SOTYLIZE SIDE EFFECTS

SIDE EFFECTS

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.

Adults

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.

Serious Adverse Reactions

SOTYLIZE 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.

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 msec 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 (QT_c) interval, as shown in Table 1 below.

Table 1: Percent Incidence of Torsade de Pointes and Mean QT_c Interval by Dose For Patients With Sustained VT/VF

Table 2 below relates the incidence of Torsade de Pointes to on-therapy QT_c and change in QT_c from baseline. 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 2: Relationship Between QT_c Interval Prolongation and Torsade de Pointes

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 QT_c 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. 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.

Other Adverse Reactions

In a pooled clinical trial population consisting of four placebo-controlled studies with 275 patients with AFIB/AFL treated with 160-320 mg of oral sotalol, the following adverse events were reported at least 2% more frequently in the 160-240 mg sotalol treated patients than in placebo patients (see Table 3). The data are presented by incidence of events in the oral sotalol and placebo groups by body system and daily dose.

Table 3: Incidence (%) of Common Adverse Reactions (≥2% more frequent in patients treated in the 160-240 mg group than on placebo) in Four Placebo-Controlled Studies of Patients with AFIB/AFL Treated with Oral Sotalol

In AFIB/AFL patients, discontinuation because of unacceptable adverse reactions 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 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 were similar to those described for the AFIB/AFL population.

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.

Pediatric Patients

In an unblinded multicenter trial of 25 patients with SVT and/or VT receiving daily doses of 30, 90 and 210 mg/m² 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/m² daily, was discontinued because of increased frequency of sinus pauses/bradycardia. Additional cardiovascular adverse events were seen at the 90 and 210 mg/m² 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 QT_c ≥525 msec were seen in 2 patients at the 210 mg/m² 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.

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.

Postmarketing experience with sotalol shows an adverse event profile similar to that described above from clinical trials. Voluntary reports since introduction include rare reports (less than one report per 10,000 patients) of: emotional liability, slightly clouded sensorium, incoordination, vertigo, paralysis, thrombocytopenia, eosinophilia, leukopenia, photosensitivity reaction, fever, pulmonary edema, hyperlipidemia, myalgia, pruritus, alopecia.