SORINE^®
(Sotalol HCl) Tablets

To minimize the risk of induced arrhythmia, patients initiated or re-initiated on sotalol should be placed for a minimum of three days (on their maintenance dose) in a facility that can provide cardiac resuscitation and continuous electrocardiographic monitoring. Creatinine clearance should be calculated prior to dosing. For detailed instructions regarding dose selection and special cautions for people with renal impairment, seeDOSAGE AND ADMINISTRATION. Sotalol is also indicated for the maintenance of normal sinus rhythm [delay in time to recurrence of atrial fibrillation/atrial flutter (AFIB/AFL)] in patients with symptomatic AFIB/AFL who are currently in sinus rhythm and is marketed under the brand name BETAPACE AF^™. This product is not approved for the AFIB/AFL indication and should not be substituted for BETAPACE AF^™ because only BETAPACE AF^™ is distributed with a patient package insert that is appropriate for patients with AFIB/AFL.

Sorine^® (Sotalol HCl) Tablets are an antiarrhythmic drug with Class II (beta-adrenoreceptor blocking) and Class III (cardiac action potential duration prolongation) properties. It is supplied as a white, capsule-shaped tablet for oral administration. Sotalol hydrochloride is a white, crystalline solid with a molecular weight of 308.8. It is hydrophilic, soluble in water, propylene glycol and ethanol, but is only slightly soluble in chloroform. Chemically, sotalol hydrochloride is d,l-N-[4-[1-hydroxy-2-[(1-methylethyl)amino]ethyl]phenyl] methane-sulfonamide monohydrochloride. The molecular formula is C₁₂H₂₀N₂O₃S•HCl and is represented by the following structural formula:

Sorine^® Tablets contain the following inactive ingredients: microcrystalline cellulose, lactose monohydrate, corn starch, stearic acid, magnesium stearate and silicon dioxide.

Oral Sorine^® (Sotalol HCl) Tablets are indicated for the treatment of documented ventricular arrhythmias, such as sustained ventricular tachycardia, that in the judgment of the physician are life-threatening. Because of the proarrhythmic effects of sotalol (see WARNINGS), including a 1.5 to 2% rate of torsade de pointes or new VT/VF in patients with either NSVT or supraventricular arrhythmias, its use in patients with less severe arrhythmias, even if the patients are symptomatic, is generally not recommended. Treatment of patients with asymptomatic ventricular premature contractions should be avoided.

Initiation of Sorine^® (Sotalol HCl) Tablets treatment or increasing doses, as with other antiarrhythmic agents used to treat life-threatening arrhythmias, should be carried out in the hospital. The response to treatment should then be evaluated by a suitable method (e.g., PES or Holter monitoring) prior to continuing the patient on chronic therapy. Various approaches have been used to determine the response to antiarrhythmic therapy, including sotalol.

In the ESVEM Trial, response by Holter monitoring was tentatively defined as 100% suppression of ventricular tachycardia, 90% suppression of non-sustained VT, 80% suppression of paired VPCs, and 75% suppression of total VPCs in patients who had at least 10 VPCs/hour at baseline; this tentative response was confirmed if VT lasting 5 or more beats was not observed during treadmill exercise testing using a standard Bruce protocol. The PES protocol utilized a maximum of three extrastimuli at three pacing cycle lengths and two right ventricular pacing sites. Response to PES was defined as prevention of induction of the following: 1) monomorphic VT lasting over 15 seconds; 2) non-sustained polymorphic VT containing more than 15 beats of monomorphic VT in patients with a history of monomorphic VT; 3) polymorphic VT or VF greater than 15 beats in patients with VF or a history of aborted sudden death without monomorphic VT; and 4) two episodes of polymorphic VT or VF of greater than 15 beats in a patient presenting with monomorphic VT. Sustained VT or NSVT producing hypotension during the final treadmill test was considered a drug failure.

In a multi-center open-label long-term study of sotalol in patients with life-threatening ventricular arrhythmias which had proven refractory to other antiarrhythmic medications, response by Holter monitoring was defined as in ESVEM. Response by PES was defined as non-inducibility of sustained VT by at least double extrastimuli delivered at a pacing cycle length of 400 msec. Overall survival and arrhythmia recurrence rates in this study were similar to those seen in ESVEM, although there was no comparative group to allow a definitive assessment of outcome.

Antiarrhythmic drugs have not been shown to enhance survival in patients with ventricular arrhythmias.

Sotalol is also indicated for the maintenance of normal sinus rhythm [delay in time to recurrence of atrial fibrillation/atrial flutter (AFIB/AFL)] in patients with symptomatic AFIB/AFL who are currently in sinus rhythm and is marketed under the brand name BETAPACE AF^™. Sorine^® is not approved for the AFIB/AFL indication and should not be substituted for BETAPACE AF^™ because only BETAPACE AF^™ is distributed with a patient package insert that is appropriate for patients with AFIB/AFL.

Sorine^® (Sotalol HCl) Tablets are contraindicated in patients with bronchial asthma, sinus bradycardia, second and third degree AV block, unless a functioning pacemaker is present, congenital or acquired long QT syndromes, cardiogenic shock, uncontrolled congestive heart failure, and previous evidence of hypersensitivity to sotalol.

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.

No evidence of carcinogenic potential was observed in rats during a 24-month study at 137-275 mg/kg/day (approximately 30 times the maximum recommended human oral dose [MRHD] as mg/kg or 5 times the MRHD as mg/m²) or in mice, during a 24-month study at 4141-7122 mg/kg/day (approximately 450-750 times the MRHD as mg/kg or 36-63 times the MRHD as mg/m²).

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/m²) prior to mating, except for a small reduction in the number of offspring per litter.

During premarketing trials, 3186 patients with cardiac arrhythmias (1363 with sustained ventricular tachycardia) received oral sotalol, of whom 2451 received the drug for at least two weeks. The most important adverse effects are torsade de pointes and other serious new ventricular arrhythmias (see WARNINGS), occurring at rates of almost 4% and 1%, respectively, in the VT/VF population. Overall, discontinuation because of unacceptable side-effects was necessary in 17% of all patients in clinical trials, and in 13% of patients treated for at least two weeks. The most common adverse reactions leading to discontinuation of sotalol are as follows: fatigue 4%, bradycardia (less than 50 bpm) 3%, dyspnea 3%, proarrhythmia 3%, asthenia 2%, and dizziness 2%.

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.

The following table uls 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.

In an unblinded multi-center 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 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 AV blocks and bradycardia have been reported in infants and/or children.

Foreign marketing experience with sotalol hydrochloride shows an adverse experience 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 lability, slightly clouded sensorium, incoordination, vertigo, paralysis, thrombocytopenia, eosinophilia, leukopenia, photosensitivity reaction, fever, pulmonary edema, hyperlipidemia, myalgia, pruritus, alopecia.

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

Intentional or accidental overdosage with sotalol hydrochloride has rarely resulted in death.

As with other antiarrhythmic agents, Sorine^® (Sotalol HCl) Tablets should be initiated and doses increased in a hospital with facilities for cardiac rhythm monitoring and assessment (see INDICATIONS AND USAGE). Sorine^® should be administered only after appropriate clinical assessment (see INDICATIONS AND USAGE), and the dosage of Sorine^® must be individualized for each patient on the basis of therapeutic response and tolerance. Proarrhythmic events can occur not only at initiation of therapy, but also with each upward dosage adjustment.

Adults: Because sotalol is excreted predominantly in urine and its terminal elimination half-life is prolonged in conditions of renal impairment, the dosing interval (time between divided doses) of Sorine^® (Sotalol HCl) Tablets should be modified (when creatinine clearance is lower than 60 mL/min) according to the following table.

Since the terminal elimination half-life of sotalol is increased in patients with renal impairment, a longer duration of dosing is required to reach steady-state. Dose escalations in renal impairment should be done after administration of at least 5-6 doses at appropriate intervals (see table above).

Extreme caution should be exercised in the use of sotalol in patients with renal failure undergoing hemodialysis. The half-life of sotalol is prolonged (up to 69 hours) in anuric patients. Sotalol, however, can be partly removed by dialysis with subsequent partial rebound in concentrations when dialysis is completed. Both safety (heart rate, QT interval) and efficacy (arrhythmia control) must be closely monitored.

Before starting Sorine^® (Sotalol HCl) Tablets, previous antiarrhythmic therapy should generally be withdrawn under careful monitoring for a minimum of 2-3 plasma half-lives if the patient's clinical condition permits (see PRECAUTIONS, Drug Interactions). Treatment has been initiated in some patients receiving I.V. lidocaine without ill effect. After discontinuation of amiodarone, Sorine^® should not be initiated until the QT interval is normalized (see WARNINGS).

Information relating to the preparation of an extemporaneous oral solution of sotalol is approved for Berlex Laboratories' sotalol hydrochloride tablets. However, due to Berlex's marketing exclusivity rights, this drug product is not labeled with that information.

Patients with a history of symptomatic AFIB/AFL who are currently receiving sotalol for the maintenance of normal sinus rhythm should be transferred to BETAPACE AF^™ because of the significant differences in labeling (i.e., patient package insert for BETAPACE AF^™, dosing administration, and safety information).

Sorine^® (Sotalol HCl) Tablets are white, capsule-shaped, scored tablets with the following tablet deboss, respectively:

Sorine^® (Sotalol HCl) Tablets are available as follows:

Store at controlled room temperature, between 15°-30°C (59°-86°F) (see USP).

Dispense in a well-closed container (USP).

BETAPACE AF is a registered trademark of Berlex Laboratories, Inc.

Manufactured by
UPSHER-SMITH LABORATORIES, INC., Minneapolis, MN 55447

Rev. 0203