Sotalol

1. INDICATIONS AND USAGE Sotalol Hydrochloride Tablets are an antiarrhythmic indicated for: the treatment of life threatening ventricular arrhythmias Limitations of Use Avoid use in patients with asymptomatic ventricular premature contraction

1.1Life-Threatening Ventricular Arrhythmias Sotalol Hydrochloride

Tablets are indicated for the treatment of life-threatening, documented ventricular arrhythmias, such as sustained ventricular tachycardia (VT). Limitation of Use: Sotalol Hydrochloride Tablets may not enhance survival in patients with ventricular arrhythmias. Because of the proarrhythmic effects of Sotalol Hydrochloride Tablets, including a 1.5 to 2% rate of Torsade de Pointes (TdP) or new ventricular tachycardia/fibrillation (VT/VF) in patients with either non-sustained ventricular tachycardia (NSVT) or supraventricular arrhythmias (SVT), its use in patients with less severe arrhythmias, even if the patients are symptomatic, is generally not recommended.

Avoid treatment of patients with asymptomatic ventricular premature contractions

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 Pediatrics: Dosage depends on age

2.1General Safety Measures for Initiation of Oral

Sotalol Therapy Withdraw other antiarrhythmic therapy before starting Sotalol Hydrochloride Tablets and monitor carefully for a minimum of 2 to 3 plasma half-lives if the patient's clinical condition permits . 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 QT c 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.

2.2Adult 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 QT c <500 msec . Continually monitor patients until steady state blood levels are achieved. In most patients, a therapeutic response is obtained at a total daily dose of 160 to 320 mg/day, given in two or three divided doses (because of the long terminal elimination half- life of sotalol, dosing more than a two times a day is usually not necessary).

Oral doses as high as 480-640 mg/day have been utilized in patients with refractory life-threatening arrhythmias.

2.4Pediatric Dose for Ventricular Arrhythmias 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 . From pediatric pharmacokinetic data the following is recommended: For initiation of treatment, 30 mg/m 2 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/m 2 (approximately equivalent to the 360 mg total daily dose for adults) can then occur. Titration should be guided by clinical response, heart rate and QT c , with increased dosing being preferably carried out in-hospital. At least 36 hours should be allowed between dose increments to attain steady-state plasma concentrations of sotalol in patients with age-adjusted normal renal function.

For children aged about 2 years or younger For children aged about 2 years or younger, the above pediatric dosage should be reduced by a factor that depends heavily upon age, as shown in the following graph, age plotted on a logarithmic scale in months. For a child aged 20 months, the dosing suggested for children with normal renal function aged 2 years or greater should be multiplied by about 0.97; the initial starting dose would be (30 X 0.97)=29.1 mg/m 2 , administered three times daily. For a child aged 1 month, the starting dose should be multiplied by 0.68; the initial starting dose would be (30 X 0.68)=20 mg/m 2 , administered three times daily.

For a child aged about 1 week, the initial starting dose should be multiplied by 0.3; the starting dose would be (30 X 0.3)=9 mg/m 2 . 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.

2.5Dosage 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 QT c . 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. 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

2.6Preparation of Extemporaneous Oral Solution Sotalol

Hydrochloride Syrup 5 mg/mL can be compounded using Simple Syrup containing 0.1% sodium benzoate (Syrup, NF) as follows: Measure 120 mL of Simple Syrup. Transfer the syrup to a 6-ounce amber plastic (polyethylene terephthalate [PET]) prescription bottle. An oversized bottle is used to allow for a headspace, so that there will be more effective mixing during shaking of the bottle.

Add five 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.

Shake the bottle to wet the entire surface of the tablets. If the tablets have been crushed, shake the bottle until the endpoint is achieved. Allow the tablets to hydrate for at least two hours. After at least two hours have elapsed, shake the bottle intermittently over the course of at least another two hours until the tablets are completely disintegrated.

The tablets can be allowed to hydrate overnight to simplify the disintegration process. The endpoint is achieved when a dispersion of fine particles in the syrup is obtained. This compounding procedure results in a solution containing 5 mg/mL of sotalol 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) and ambient humidity.

5 WARNINGS AND PRECAUTIONS QT prolongation, bradycardia, AV block, hypotension, worsening heart failure: Reduce dose or discontinue Acute exacerbation of coronary artery disease upon cessation of therapy: Do not abruptly discontinue Correct any electrolyte disturbances May mask symptoms of hypoglycemia or worsen hyperglycemia in diabetic patients; monitor

5.1QT Prolongation and Proarrhythmia Sotalol Hydrochloride

Tablets 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 . Correct hypokalemia or hypomagnesemia prior to initiating Sotalol Hydrochloride Tablets, 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 . In general, do not use sotalol with other drugs known to cause QT prolongation .

5.2Bradycardia/Heart Block/Sick Sinus Syndrome Sinus

bradycardia (heart rate less than 50 bpm) occurred in 13% of patients receiving sotalol in clinical trials, and led to discontinuation in about 3% of patients. Bradycardia itself increases the risk of Torsade de Pointes. Sinus pause, sinus arrest and sinus node dysfunction occur in less than 1% of patients.

The incidence of 2nd- or 3rd-degree AV block is approximately 1%. Sotalol Hydrochloride Tablets are contraindicated in patients with sick sinus syndrome because it may cause sinus bradycardia, sinus pauses or sinus arrest.

5.3Hypotension Sotalol

produces significant reductions in both systolic and diastolic blood pressures and may result in hypotension. Monitor hemodynamics in patients with marginal cardiac compensation.

5.4Heart 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.

5.5Cardiac Ischemia

after Abrupt Discontinuation Following abrupt cessation of therapy with beta adrenergic blockers, exacerbations of angina pectoris and myocardial infarction may occur. When discontinuing chronically administered Sotalol Hydrochloride Tablets, particularly in patients with ischemic heart disease, gradually reduce the dosage over a period of 1–2 weeks, if possible, and monitor the patient. If angina markedly worsens or acute coronary ischemia develops, treat appropriately (consider use of an alternative beta blocker).

Warn patients not to interrupt therapy without their physician’s advice. Because coronary artery disease may be common, but unrecognized, in patients treated with sotalol, abrupt discontinuation may unmask latent coronary insufficiency.

5.6Bronchospasm Patients with

bronchospastic diseases (for example chronic bronchitis and emphysema) should not receive beta- blockers. If Sotalol Hydrochloride 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.

5.7Masked 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.

5.8Thyroid 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.

5.9Anaphylaxis 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.

5.10Major 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.

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 ventricular arrythmias Sinus bradycardia, 2nd or 3rd degree AV block, sick sinus syndrome Congenital or acquired long QT syndrome, Serum potassium <4 mEq/L Cardiogenic shock, decompensated heart failure Bronchial asthma or related bronchospastic conditions Hypersensitivity to sotalol

8.1Pregnancy 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.

8.3Nursing Mothers Sotalol

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

The most common adverse reactions (≥2%) for Sotalol Hydrochloride Tablets are: fatigue 4%, bradycardia (less than 50 bpm) 3%, dyspnea 3%, proarrhythmia 3%, asthenia 2%, and dizziness 2%. To report SUSPECTED ADVERSE REACTIONS, contact Beximco Pharmaceuticals USA Inc. at 877-372-6093 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1Clinical 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 highest on-therapy value (msec) 80 0 463 160 0.5 467 320 1.6 473 480 4.4 483 640 3.7 490 >640 5.8 512 ( ) Number of patients assessed Table 4 below relates the incidence of Torsade de Pointes to on-therapy QT c and change in QT c from baseline in patients with ventricular arrhythmias. It should be noted, however, that the highest on-therapy QT c was in many cases the one obtained at the time of the Torsade de Pointes event, so that the table overstates the predictive value of a high QT c . Table 4: Relationship Between QTc Interval Prolongations and Torsade de Pointes On-Therapy QT c Interval (msec) Incidence of Torsade de Pointes Change from Baseline in QT c (msec) Incidence of Torsade de Pointes <500 1.3% <65 1.6% 500-525 3.4% 65-80 3.2% 525-550 5.6% 80-100 4.1% >550 10.8% 100-130 5.2% >130 7.1% ( ) Number of patients assessed Table 5: Incidence (%) of Common Adverse Reactions (2% in the Placebo group and less frequent than Sotalol Hydrochloride Tablets 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

15.4Dyspnea

2.7 18.4

20.5Palpitation

2.7 7.9

5.4Vasodilation

2.7 0.0

5.1NERVOUS

SYSTEM Asthenia 8.1 10.5

20.5Dizziness

5.4 13.2

17.9Fatigue

10.8 26.3

25.6Headache

5.4 5.3

7.7Lightheaded

8.1 15.8

5.1Sleep Problem

2.7 2.6

7.7RESPIRATORY Upper Respiratory Tract Problem

2.7 2.6

12.8SPECIAL

SENSES Visual Problem 2.7 5.3

0.0The

most common adverse reactions leading to discontinuation of Sotalol Hydrochloride Tablets 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 Tablets and recurred when the patient was rechallenged with the drug was reported in an early dose tolerance study. Pediatric Patients In an unblinded multicenter trial of 25 pediatric patients with SVT and/or VT receiving daily doses of 30, 90 and 210 mg/m 2 with dosing every 8 ours for a total of 9 doses, no Torsade de Pointes or other serious new arrhythmias were observed.

One patient, receiving 30 mg/m 2 daily, was discontinued because of increased frequency of sinus pauses/bradycardia. Additional cardiovascular AEs were seen at the 90 and 210 mg/m 2 daily dose levels. They included QT prolongation (2 patients), sinus pauses/bradycardia (1 patient), increased severity of atrial flutter and reported chest pain (1 patient).

Values for QT c 525 msec were seen in 2 patients at the 210 mg/m 2 daily dose level. Serious adverse events including death, Torsade de Pointes, other proarrhythmias, high-degree A-V blocks, and bradycardia have been reported in infants and/or children.