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Adverse events that are clearly related to BETAPACE AF (sotalol hcl) 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 events (bradycardia, dyspnea, and fatigue) and Class III effects (QT interval prolongation) are dose related.

In a pooled clinical trial population consisting of four placebocontrolled studies with 275 patients with AFIB/AFL treated with 160-320 mg doses of BETAPACE AF, 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 8). The data are presented by incidence of events in the BETAPACE AF and placebo groups by body system and daily dose. No significant irreversible non-cardiac end-organ toxicity was observed.

Table 8: Incidence (%) of Common Adverse Events ( ≥ 2% in the 160-240 mg group and more frequent than on placebo) in Four Placebo-Controlled Studies of Patients with AFIB/AFL

Body System/Adverse Event
(Preferred Term)
Placebo
N=282
BETAPACE AF Total Daily Dose
160-240
N=153
>240-320
N=122
CARDIO VASCULAR
  Abnormality ECG 0.4 3.3 2.5
  Angina Pectoris 1.1 2.0 1.6
  Bradycardia 2.5 13.1 12.3
  Chest Pain Cardiac/Non-Anginal 4.6 4.6 2.5
  Disturbance Rhythm Atrial 2.1 2.0 1.6
  Disturbance Rhythm Subjective 9.9 9.8 7.4
GASTROINTESTINAL
  Appetite Decreased 0.4 2.0 1.6
  Diarrhea 2.1 5.2 5.7
  Distention Abdomen 0.4 0.7 2.5
  Dyspepsia/Heartburn 1.8 2.0 2.5
  Nausea/Vomiting 5.3 7.8 5.7
  Pain Abdomen 2.5 3.9 2.5
GENERAL
  Fatigue 8.5 19.6 18.9
  Fever 0.7 0.7 3.3
  Hyperhidrosis 3.2 5.2 4.9
  Influenza 0.4 2.0 0.8
  Sensation Cold 0.7 2.0 2.5
  Weakness 3.2 5.2 4.9
MUSCULOSKELETAL/CONNECTIVE TISSUE
  Pain Chest Musculoskeletal 1.4 2.0 2.5
  Pain Musculoskeletal 2.8 2.6 4.1
NERVOUS SYSTEM
  Dizziness 12.4 16.3 13.1
  Headache 5.3 3.3 11.5
  Insomnia 1.1 2.6 4.1
RESPIRATORY
  Cough 2.5 3.3 2.5
  Dyspnea 7.4 9.2 9.8
  Infection Upper Respiratory 1.1 2.6 3.3
  Tracheobronchitis 0.7 0.7 3.3
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 BETAPACE AF (sotalol hcl) 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.

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.

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 AEs 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 QTc 525 msec were seen in 2 patients at the 210 mg/m2 daily dose level. Serious adverse events including death, Torsades de Pointe, other proarrhythmias, high-degree A-V blocks and bradycardia have been reported in infants and/or children.

Potential Adverse Effects

Foreign marketing experience with sotalol hydrochloride shows an adverse experience 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, alopecia.

The oculomucocutaneous syndrome associated with the beta-blocker practolol has not been associated with BETAPACE AF (sotalol hcl) during investigational use and foreign marketing experience.