Sotylize Drug Information

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 SOTYLIZE 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 oral sotalol, the following adverse events presented in Table 2 occurred in at least 2% of placebo-treated patients and at a lesser rate than oral sotalol-treated patients. The data are presented by incidence reactions in the oral sotalol 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 Sotalol Groups) in Four Placebo-controlled Studies of Patients with AFIB/AFL Placebo Oral Sotalol Total Daily Dose Adverse Reaction N=282 (%) 160-240 N=153 (%) >240-320 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 oral sotalol were: fatigue 4.6%, bradycardia 2.4%, proarrhythmia 2.2%, dyspnea 2%, and QT interval prolongation 1.4%.

Postmarketing Experience

The following adverse 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 estimate reliably their frequency or establish a causal relationship to drug exposure: emotional liability, slightly clouded sensorium, incoordination, vertigo, paralysis, thrombocytopenia, eosinophilia, leukopenia, photosensitivity reaction, fever, pulmonary edema, hyperlipidemia, myalgia, pruritus, alopecia.

Antiarrhythmics and Other QT Prolonging Drugs Discontinue Class I or Class

III antiarrhythmic agents for at least three half-lives prior to dosing with sotalol. Class Ia antiarrhythmic drugs such as disopyramide, quinidine and procainamide and other Class III drugs (for example, amiodarone) are not recommended as concomitant therapy with sotalol because of their potential to prolong refractoriness .

Negative Chronotropes Digitalis glycosides, diltiazem, verapamil, and beta-blockers slow atrioventricular conduction and

decrease heart rate. Concomitant use with negative chronotropes can increase the risk of bradycardia or 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. Monitor such patients for 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

Beta-2-Receptor Stimulants Beta-agonists such as albuterol, terbutaline and isoproterenol may have to

be administered in increased dosages when used concomitantly with sotalol.

Clonidine

Concomitant use with sotalol increases the risk of bradycardia and AV block. 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.

Antacids

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

Drug/Laboratory Test Interactions

The presence of sotalol in the urine may result in falsely elevated levels of urinary metanephrine when measured by flourimetric or photometric methods.

Pregnancy 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 ( see Clinical Considerations ). 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 single dose. Sotalol did not reveal any teratogenic potential in rats or rabbits at 15 and 2 times the MRHD respectively ( see Data ). 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 newborns for symptoms and adverse reactions associated with beta-blockers. Labor or Delivery Generally, risk of arrhythmias increases during 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.

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 . Associated side effects of sotalol use in pediatric patients are those typical of a beta-blocking agent, and lead to discontinuation of the drug in 3 to 6% of patients. As in adults, the Class III antiarrhythmic action of sotalol in pediatric patients is associated with a significant proarrhythmic potential for adverse effects.

In pediatric patients, the incidence of proarrhythmic side effects of sotalol varies from 0 to 22%; however, sotalol-induced Torsade de Pointes tachycardias are observed less frequently in the pediatric population. Proarrhythmic effects of sotalol in pediatric patients included increased ventricular ectopy and exacerbation of bradycardia, the latter predominantly in patients with sinus node dysfunction following surgery for congenital cardiac defects. Bradycardia may require emergency pacemaker implantation.

Close in-patient monitoring is recommended for several days.

For the treatment of AFIB/AFL or ventricular arrhythmias, SOTYLIZE is contraindicated in patients with: Baseline QT interval ˃450 msec 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 or ventricular arrhythmias Baseline QT interval ˃450 msec Sinus bradycardia, 2 nd or 3 rd degree AV block, sick sinus syndrome Congenital or acquired long QT syndromes Serum potassium ˂4 mEq/L Cardiogenic shock, decompensated heart failure Bronchial asthma or related bronchospastic conditions Hypersensitivity to sotalol

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 to16 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.