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 )] . WARNING: LIFE THREATENING PROARRHYTHMIA See full prescribing information for complete boxed warning. Sotalol hydrochloride/ Sotalol hydrochloride AF 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.
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warnings and cautions
5 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 ) 5.1 QT Prolongation and Proarrhythmia Sotalol hydrochloride/Sotalol hydrochloride 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 [see Dosage and Administration ( 2.1 )] . Correct hypokalemia or hypomagnesemia prior to initiating sotalol hydrochloride/sotalol hydrochloride 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 [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%. Sotalol hydrochloride/Sotalol hydrochloride AF is 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 sotalol hydrochloride/sotalol hydrochloride AF, 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. 5.6 Bronchospasm Patients with bronchospastic diseases (for example chronic bronchitis and emphysema) should not receive beta- blockers. If sotalol hydrochloride/sotalol hydrochloride 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. 5.7 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 The most common adverse reactions (≥2%) for sotalol hydrochloride 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 AvKARE at 1-855-361-3993 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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 QT c Interval by Dose For Patients With Sustained VT/VF Daily Dose (mg) Torsade de Pointes Incidence Mean QT c * (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) ( ) Number of patients assessed *highest on-therapy value 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 QT c Interval Incidence of Torsade de Pointes Change from Baseline in QT c Incidence of Torsade de Pointes (msec) (msec) <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) ( ) Number of patients assessed Table 5: Incidence (%) of Common Adverse Reactions (≥ 2% in the Placebo group and less frequent than in the sotalol groups) in a Placebo-controlled Parallel-group Comparison Study of Patients with Ventricular Ectopy Placebo Sotalol hydrochloride Total Daily Dose 320 mg 640 mg Body System/ N = 37 N = 38 N = 39 Adverse Reaction (Preferred Term) (%) (%) (%) 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/m 2 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/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. 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 AF, the following adverse reactions presented in Table 6 occurred in at least 2% of placebo-treated patients and at a lesser rate than sotalol-treated patients. The data are presented by incidence of reactions in the sotalol hydrochloride AF 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 AF groups) in Four Placebo-controlled Studies of Patients with AFIB/AFL Placebo sotalol hydrochloride AF Total Daily Dose 160-240 mg > 240-320 mg Body System/ N = 282 N = 153 N = 122 Adverse Reaction (Preferred Term) (%) (%) (%) 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 AF 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. To report SUSPECTED ADVERSE REACTIONS contact AvKARE at 1-855-361-3993; email drugsafety@avkare.com; or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.