impairment can be found under DOSAGE AND ADMINISTRATION.

Drug Interactions

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

Antiarrhythmics: Class Ia antiarrhythmic drugs, such as disopyramide, quinidine and procainamide and other Class III drugs (e.g., amiodarone) are not recommended as concomitant therapy with Sorine , because of their potential to prolong refractoriness (see WARNINGS). There is only limited experience with the concomitant use of Class Ib or Ic antiarrhythmics. Additive Class II effects would also be anticipated with the use of other beta-blocking agents concomitantly with Sorine .

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

Calcium-blocking drugs: Sorine 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 Sorine 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 Sorine .

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 Sorine .

Other: No pharmacokinetic interactions were observed with hydrochlorothiazide or warfarin.

Antacids: Administration of Sorine 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 Sorine has no effect on the pharmacokinetics or pharmacodynamics of sotalol.

Drugs prolonging the QT interval: Sorine should be administered with caution in conjunction with other drugs known to prolong the QT interval such as Class I and Class III antiarrhythmic agents, phenothiazines, tricyclic antidepressants, astemizole, bepridil, certain oral macrolides, and certain quinolone antibiotics (see WARNINGS).

Drug/Laboratory Test Interactions

The presence of sotalol in the urine may result in falsely elevated levels of urinary metanephrine when measured by fluorimetric or photometric methods. In screening patients suspected of having a pheochromocytoma and being treated with sotalol, a specific method, such as a high performance liquid chromatographic assay with solid phase extraction (e.g., J. Chromatogr. 385:241, 1987) should be employed in determining levels of catecholamines.

Carcinogenesis, Mutagenesis, Impairment of Fertility

No evidence of carcinogenic potential was observed in rats during a 24-month study at 137-275 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 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 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 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 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.

Although there are no adequate and well-controlled studies in pregnant women, sotalol HCl 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, Sorine (Sotalol HCl) Tablets should be used during pregnancy only if the potential benefit outweighs the potential risk.

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

Pediatric Use: The safety and effectiveness of sotalol in children have not been established. However, the Class III electrophysiologic and beta-blocking effects, the pharmacokinetics, and the relationship between the effects (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).

Adverse Reactions ⮝

The most common adverse reactions ( 2%) for SORINE 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 Upsher-Smith Laboratories, LLC at 1-855-899-9180 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Overdosage ⮝

Intentional or accidental overdosage with sotalol hydrochloride 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 (2-16 grams) of sotalol hydrochloride 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 Sorine (Sotalol HCl) Tablets 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.

Dosage And Administration ⮝

• SORINE (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)

How Supplied ⮝

Sorine (Sotalol Hydrochloride Tablets, USP) are white, capsule-shaped, scored tablets with the following tablet deboss, respectively:

80 mg	"US" to the left and "12" to the right of the score,
	"80" strength on the unscored side

Overbagged with 10 tablets per bag, NDC 55154-5616-0

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

Dispense in a well-closed container (USP).

Manufactured by
UPSHER-SMITH LABORATORIES, INC.
Maple Grove, MN 55369

Repackaged By:
Cardinal Health

Dublin, OH 43017

L35230570419

Revised 0515

Package/label Display Panel  ⮝

Sorine 80 mg

Sotalol HCl Tablets, USP

10 Tablets

SORINE sotalol hydrochloride tablet

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:55154-5616(NDC:0245-0012) 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 MICROCRYSTALLINE CELLULOSE (UNII: OP1R32D61U) lactose monohydrate (UNII: EWQ57Q8I5X) starch, corn (UNII: O8232NY3SJ) stearic acid (UNII: 4ELV7Z65AP) magnesium stearate (UNII: 70097M6I30) silicon dioxide (UNII: ETJ7Z6XBU4)

Product Characteristics Color WHITE Score 2 pieces Shape OVAL Size 12mm Flavor Imprint Code US;12;80 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:55154-5616-0 10 in 1 BAG 02/15/2011 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 ANDA075500 02/15/2011

Labeler - Cardinal Health (603638201)

Revised: 4/2019 Document Id: 05626057-c283-4147-9b40-a1c9d3c1aa90 34391-3 Set id: f16f9ae6-d29f-4b31-a240-c7ebb0d7d36a Version: 8 Effective Time: 20190424 Cardinal Health