Sotalol Hydrochloride 80 mg Tablet, 90-count

WARNINGS Ventricular Arrhythmia Sotalol (AF) 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 dose of sotalol (AF). Factors such as reduced creatinine clearance, gender (female) and larger doses increase the risk of TdP.

The risk of TdP can be reduced by adjustment of the sotalol (AF) dose according to creatinine clearance and by monitoring the ECG for excessive increases in the QT interval. Treatment with sotalol (AF) must therefore be started only in patients observed for a minimum of three days on their maintenance dose in a facility that can provide electrocardiographic monitoring and in the presence of personnel trained in the management of serious ventricular arrhythmias. Calculation of the creatinine clearance must precede administration of the first dose of sotalol (AF).

For detailed instructions regarding dose selection, see DOSAGE AND ADMINISTRATION . Proarrhythmia in Atrial Fibrillation/Atrial Flutter Patients In eight controlled trials of patients with AFIB/AFL and other supraventricular arrhythmias (N=659) there were four cases of Torsade de Pointes reported (0.6%) during the controlled phase of treatment with sotalol (AF). The incidence of Torsade de Pointes was significantly lower in those patients receiving total daily doses of 320 mg or less (0.3%), as summarized in Table 5 below.

Both patients who had Torsade de Pointes in the group receiving >320 mg/day were receiving 640 mg/day. In the group receiving ≤320 mg daily, one case of TdP occurred at a daily dose of 320 mg on day 4 of treatment and one case occurred on a daily dose of 160 mg on day 1 of treatment. Table 5 Incidence of Torsade de Pointes in Controlled Trials of AFIB and Other Supraventricular Arrhythmias Sotalol Hydrochloride (AF) (Daily Dose) Any Dose (N=659) >320 mg/day (N=62) ≤320 mg/day (N=597) ≤240 mg/day (N=340) Placebo (N=358) n(%) n(%) n(%) n(%) n(%) Torsade de Pointes 4(0.6%) 2(3.2%) 2(0.3%) 1(0.3%) 0 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 clinical dose-response study.

In this clinical trial sotalol (AF) treatment was not initiated if the QT interval was greater than 450 msec and during therapy the dose was reduced or discontinued if the QT interval was ≥520 msec. Experience in patients with ventricular arrhythmias is also pertinent to the risk of Torsade de Pointes in patients with AFIB/AFL (see below). Proarrhythmia in Ventricular Arrhythmia Patients [ see Sotalol Hydrochloride Package Insert] In patients with a history of sustained ventricular tachycardia, the incidence of Torsade de Pointes during sotalol treatment was 4% and worsened VT in about 1%; in patients with other less serious ventricular arrhythmias the incidence of Torsade de Pointes was 1% and new or worsened VT in 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 6 below. Table 6 Percent Incidence of Torsade de Pointes and Mean QT c Interval by Dose For Patients With Sustained VT/VF Daily Dose (mg) Incidence of Torsade de Pointes 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 7 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 Po…

ADVERSE REACTIONS Adverse events that are clearly related to sotalol AF 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 placebo-controlled studies with 275 patients with AFIB/AFL treated with 160 to 320 mg doses of sotalol hydrochloride (AF), the following adverse events were reported at a rate of 2% or more in the 160 to 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 sotalol (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 to 240 mg group and more frequent than on placebo) in Four Placebo-Controlled Studies of Patients with AFIB/AFL Placebo Sotalol Hydrochloride(AF) Total Daily Dose Body System/ Adverse Event (Preferred Term) N=282 160-240 N=153 >240-320 N=122 CARDIOVASCULAR Abnormality ECG 0.4 3.3

2.5Angina Pectoris 1.1 2.0

1.6Bradycardia 2.5 13.1

12.3Chest Pain Cardiac/Non-Anginal 4.6 4.6

2.5Disturbance Rhythm Atrial 2.1 2.0

1.6Disturbance Rhythm Subjective 9.9 9.8

7.4GASTROINTESTINAL Appetite Decreased 0.4 2.0

1.6Diarrhea 2.1 5.2

5.7Distention Abdomen 0.4 0.7

2.5Dyspepsia/Heartburn 1.8 2.0

2.5Nausea/Vomiting 5.3 7.8

5.7Pain Abdomen 2.5 3.9

2.5GENERAL Fatigue 8.5 19.6

18.9Fever 0.7 0.7

3.3Hyperhidrosis 3.2 5.2

4.9Influenza 0.4 2.0

0.8Sensation Cold 0.7 2.0

2.5Weakness 3.2 5.2

4.9MUSCULOSKELETAL/CONNECTIVE TISSUE Pain Chest Musculoskeletal 1.4 2.0

2.5Pain Musculoskeletal 2.8 2.6

4.1NERVOUS SYSTEM Dizziness 12.4 16.3

13.1Headache 5.3 3.3

11.5Insomnia 1.1 2.6

4.1RESPIRATORY Cough 2.5 3.3

2.5Dyspnea 7.4 9.2

9.8Infection Upper Respiratory 1.1 2.6

3.3Tracheobronchitis 0.7 0.7

3.3SPECIAL SENSES Disturbance Vision 0.7 2.6

0.8Overall, 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 hydrochloride (AF) 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/m 2 with dosing every 8 hours for a total of 9 doses, no Torsades 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 QT c ≥525 msec were seen in 2 patients at the 210 mg/m 2 daily dose level. Serious adverse events including death, Torsades de Pointes, other proarrhythmias, high-degree A-V blocks and bradycardia have been reported in infants and/or children.

Potential Adverse Effects Foreign marketing experience wit…

Drug Interactions Drugs undergoing CYP450 metabolism Sotalol is primarily eliminated by renal excretion; therefore, drugs that are metabolized by CYP450 are not expected to alter the pharmacokinetics of sotalol. Digoxin Proarrhythmic events were more common in sotalol treated patients also receiving digoxin; it is not clear whether this represents an interaction or is related to the presence of CHF, a known risk factor for proarrhythmia, in the patients receiving digoxin. Both digitalis glycosides and beta-blockers slow atrioventricular conduction and decrease heart rate.

Concomitant use can increase the risk of bradycardia. Calcium blocking drugs Sotalol (AF) should be administered with caution in conjunction with calcium blocking drugs because of possible additive effects on atrioventricular conduction or ventricular function. Additionally, concomitant use of these drugs may have additive effects on blood pressure, possibly leading to 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. Patients treated with sotalol (AF) plus a catecholamine depletor should therefore be closely monitored for evidence of 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.

Symptoms of hypoglycemia may be masked. Beta-2-receptor stimulants Beta-agonists such as salbutamol, terbutaline and isoprenaline may have to be administered in increased dosages when used concomitantly with sotalol (AF). Clonidine Beta-blocking drugs may potentiate the rebound hypertension sometimes observed after discontinuation of clonidine; therefore, caution is advised when discontinuing clonidine in patients receiving sotalol (AF).

Other No pharmacokinetic interactions were observed with hydrochlorothiazide or warfarin. Antacids Administration of sotalol (AF) within 2 hours of antacids containing aluminum oxide and magnesium hydroxide should be avoided because it may result in a reduction in C max and AUC of 26% and 20%, respectively and consequently in a 25% reduction in the bradycardic effect at rest. Administration of the antacid two hours after sotalol (AF) has no effect on the pharmacokinetics or pharmacodynamics of sotalol.

Drug/Laboratory Test Interactions The presence of sotalol in the urine may result in falsely elevated levels of urinary metanephrine when measured by fluorimetric or photometric methods. In screening patients suspected of having a pheochromocytoma and being treated with sotalol, a specific method, such as a high performance liquid chromatographic assay with solid phase extraction (e.g., J. Chromatogr.

385:241, 1987) should be employed in determining levels of catecholamines. Carcinogenesis, Mutagenesis, Impairment of Fertility No evidence of carcinogenic potential was observed in rats during a 24-month study at 137 to 275 mg/kg/day (approximately 30 times the maximum recommended human oral dose (MRHD) as mg/kg or 5 times the MRHD as mg/m 2 ) or in mice, during a 24-month study at 4141 to 7122 mg/kg/day (approximately 450 to 750 times the MRHD as mg/kg or 36 to 63 times the MRHD as mg/m 2 ). Sotalol has not been evaluated in any specific assay of mutagenicity or clastogenicity.

No significant reduction in fertility occurred in rats at oral doses of 1000 mg/kg/day (approximately 100 times the MRHD as mg/kg or 9 times the MRHD as mg/m 2 ) prior to mating, except for a small reduction in the number of offspring per litter. Pregnancy Category B Reproduction studies in rats and rabbits during organogenesis at 100 and 22 times the MRHD as mg/kg (9 and 7 times the MRHD as mg/m 2 ), respectively, did not reveal any teratogenic potential associated with sotalol hydrochloride. In rabbits, a high dose of sotalol hydrochloride (160 mg/kg/day) at 16 tim…

Drug/Laboratory Test Interactions The presence of sotalol in the urine may result in falsely elevated levels of urinary metanephrine when measured by fluorimetric or photometric methods. In screening patients suspected of having a pheochromocytoma and being treated with sotalol, a specific method, such as a high performance liquid chromatographic assay with solid phase extraction (e.g., J. Chromatogr.

385:241, 1987) should be employed in determining levels of catecholamines.