Betapace

Common Side Effects of Sotalol

Tell your doctor if any of the following side effects become severe or don't go away:

• Dizziness or lightheadedness
• Tiredness
• Weakness
• Headache
• Upset stomach, constipation, or diarrhea
• Muscle aches

Serious Side Effects of Sotalol

Tell your doctor immediately if you experience any of the following serious side effects:

• Chest pain
• Fainting
• Shortness of breath or wheezing
• Swelling of the feet and lower legs
• An irregular heartbeat that is new or worse
• Sudden, unexplained weight gain
• Unusual sweating
• Signs of an allergic reaction, which may include rash, hives, difficulty breathing, chest tightness, or swelling of the mouth, face, lips, or tongue

Included as part of the PRECAUTIONS section.

Betapace is a prescription medication used to treat certain types of irregular heartbeats (known medically as arrhythmias).

This medication may be prescribed for other uses. Ask your doctor or pharmacist for more information.

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

It is very important that your doctor check your progress at regular visits to make sure this medicine is working properly. Blood, urine, and ECG tests will be needed to check for unwanted effects.

Contact your doctor right away if you have any changes to your heart rhythm. You might feel dizzy or faint, or you might have a fast, pounding, or uneven heartbeat. Make sure your doctor knows if you or anyone in your family has ever had a heart rhythm problem such as QT prolongation.

This medicine may make you dizzy. Do not drive or do anything else that could be dangerous until you know how this medicine affects you. Stand up slowly if you feel dizzy or lightheaded.

Do not interrupt or stop taking this medicine without first checking with your doctor. Your doctor may want you to gradually reduce the amount you are taking before stopping it completely. Some conditions may become worse when the medicine is stopped suddenly, which can be dangerous.

Sotalol may cause heart failure in some patients. Check with your doctor right away if you are having chest pain or discomfort, dilated neck veins, extreme fatigue, irregular breathing, an irregular heartbeat, swelling of the face, fingers, feet, or lower legs, or weight gain.

This medicine may cause changes in your blood sugar levels. Also, this medicine may cover up signs of low blood sugar, such as a rapid pulse rate. Check with your doctor if you have these problems or if you notice a change in the results of your blood or urine sugar tests.

Make sure any doctor or dentist who treats you knows that you are using this medicine. Do not stop taking this medicine before surgery without your doctor's approval.

This medicine may cause a serious type of allergic reaction called anaphylaxis. Anaphylaxis can be life-threatening and requires immediate medical attention. Call your doctor right away if you have a rash, itching, hoarseness, trouble breathing, trouble swallowing, or any swelling of your hands, face, or mouth while you are using this medicine.

Do not take other medicines unless they have been discussed with your doctor. This includes prescription or nonprescription (over-the-counter [OTC]) medicines and herbal or vitamin supplements.

General Safety Measures for Initiation of Oral Sotalol Therapy

Withdraw other antiarrhythmic therapy before starting Betapace/Betapace AF 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.

Adult Dose for Ventricular Arrhythmias

The recommended initial dose is 80 mg twice daily. This dose may be increased in increments of 80 mg per day every 3 days provided the QTc <500 msec [see Warnings and Precautions (5.1)]. Continually monitor patients until steady state blood levels are achieved. In most patients, a therapeutic response is obtained at a total daily dose of 160 to 320 mg/day, given in two or three divided doses (because of the long terminal elimination half-life of sotalol, dosing more than a two times a day is usually not necessary). Oral doses as high as 480-640 mg/day have been utilized in patients with refractory life-threatening arrhythmias.

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)].

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.

Figure 1

For a child aged 20 months, the dosing suggested for children with normal renal function aged 2 years or greater should be multiplied by about 0.97; the initial starting dose would be (30 X 0.97)=29.1 mg/m2, administered three times daily. For a child aged 1 month, the starting dose should be multiplied by 0.68; the initial starting dose would be (30 X 0.68)=20 mg/m2, administered three times daily. For a child aged about 1 week, the initial starting dose should be multiplied by 0.3; the starting dose would be (30 X 0.3)=9 mg/m2. Use similar calculations for dose titration.

Since the half-life of sotalol decreases with decreasing age (below about 2 years), time to steady-state will also increase. Thus, in neonates the time to steady-state may be as long as a week or longer.

Dosage for Patients with Renal Impairment

Adults

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

Dose escalations in renal impairment should be done after administration of at least 5 doses at appropriate intervals (Table 1). Sotalol is partly removed by dialysis; specific advice is unavailable on dosing patients on dialysis.

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

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

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

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

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

Preparation of Extemporaneous Oral Solution

Betapace/Betapace AF 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) Betapace/Betapace AF 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 HCl. The fine solid particles are the water-insoluble inactive ingredients of the tablets.

Stability studies indicate that the suspension is stable for three months when stored at 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature] and ambient humidity.

Ventricular Arrhythmias

Betapace (sotalol hydrochloride) has been studied in life-threatening and less severe arrhythmias. In patients with frequent premature ventricular complexes (VPC), Betapace (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. Betapace was also superior, at the doses evaluated, to propranolol (40–80 mg TID) and similar to quinidine (200–400 mg QID) in reducing VPCs. In patients with life-threatening arrhythmias [sustained ventricular tachycardia/fibrillation (VT/VF)], Betapace 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 Betapace and procainamide given intravenously (total of 2 mg/kg Betapace vs. 19 mg/kg of procainamide over 90 minutes), Betapace 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 Betapace 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 Betapace and 30% for the pooled other drugs. Acute response rate for first drug randomized using suppression of PES induction was 36% for Betapace 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), Betapace 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), Betapace, when compared to the pool of other drugs, had the lowest two-year mortality (13% vs. 22%), the lowest two-year VT recurrence rate (30% vs. 60%), and the lowest withdrawal rate (38% vs. about 75–80%). The most commonly used doses of Betapace in this trial were 320–480 mg/day (66% of patients), with 16% receiving 240 mg/day or less and 18% receiving 640 mg or more.

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

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

Clinical Studies in Supra-ventricular Arrhythmias

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

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

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

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

Table 7: Study 1 - Patient Status at 12 Months

a  Symptomatic AFIB/AFL b  Efficacy endpoint of Study 1; study treatment stopped. Note that columns do not add up to 100% due to discontinuations (D/C) for “other” reasons.
	Placebo	Betapace AF Dose
		80 mg	120 mg	160 mg
Randomized	69	59	63	62
On treatment in NSR at 12 months without recurrencea	23%	22%	29%	23%
Recurrenceab	67%	58%	49%	42%
D/C for AEs	6%	12%	18%	29%

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

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

Discontinuation because of adverse events was dose related.

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

Table 9 and Table 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

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

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

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

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

Clinical Studies in Patients with Myocardial Infarction

In a large double-blind, placebo controlled secondary prevention (postinfarction) trial (n=1,456); Betapace (sotalol hydrochloride) was given as a non-titrated initial dose of 320 mg once daily. Betapace did not produce a significant increase in survival (7.3% mortality on Betapace 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 Betapace vs. 2% on placebo).

In a second small trial (n=17 randomized to Betapace) where Betapace 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 Betapace.

NDC 70515-105-10          100 Tablets

Betapace®
(sotalol HCl)

80 mg

Rx only

COVIS

Each tablet contains 80 mg of
sotalol hydrochloride.

Dosage: See package insert.

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

Rev 5/16     84607509

Dispense in a
well-closed
container (USP).

Mfd for:
Covis Pharma
Zug, 6300
Switzerland

Made in Switzerland

NDC 70515-106-10          100 Tablets

Betapace®
(sotalol HCl)

160 mg

Rx only

COVIS

Each tablet contains 160 mg
of sotalol hydrochloride.

Dosage: See package insert.

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

Dispense in a well-closed
container (USP).

Rev 5/16     84607479

Mfd for:
Covis Pharma
Zug, 6300
Switzerland

Made in
Switzerland

NDC 70515-115-06
60 tablets unit of use

Betapace AF®
(sotalol HCl)
Patient Pack

80 mg

Rx only

COVIS          84607444

Each tablet contains 80 mg
of sotalol hydrochloride.

Dosage: Take as prescribed by
your physician.

Please see patient information.

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

Manufactured for:
Covis Pharma
Zug, 6300 Switzerland

Made in Switzerland     Rev. 5/16

Sotalol is a beta-blocker that affects the heart and circulation (blood flow through arteries and veins).

Sotalol is used to help keep the heart beating normally in people with certain heart rhythm disorders of the ventricles (the lower chambers of the heart that allow blood to flow out of the heart). Sotalol is used in people with ventricular tachycardia or ventricular fibrillation.

Another form of this medicine, called sotalol AF, is used to treat heart rhythm disorders of the atrium (the upper chambers of the heart that allow blood to flow into the heart). Sotalol AF is used in people with atrial fibrillation or atrial flutter.

Sotalol (Betapace, Sorine) is not used for the same conditions that sotalol AF (Betapace AF) is used for.

Sotalol may also be used for purposes not listed in this medication guide.

A decision should be made to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Excreted into human milk: Yes Comments: -Other beta-adrenergic blocking drugs are preferred to this drug, especially while nursing a newborn or preterm infant, because of its extensive excretion into breastmilk, its renal excretion, and minimal safety data in breastfed infants. -Adverse effects in the infant are possible.

Substance Name

Sotalol

CAS Registry Number

3930-20-9

Drug Class

Antihypertensive Agents

Adrenergic Beta-Antagonists

Antiarrhythmics

LactMed Record Number

304

Last Revision Date

20150107

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Information presented in this database is not meant as a substitute for professional judgment. You should consult your healthcare provider for breastfeeding advice related to your particular situation. The U.S. government does not warrant or assume any liability or responsibility for the accuracy or completeness of the information on this Site.