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adverse reactions
6 ADVERSE REACTIONS Most common adverse reactions (>10%) seen with oral sotalol (dose related) are fatigue, dizziness, lightheadedness, headache, asthenia, nausea, dyspnea, bradycardia, chest pain, and palpitation ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact DRUG SAFETY at 1-888-875-1671 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Trials Experience There is no clinical experience with intravenous sotalol. However, because of the similarity of exposure with intravenous sotalol and oral sotalol, the adverse reactions should be similar. 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. The common documented beta-blocking adverse reactions (bradycardia, dyspnea, and fatigue) and Class III effects (QT interval prolongation) are dose related. 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. Serious Adverse Reactions Sotalol can cause serious ventricular arrhythmias, primarily Torsade de Pointes (TdP) type ventricular tachycardia, a polymorphic ventricular tachycardia associated with QT interval prolongation. QT interval prolongation is directly related to the plasma level of sotalol. Factors such as reduced creatinine clearance, gender (female) and larger doses increase the risk of TdP [see Warning and Precautions (5.1 ] . Proarrhythmia in Atrial Fibrillation Patients: In eight controlled trials of patients with AFIB/AFL and other supraventricular arrhythmias (N=659) there were four cases of TdP reported (0.6%) during the controlled phase of treatment with oral sotalol. Prolongation of the QT interval is dose related, increasing from baseline an average of 25, 40, and 50 ms in the 80, 120, and 160 mg groups, respectively, in the oral dose-response study. Proarrhythmia in Ventricular Arrhythmia Patients: 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%. Additionally, in approximately 1% of patients, deaths were considered possibly drug related; such cases, although difficult to evaluate, may have been associated with proarrhythmic events. Torsade de Pointes arrhythmias in patients with VT/VF were dose related, as was the prolongation of QT (QTc) interval, as shown in Table 1 below. Table 1: Percentage Incidence of Torsade de Pointes and Mean QTc Interval by Oral Dose for Patients with Sustained VT/VF Daily Dose [mg] Incidence of Torsade de Pointes Mean QTc highest on-therapy value [ms] ( ) Number of patients assessed 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) Table 2 below relates the incidence of Torsade de Pointes to on-therapy QTc and change in QTc from baseline. 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 2: Relationship Between QTc Interval Prolongation and Torsade de Pointes On-Therapy QTc Interval [ms] Incidence of Torsade de Pointes Change in QTc Interval From Baseline [ms] Incidence of Torsade de Pointes ( ) Number of patients assessed less than 500 1.3% (1787) less than 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) In addition to dose and presence of sustained VT, other risk factors for Torsade de Pointes were gender (females had a higher incidence), excessive prolongation of the QTc interval and history of cardiomegaly or congestive heart failure. Patients with sustained ventricular tachycardia and a history of congestive heart failure appear to have the highest risk for serious proarrhythmia (7%). Of the ventricular arrhythmia patients experiencing Torsade de Pointes, approximately two-thirds spontaneously reverted to their baseline rhythm. The others were either converted electrically (D/C cardioversion or overdrive pacing) or treated with other drugs [see Overdosage (10) ] . It is not possible to determine whether some sudden deaths represented episodes of Torsade de Pointes, but in some instances sudden death did follow a documented episode of Torsade de Pointes. Although sotalol therapy was discontinued in most patients experiencing Torsade de Pointes, 17% were continued on a lower dose. Nonetheless, intravenous sotalol should be used with particular caution if the QTc is greater than 500 ms on-therapy and serious consideration should be given to reducing the dose or discontinuing therapy when the QTc exceeds 520 ms. Proarrhythmic events must be anticipated not only on initiating therapy, but with every upward dose adjustment. Other Adverse Reactions No data are available with intravenous sotalol. In a pooled clinical trial population consisting of four placebo-controlled studies with 275 patients with AFIB/AFL treated with 160-320 mg doses of oral sotalol the following adverse events were reported at a rate of 2% or more in the 160-240 mg treated patients and greater than the rate in placebo patients (See Table 3 ). The data are presented by incidence of events in the sotalol and placebo groups by body system and daily dose. No significant irreversible non-cardiac end-organ toxicity was observed. Table 3: Incidence (%) of Common Adverse Reactions (≥2% in the 160-240 mg group and more frequent than on placebo) in Four Placebo-Controlled Studies of Patients with AFIB/AFL Treated with Oral Sotalol Placebo Sotalol Total Daily Dose Body System/ Adverse Reactions (Preferred Term) N=282 160-240 N=153 >240-320 N=122 CARDIOVASCULAR Bradycardia 2.5 13.1 12.3 Disturbance Rhythm Subjective 9.9 9.8 7.4 Abnormality ECG 0.4 3.3 2.5 Chest Pain Cardiac/Non-Anginal 4.6 4.6 2.5 Angina Pectoris 1.1 2.0 1.6 Disturbance Rhythm Atrial 2.1 2.0 1.6 GASTROINTESTINAL Diarrhea 2.1 5.2 5.7 Nausea/Vomiting 5.3 7.8 5.7 Distention Abdomen 0.4 0.7 2.5 Dyspepsia/Heartburn 1.8 2.0 2.5 Pain Abdomen 2.5 3.9 2.5 Appetite Decreased 0.4 2.0 1.6 GENERAL Fatigue 8.5 19.6 18.9 Hyperhidrosis 3.2 5.2 4.9 Weakness 3.2 5.2 4.9 Fever 0.7 0.7 3.3 Sensation Cold 0.7 2.0 2.5 Influenza 0.4 2.0 0.8 MUSCULOSKELETAL/CONNECTIVE TISSUE Pain Musculoskeletal 2.8 2.6 4.1 Pain Chest Musculoskeletal 1.4 2.0 2.5 NERVOUS SYSTEM Dizziness 12.4 16.3 13.1 Headache 5.3 3.3 11.5 Insomnia 1.1 2.6 4.1 RESPIRATORY Dyspnea 7.4 9.2 9.8 Infection Upper Respiratory 1.1 2.6 3.3 Tracheobronchitis 0.7 0.7 3.3 Cough 2.5 3.3 2.5 SPECIAL SENSES Disturbance Vision 0.7 2.6 0.8 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 events leading to discontinuation of sotalol were: fatigue 4.6%, bradycardia 2.4%, proarrhythmia 2.2%, dyspnea 2%, and QT interval prolongation 1.4%. In clinical trials involving 1292 patients with sustained VT/VF, the common adverse events (occurring in ≥2% of patients) were similar to those described for the AFIB/AFL population. Table 4 lists as a function of dosage the most common (incidence of 2% or greater) adverse events, regardless of relationship to therapy and the percent of patients discontinued due to the event, as collected from clinical trials involving 1292 patients with sustained VT/VF. Table 4: Incidence (%) of Adverse Events and Discontinuations (Disc) in 1292 patients with sustained VT/VF Receiving Oral Sotalol Therapy Daily Dose % Disc 160 mg 240 mg 320 mg 480 mg 640 mg Any Dose Because patients are counted at each dose level tested, the Any Dose column cannot be determined by adding across the doses. Body System n=832 n=263 n=835 n=459 n=324 n=1292 n=1292 BODY AS A WHOLE Infection 1 2 2 2 3 4 <1 Fever 1 2 3 2 2 4 <1 Localized pain 1 1 2 2 2 3 <1 CARDIOVASCULAR (CV) Dyspnea 5 8 11 15 15 21 2 Bradycardia 8 8 9 7 5 16 2 Chest pain 4 3 10 10 14 16 <1 Palpitation 3 3 8 9 12 14 <1 Edema 2 2 5 3 5 8 1 ECG abnormal 4 2 4 2 2 7 1 Hypotension 3 4 3 2 3 6 2 Proarrhythmia <1 <1 2 4 5 5 3 Syncope 1 1 3 2 5 5 1 Heart failure 2 3 2 2 2 5 1 Presyncope 1 2 2 4 3 4 <1 Periph vascular 1 2 1 1 2 3 <1 CV disorder 1 <1 2 2 2 3 <1 Vasodilation 1 <1 1 2 1 3 <1 AICD discharge <1 2 2 2 2 3 <1 Hypertension <1 1 1 1 2 2 <1 NERVOUS Fatigue 5 8 12 12 13 20 2 Dizziness 7 6 11 11 14 20 1 Asthenia 4 5 7 8 10 13 1 Light-headed 4 3 6 6 9 12 1 Headache 3 2 4 4 4 8 <1 Sleep problem 1 1 5 5 6 8 <1 Perspiration 1 2 3 4 5 6 <1 Altered consciousness 2 3 1 2 3 4 <1 Depression 1 2 2 2 3 4 <1 Paresthesia 1 1 2 3 2 4 <1 Anxiety 2 2 2 3 2 4 <1 Mood change <1 <1 1 3 2 3 <1 Appetite disorder 1 2 2 1 3 3 <1 Stroke <1 <1 1 1 <1 1 <1 DIGESTIVE Nausea/vomiting 5 4 4 6 6 10 1 Diarrhea 2 3 3 3 5 7 <1 Dyspepsia 2 3 3 3 3 6 <1 Abdominal pain <1 <1 2 2 2 3 <1 Colon problem 2 1 1 <1 2 3 <1 Flatulence 1 <1 1 1 2 2 <1 RESPIRATORY Pulmonary problem 3 3 5 3 4 8 <1 Upper resp. tract problem 1 1 3 4 3 5 <1 Asthma 1 <1 1 1 1 2 <1 UROGENITAL Genitourinary disorder 1 0 1 1 2 3 <1 Sex. dysfunction <1 1 1 1 3 2 <1 METABOLIC Abnormal lab 1 2 3 2 1 4 <1 Weight change 1 1 1 <1 2 2 <1 MUSCULOSKELETAL Extremity pain 2 2 4 5 3 7 <1 Back pain 1 <1 2 2 2 3 <1 SKIN AND APPENDAGES Rash 2 3 2 3 4 5 <1 HEMATOLOGIC Bleeding 1 <1 1 <1 2 2 <1 SPECIAL SENSES Visual Problem 1 1 2 4 5 5 <1 Occasional reports of elevated serum liver enzymes have occurred with sotalol therapy but no cause and effect relationship has been established. One case of peripheral neuropathy which resolved on discontinuation of sotalol and recurred when the patient was rechallenged with the drug was reported in an early dose tolerance study. Elevated blood glucose levels and increased insulin requirements can occur in diabetic patients. Pediatrics There are no studies of intravenous sotalol in pediatric patients. In an unblinded multicenter trial of 25 pediatric patients with SVT and/or VT receiving daily oral 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 prolongations (2 patients), sinus pauses/bradycardia (1 patient), increased severity of atrial flutter and reported chest pain (1 patient). Values for QTc ≥525 ms 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. 6.2 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 reliably estimate their frequency of reporting, or strength of causal connection to the drug. Postmarketing experience with sotalol shows an adverse reaction profile similar to that described above from clinical trials. Voluntary reports since introduction also include rare reports of: emotional liability, slightly clouded sensorium, incoordination, vertigo, paralysis, thrombocytopenia, eosinophilia, leukopenia, photosensitivity reaction, fever, pulmonary edema, hyperlipidemia, myalgia, pruritis, and alopecia. Foreign postmarketing experience with intravenous sotalol shows an adverse reaction profile similar to that described above from clinical trials. Sotalol related cardiovascular adverse events occurring in 1% or more of the patients are bradycardia, dyspnea, chest pain, palpitations, edema, ECG abnormalities, hypotension, proarrhythmia, syncope, heart failure, and presyncope.