Betapace

Betapace/Betapace AF is an antiarrhythmic indicated for: the treatment of life-threatening ventricular arrhythmias the maintenance of normal sinus rhythm in patients with atrial fibrillation or flutter (AFIB/AFL) Limitations of Use Betapace has not been shown to enhance survival in patients with life threatening ventricular arrhythmias Avoid use in patients with minimally symptomatic or easily reversible AFIB/AFL

1.1Life-Threatening Ventricular Arrhythmias Betapace/Betapace

AF is indicated for the treatment of documented, life-threatening ventricular arrhythmias, such as sustained ventricular tachycardia (VT) . Limitation of Use: Betapace/Betapace AF has not been shown to enhance survival in patients with life-threatening ventricular arrhythmias.

1.2Delay in Recurrence of Atrial Fibrillation/Atrial Flutter

(AFIB/AFL) Betapace/Betapace AF is indicated for the maintenance of normal sinus rhythm (delay in time to recurrence of AFIB/AFL) in patients with highly symptomatic AFIB/AFL who are currently in sinus rhythm. Limitation of Use: Because Betapace/Betapace AF 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 Betapace/Betapace AF.

Betapace/Betapace AF: 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 Betapace/Betapace AF and monitor for a minimum of 2 to 3 plasma half-lives prior to initiating Betapace/Betapace AF therapy if the patient's clinical condition permits . Hospitalize patients being 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. Monitor QTc 2 to 4 hours after each uptitration in 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 QTc <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.

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

2.3Adult 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 . 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 QTc >450 msec is contraindicated .

2.4Pediatric 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 . For initiation of treatment, 1.2 mg/kg three times a day (3.6 mg/kg total daily dose) is approximately equivalent to the initial 160 mg total daily dose for adults.

Subsequent titration to a maximum of 2.4 mg/kg three times a day (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 conducted in-hospital. Allow at least 36 hours 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 pediatric dosage should be reduced by a factor that depends upon age, as shown in the following graph (age plotted on a logarithmic scale in months): For a child aged 1 month, multiply the starting dose by 0.7; the initial starting dose would be (1.2 mg/kg X 0.7)=0.8 mg/kg, administered three times daily. For a child aged about 1 week, multiply the initial starting dose by 0.3; the starting dose would be (1.2 mg/kg X 0.3)=0.4 mg/kg. Use similar calculations for dose titration. image description

2.5Dosage for Patients with Renal Impairment Adults

In any age group with decreased renal function, sotalol doses should be lowered or the intervals between doses increased. 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. Administer the initial dose of 80 mg and subsequent doses at the intervals listed in Table 1. Table 1: Dosing Intervals 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 Betapace/Betapace

AF 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 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, take care 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 Correct any electrolyte disturbances Acute exacerbation of coronary artery disease upon cessation of therapy: Do not abruptly discontinue Diabetes: May mask symptoms of hypoglycemia and alter glucose levels; monitor

5.1QT Prolongation and Proarrhythmia Betapace/Betapace

AF 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 Betapace/Betapace AF, 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 . Avoid use 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%. Betapace/Betapace AF is 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 Betapace/Betapace AF, 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 and consider use of an alternative beta-blocker.

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

5.6Bronchospasm Patients with

bronchospastic diseases (for example chronic bronchitis and emphysema) should not receive beta-blockers. If Betapace/Betapace AF is to be administered, use the smallest effective dose to minimize inhibition of bronchodilation produced by endogenous or exogenous catecholamine stimulation of beta-2-receptors.

5.7Effects on Blood Sugar Beta-blockers

may prevent early warning signs of hypoglycemia, such as tachycardia, and increase the risk for severe or prolonged hypoglycemia at any time during treatment, especially in patients with diabetes mellitus or children and patients who are fasting (i.e., surgery, not eating regularly, or are vomiting). If severe hypoglycemia occurs, patients should be instructed to seek emergency treatment. 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.

Betapace/Betapace AF is contraindicated in patients with: Sinus bradycardia, sick sinus syndrome, second and third degree AV block, unless a functioning pacemaker is present Congenital or acquired long QT syndromes Cardiogenic shock or decompensated heart failure Serum potassium <4 mEq/L Bronchial asthma or related bronchospastic conditions Hypersensitivity to sotalol For the treatment of AFIB/AFL, Betapace/Betapace AF is also contraindicated in patients with: Baseline QT interval >450 msec For the treatment of AFIB/AFL or ventricular arrhythmias Sinus bradycardia, 2 nd or 3 rd 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 For the treatment of AFIB/AFL also contraindicated for: QT interval >450 msec

8.1Pregnancy Risk Summary Both the

untreated underlying condition in pregnancy and the use of sotalol in pregnancy cause adverse outcomes to the mother and fetus/neonate . In animal reproduction studies in rats, early resorptions were increased at 15 times the maximum recommended human dose (MRHD). In rabbits an increase in fetal death was observed at 2 times the MRHD administered as a single dose. Sotalol did not reveal any teratogenic potential in rats or rabbits at 15 and 2 times the MRHD respectively . All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the United States (U.S.) general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Clinical Considerations The incidence of VT is increased and may be more symptomatic during pregnancy.

Most tachycardia episodes are initiated by ectopic beats and the occurrence of arrhythmia episodes may, therefore, increase during pregnancy. Breakthrough arrhythmias may also occur during pregnancy, as therapeutic treatment levels may be difficult to maintain due to the increased volume of distribution and increased drug metabolism inherent in the pregnant state. Fetal/Neonatal Adverse Reactions Sotalol has been shown to cross the placenta and is found in amniotic fluid.

From published observational studies, the potential fetal adverse effects of sotalol use during pregnancy are growth restriction, transient fetal bradycardia, hyperbilirubinemia, hypoglycemia, uterine contractions, and possible intrauterine death. Sotalol may have a greater effect on QT prolongation in the immature heart than in the adult heart, and therefore, conveys an increased risk of serious fetal arrhythmia and/or possible intrauterine death. Monitor the newborn for symptoms of beta blockade.

Labor or Delivery Generally, risk of arrhythmias increases during the labor and delivery process; therefore, considering the proarrhythmia potential of the drug, patients treated with sotalol should be monitored continuously during labor and delivery. Data Animal Data Reproduction studies in rats and rabbits administered sotalol during organogenesis at 15 times and 2 times the MRHD as mg/m 2 , respectively, did not reveal any teratogenic potential associated with sotalol. In pregnant rats, sotalol doses administered during organogenesis at approximately 15 times the MRHD as mg/m 2 , increased the number of early resorptions, while no increase in early resorptions was noted at 2 times the MRHD as mg/m 2 . In reproductive studies in rabbits, a sotalol dose (160 mg/kg/day) at 5 times the MRHD as mg/m 2 produced a slight increase in fetal death, and maternal toxicity.

However, one study from published data reported an increase in fetal deaths in rabbits receiving a single dose (50 mg/kg) at 2 times the MRHD as mg/m 2 on gestation day 14.

The most common adverse reactions (≥2%) for Betapace are: fatigue 4%, bradycardia (less than 50 bpm) 3%, dyspnea 3%, proarrhythmia 3%, asthenia 2%, and dizziness 2%. To report SUSPECTED ADVERSE REACTIONS, contact Legacy Pharma Inc. at 1-800-727-7151 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 Betapace/Betapace AF can cause serious and potentially fatal ventricular arrhythmias such as sustained VT/VF, primarily Torsade de Pointes (TdP) . The effect on QT and the risk of Torsade de Pointes are both dose related.

Pediatric Patients In an unblinded multicenter trial of 25 pediatric patients aged ≤ 1 month to 12 years with SVT and/or VT receiving daily doses of 30, 90, and 210 mg/m 2 with dosing every 8 hours for a total of 9 doses, no Torsade de Pointes or other serious new arrhythmias were observed. The clinical trial safety profile in pediatric patients was similar to that in adult patients. Both the Class III and beta-blocking effects of sotalol were linearly related to the plasma concentration . 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 of Betapace AF, the following adverse reactions presented in Table 2 occurred in at least 2% of placebo-treated patients and at a lesser rate than Betapace-treated patients.

The data are presented by incidence of reactions in the Betapace AF and placebo groups by body system and daily dose. Table 2: Incidence (%) of Common Adverse Reactions (≥ 2% in the Placebo Group and Less Frequent Than in the Betapace AF Groups) in Four Placebo-controlled Studies of Patients with AFIB/AFL Adverse Reaction Placebo Betapace AF Total Daily Dose N = 282 (%) 160-240 mg N = 153 (%) >240-320 mg N = 122 (%) Bradycardia 3 13 12 Diarrhea 2 5 6 Nausea/Vomiting 5 8 6 Fatigue 9 20 19 Hyperhidrosis 3 5 5 Weakness 3 5 5 Dizziness 12 16 13 Headache 5 3 12 Dyspnea 7 9 10 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 Betapace AF were: fatigue 4.6%, bradycardia 2.4%, proarrhythmia 2.2%, dyspnea 2%, and QT interval prolongation 1.4%.

6.2Postmarketing 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: emotional lability, slightly clouded sensorium, incoordination, vertigo, paralysis, thrombocytopenia, eosinophilia, leukopenia, photosensitivity reaction, fever, pulmonary edema, hyperlipidemia, myalgia, pruritis, and alopecia.