İHALE DÜNYASI
İHALE DÜNYASI
Sotalol Hydrochloride Tablets, USP (AF) is 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]methanesulfonamide monohydrochloride. The molecular formula is C 12 H 20 N 2 O 3 S*HCl and is represented by the following structural formula: Sotalol Hydrochloride Tablets, USP (AF) contain the following inactive ingredients: microcrystalline cellulose, lactose monohydrate, pregelatinized starch, stearic acid, magnesium stearate and colloidal silicon dioxide. structural formula
Sotalol AF are 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. Because Sotalol AF can cause life-threatening ventricular arrhythmias, it should be reserved for patients in whom AFIB/AFL is highly symptomatic. Patients with paroxysmal AFIB whose AFIB/AFL that is easily reversed (by Valsalva maneuver, for example) should usually not be given Sotalol AF (see WARNINGS ). In general, antiarrhythmic therapy for AFIB/AFL aims to prolong the time in normal sinus rhythm. Recurrence is expected in some patients (see Clinical Studies ). Sotalol is also indicated for the treatment of documented life-threatening ventricular arrhythmias and is marketed under the brand name Betapace(R) (sotalol hydrochloride) . Sotalol hydrochloride tablets, however, must not be substituted for sotalol hydrochloride tablets (AF) because of significant differences in labeling (i.e., patient package insert, dosing administration and safety information).
Dosing and Administration in Adults Therapy with Sotalol AF must be initiated (and, if necessary, titrated) in a setting that provides continuous electrocardiographic (ECG) monitoring and in the presence of personnel trained in the management of serious ventricular arrhythmias. Patients should continue to be monitored in this way for a minimum of 3 days on the maintenance dose. In addition, patients should not be discharged within 12 hours of electrical or pharmacological conversion to normal sinus rhythm. The QT interval is used to determine patient eligibility for Sotalol AF treatment and for monitoring safety during treatment. The baseline QT interval must be ?450 msec in order for a patient to be started on Sotalol AF therapy. During initiation and titration, the QT interval should be monitored 2 to 4 hours after each dose. If the QT interval prolongs to 500 msec or greater, the dose must be reduced or the drug discontinued. The dose of Sotalol AF must be individualized according to calculated creatinine clearance. In patients with a creatinine clearance >60 mL/min Sotalol AF is administered twice daily (BID) while in those with a creatinine clearance between 40 and 60 mL/min, the dose is administered once daily (QD). In patients with a creatinine clearance less than 40 mL/min Sotalol AF is contraindicated. The recommended initial dose of Sotalol AF is 80 mg and is initiated as shown in the dosing algorithm described below. The 80 mg dose can be titrated upward to 120 mg during initial hospitalization or after discharge on 80 mg in the event of recurrence, by rehospitalization and repeating the same steps used during the initiation of therapy (see Upward Titration of Dose ). Patients with atrial fibrillation should be anticoagulated according to usual medical practice. Hypokalemia should be corrected before initiation of Sotalol AF therapy (see WARNINGS , Ventricular Arrhythmia ). Patients to be discharged on Sotalol AF therapy from an in-patient setting should have an adequate supply of Sotalol AF, to allow uninterrupted therapy until the patient can fill a Sotalol AF prescription. Initiation of Sotalol AF Therapy Step 1. Electrocardiographic assessment: Prior to administration of the first dose, the QT interval must be determined using an average of 5 beats. If the baseline QT is greater than 450 msec (JT ?330 msec if QRS over 100 msec), Sotalol AF is contraindicated. Step 2 . Calculation of creatinine clearance: Prior to the administration of the first dose, the patient's creatinine clearance should be calculated using the following formula: When serum creatinine is given in ?mol/L, divide the value by 88.4 (1 mg/dL = 88.4 ?mol/L). Step 3 . Starting Dose: The starting dose of Sotalol AF is 80 mg twice daily (BID) if the creatinine clearance is >60 mL/min, and 80 mg once daily (QD) if the creatinine clearance is 40 to 60 mL/min. If the creatinine clearance is <40 mL/min Sotalol AF is contraindicated. Step 4 . Administer the appropriate daily dose of Sotalol AF and begin continuous ECG monitoring with QT interval measurements 2 to 4 hours after each dose. Step 5 . If the 80 mg dose level is tolerated and the QT interval remains <500 msec after at least 3 days (after 5 or 6 doses if patient receiving QD dosing), the patient can be discharged. Alternatively, during hospitalization, the dose can be increased to 120 mg bid and the patient followed for 3 days on this dose (followed for 5 or 6 doses if patient receiving QD doses). The steps described above are summarized in the following diagram: Place Patient on Telemetry Check Baseline QT If QT >450 msec Sotalol AF is CONTRAINDICATED If QT ?450 msec, proceed Calculate Creatine Clearance (Clcr) If Clcr is <40 mL/min Sotalol AF is CONTRAINDICATED If Clcr is 40 to 60 mL/min start Sotalol AF 80 mg QD If Clcr is >60 mL/min start Sotalol AF 80 mg BID Monitor QT 2 to 4 hours after each dose. If QT ?500 msec discontinue Sotalol AF If QT <500 msec after 3 days (after 5th or 6th dose if patient receiving QD dosing) discharge patient on current treatment. Alternatively, during hospitalization, the dose can be increased to 120 mg BID and the patient followed for 3 days on this dose (followed for 5 or 6 doses if patient receiving QD doses). formula Upward Titration of Dose If the 80 mg dose level (given BID or QD depending upon the creatinine clearance) does not reduce the frequency of relapses of AFIB/AFL and is tolerated without excessive QT interval prolongation (i.e., ?520 msec), the dose level may be increased to 120 mg (BID or QD depending upon the creatinine clearance). As proarrhythmic events can occur not only at initiation of therapy, but also with each upward dosage adjustment, Steps 2 through 5 used during initiation of Sotalol AF therapy should be followed when increasing the dose level. In the U.S. multicenter dose-response study, the 120 mg dose (BID or QD) was found to be the most effective in prolonging the time to ECG documented symptomatic recurrence of AFIB/AFL. If the 120 mg dose does not reduce the frequency of early relapse of AFIB/AFL and is tolerated without excessive QT interval prolongation (?520 msec), an increase to 160 mg (BID or QD depending upon the creatinine clearance), can be considered. Steps 2 through 5 used during the initiation of therapy should be used again to introduce such an increase. Maintenance of Sotalol AF Therapy Renal function and QT should be re-evaluated regularly if medically warranted. If QT is 520 msec or greater (JT 430 msec or greater if QRS is > 100 msec), the dose of Sotalol AF therapy should be reduced and patients should be carefully monitored until QT returns to less than 520 msec. If the QT interval is ?520 msec while on the lowest maintenance dose level (80 mg) the drug should be discontinued. If renal function deteriorates, reduce the daily dose in half by administering the drug once daily as described in Initiation of Sotalol AF Therapy, Step 3. Special Considerations The maximum recommended dose in patients with a calculated creatinine clearance greater than 60 mL/min is 160 mg BID, doses greater than 160 mg BID have been associated with an increased incidence of Torsade de Pointes and are not recommended. A patient who misses a dose should NOT double the next dose. The next dose should be taken at the usual time. Dosing and Administration in Children As in adults the following precautionary measures should be considered when initiating sotalol treatment in children: initiation of treatment in the hospital after appropriate clinical assessment; individualized regimen as appropriate; gradual increase of doses if required; careful assessment of therapeutic response and tolerability; and frequent monitoring of the QT c interval and heart rate. For children aged about 2 years and greater For children aged about 2 years and greater, with normal renal function, doses normalized for body surface area are appropriate for both initial and incremental dosing. Since the Class III potency in children (see CLINICAL PHARMACOLOGY ) is not very different from that in adults, reaching plasma concentrations that occur within the adult dose range is an appropriate guide. From pediatric pharmacokinetic data the following is recommended. For initiation of treatment, 30 mg/m 2 three times a day (90 mg/m 2 total daily dose) is approximately equivalent to the initial 160 mg total daily dose for adults. Subsequent titration to a maximum of 60 mg/m 2 (approximately equivalent to the 360 mg total daily dose for adults) can then occur. Titration should be guided by clinical response, heart rate and QT c , with increased dosing being preferably carried out in-hospital. At least 36 hours should be allowed between dose increments to attain steady- state plasma concentrations of sotalol in patients with age-adjusted normal renal function. For children aged about 2 years or younger For children aged about 2 years or younger, the above pediatric dosage should be reduced by a factor that depends heavily upon age, as shown in the following graph, age plotted on a logarithmic scale in months. For a child aged 20 months, the dosing suggested for children with normal renal function aged 2 years or greater should be multiplied by about 0.97; the initial starting dose would be (30 X 0.97)=29.1 mg/m 2 , administered three times daily. For a child aged 1 month, the starting dose should be multiplied by 0.68; the initial starting dose would be (30 X 0.68)=20 mg/m 2 , administered three times daily. For a child aged about 1 week, the initial starting dose should be multiplied by 0.3; the starting dose would be (30 X 0.3)=9 mg/m 2 . Similar calculations should be made for increased doses as titration proceeds. Since the half-life of sotalol decreases with decreasing age (below about 2 years), time to steady-state will also increase. Thus, in neonates the time to steady-state may be as long as a week or longer. In all children, individualization of dosage is required. As in adults Sotalol AF (sotalol hydrochloride) should be used with particular caution in children if the QT c is greater than 500 msec on therapy and serious consideration should be given to reducing the dose or discontinuing therapy when QT c exceeds 550 msec. The use of Sotalol AF in children with renal impairment has not been investigated. Sotalol elimination is predominantly via the kidney in the unchanged form. Use of sotalol in any age group with decreased renal function should be at lower doses or at increased intervals between doses. Monitoring of heart rate and QT c is more important and it will take much longer to reach steady-state with any dose and/or frequency of administration. Transfer to Sotalol AF from Sotalol Patients with a history of symptomatic AFIB/AFL who are currently receiving sotalol the maintenance of normal sinus should be transferred to Sotalol AF because of the significant differences in labeling (i.e., patient package insert, dosing administration, and safety information). Transfer to Sotalol AF from Other Antiarrhythmic Agents Before starting Sotalol AF, previous antiarrhythmic therapy should generally be withdrawn under careful monitoring for a minimum of 2 to 3 plasma half-lives if the patient's clinical condition permits (see Drug Interactions ). Treatment has been initiated in some patients receiving I.V. lidocaine without ill effect. After discontinuation of amiodarone, Sotalol AF should not be initiated until the QT interval is normalized (see WARNINGS ). Preparation of Extemporaneous Oral Solution Sotalol AF Syrup 5 mg/mL can be compounded using Simple Syrup containing sucrose 85%w/v, purified water, citric acid and 0.1% Methyl Paraben as preservative: Measure 120 mL of Simple Syrup Transfer the syrup to a 150 mL amber plastic (polyethylene terephthalate [PET]) prescription bottle. NOTE: An oversized bottle is used to allow for a headspace, so that there will be more effective mixing during shaking of the bottle. Add five (5) Sotalol AF 120 mg tablets to the bottle. These tablets are added intact; it is not necessary to crush the tablets. NOTE: The addition of the tablets can also be done first. The tablets can also be crushed if preferred. If the tablets are crushed, care should be taken to transfer the entire quantity of tablet powder into the bottle containing the syrup. Shake the bottle to wet the entire surface of the tablets. If the tablets have been crushed, shake the bottle until the endpoint is achieved. Allow the tablets to hydrate for approximately two hours. After at least two hours have elapsed, shake the bottle intermittently over the course of at least another two hours until the tablets are completely disintegrated. NOTE: The tablets can be allowed to hydrate overnight to simplify the disintegration process. The endpoint is achieved when a dispersion of fine particles in the syrup is obtained. This compounding procedure results in a solution containing 5 mg/mL of sotalol HCl. The fine solid particles are the water-insoluble inactive ingredients of the tablets. This extemporaneously prepared oral solution of sotalol HCl (with suspended inactive particles) must be shaken well prior to administration. This is to ensure that the amount of inactive solid particles per dose remains constant throughout the duration of use. Stability studies indicate that the suspension is stable when stored at controlled room temperature (15° to 30°C/59° to 86°F) and ambient humidity for three (3) months. graph
Sotalol AF is contraindicated in patients with sinus bradycardia (<50 bpm during waking hours), sick sinus syndrome or second and third degree AV block (unless a functioning pacemaker is present), congenital or acquired long QT syndromes, baseline QT interval >450 msec, cardiogenic shock, uncontrolled heart failure, hypokalemia (<4 meq/L), creatinine clearance <40 mL/min, bronchial asthma and previous evidence of hypersensitivity to sotalol.
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 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 AF Total Daily Dose Body System/ Adverse Event (Preferred Term) N=282 160 to 240 >240 to 320 N=153 N=122 CARDIOVASCULAR 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 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 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 Sotalol 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 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 Sotalol AF during investigational use and foreign marketing experience.
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 s tarted 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 firs t dose of Sotalol AF. For detailed instructions regarding dose selection, see DOSAGE AND ADMINISTRATION . Proarrhythmia in Atri al 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 AF (Daily Dose) Any Dose >320 mg/day ?320 mg/day ?240 mg/day Placebo (N=659) (N=62) (N=597) (N=340) (N=358) n(%) n(%) n(%) n(%) n(%) Torsade de 4(0.6%) 2(3.2%) 2(0.3%) 1(0.3%) 0 Pointes 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 (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 (QTc) 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) ? * highest on- therapy value ? ( ) Number of patients assessed 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 Pointes event, so that the table overstates the predictive value of a high QT c . Table 7 Relationship Between QT c Interval Prolongation and Torsade de Pointes On-Therapy QT c Interval (msec) Incidence of Torsade de Pointes Change in QT c Interval From Baseline (msec) Incidence of Torsade de Pointes less than 500 1.3% (1787) * less than 65 1.6% (1516) * 500 to 525 3.4% (236) * 65 to 80 3.2% (158) * 525 to 550 5.6% (125) * 80 to 100 4.1% (146) * >550 10.8% (157) * 100 to 30 5.2% (115) * >130 7.1% (99) * * ( ) Number of patients assessed 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 (see OVERDOSAGE ). 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. Use with Drugs that Prolong QT Interval and Antiarrhythmic Agents The use of Sotalol AF in conjunction with other drugs that prolong the QT interval has not been studied and is not recommended. Such drugs include many antiarrhythmics, some phenothiazines, bepridil, tricyclic antidepressants, and certain oral macrolides. Class I or Class III antiarrhythmic agents should be withheld for at least three half-lives prior to dosing with Sotalol AF. In clinical trials, Sotalol AF was not administered to patients previously treated with oral amiodarone for >1 month in the previous three months. Class Ia antiarrhythmic drugs, such as disopyramide, quinidine and procainamide and other Class III drugs (e.g., amiodarone) are not recommended as concomitant therapy with Sotalol AF because of their potential to prolong refractoriness (see WARNINGS ). There is only limited experience with the concomitant use of Class Ib or Ic antiarrhythmics. Congestive Heart Failure Sympathetic stimulation is necessary in supporting circulatory function in congestive heart failure, and beta-blockade carries the potential hazard of further depressing myocardial contractility and precipitating more severe failure. In patients who have heart failure controlled by digitalis and/or diuretics, Sotalol AF should be administered cautiously. Both digitalis and sotalol slow AV conduction. As with all beta-blockers, caution is advised when initiating therapy in patients with any evidence of left ventricular dysfunction. In a pooled data base of four placebo-controlled AFIB/AFL and PSVT studies, new or worsening CHF occurred during therapy with Sotalol AF in 5 (1.2%) of 415 patients. In these studies patients with uncontrolled heart failure were excluded (i.e., NYHA Functional Classes III or IV). In other premarketing sotalol studies, new or worsened congestive heart failure (CHF) occurred in 3.3% (n=3257) of patients and led to discontinuation in approximately 1% of patients receiving sotalol. The incidence was higher in patients presenting with sustained ventricular tachycardia/fibrillation (4.6%, n=1363), or a prior history of heart failure (7.3%, n=696). Based on a life-table analysis, the one-year incidence of new or worsened CHF was 3% in patients without a prior history and 10% in patients with a prior history of CHF. NYHA Classification was also closely associated to the incidence of new or worsened heart failure while receiving sotalol (1.8% in 1395 Class I patients, 4.9% in 1254 Class II patients and 6.1% in 278 Class III or IV patients). Electrolyte Disturbances Sotalol AF should not be used in patients with hypokalemia or hypomagnesemia prior to correction of imbalance, as these conditions can exaggerate the degree of QT prolongation, and increase the potential for Torsade de Pointes. Special attention should be given to electrolyte and acid-base balance in patients experiencing severe or prolonged diarrhea or patients receiving concomitant diuretic drugs. Bradycardia/Heart Block The incidence of bradycardia (as determined by the investigators) in the supraventricular arrhythmia population treated with Sotalol AF (N = 415) was 13%, and led to discontinuation in 2.4% of patients. Bradycardia itself increases the risk of Torsade de Pointes. Recent Acute MI Sotalol has been used in a controlled trial following an acute myocardial infarction without evidence of increased mortality (see Safety in Patients with Structural Heart Disease ). Although specific studies of its use in treating atrial arrhythmias after infarction have not been conducted, the usual precautions regarding heart failure, avoidance of hypokalemia, bradycardia or prolonged QT interval apply. The following warnings are related to the beta-blocking activity of Sotalol AF. Abrupt Withdrawal Hypersensitivity to catecholamines has been observed in patients withdrawn from beta-blocker therapy. Occasional cases of exacerbation of angina pectoris, arrhythmias and, in some cases, myocardial infarction have been reported after abrupt discontinuation of beta-blocker therapy. Therefore, it is prudent when discontinuing chronically administered Sotalol AF, particularly in patients with ischemic heart disease, to carefully monitor the patient and consider the temporary use of an alternate beta- blocker if appropriate. If possible, the dosage of Sotalol AF should be gradually reduced over a period of one to two weeks. If angina or acute coronary insufficiency develops, appropriate therapy should be instituted promptly. Patients should be warned against interruption or discontinuation of therapy without the physician's advice. Because coronary artery disease is common and may be unrecognized in patients receiving Sotalol AF, abrupt discontinuation in patients with arrhythmias may unmask latent coronary insufficiency. Non-Allerg ic Bronchospasm (e.g., chronic bronchitis and emphysema) PATIENTS WITH BRONCHOSPASTIC D ISEASES SHOULD IN GENERAL NOT RECEIVE BETA-BLOCKERS. It is prudent, if Sotalol AF (sotalol hydrochloride) is to be administered, to use the smallest effective dose, so that inhibition of bronchodilation produced by endogenous or exogenous catecholamine stimulation of beta 2 receptors may be minimized. Anaphylaxis While taking beta-blockers, patients with a history of anaphylactic reaction to a variety of allergens may have a more severe reaction on repeated challenge, either accidental, diagnostic or therapeutic. Such patients may be unresponsive to the usual doses of epinephrine used to treat the allergic reaction. Major Surgery Chronically administered beta-blocking therapy should not be routinely withdrawn prior to major surgery, however the impaired ability of the heart to respond to reflex adrenergic stimuli may augment the risks of general anesthesia and surgical procedures. Diabetes In patients with diabetes (especially labile diabetes) or with a history of episodes of spontaneous hypoglycemia, Sotalol AF should be given with caution since beta-blockade may mask some important premonitory signs of acute hypoglycemia; e.g., tachycardia. Sick Sinus Syndrome Sotalol AF should be used only with extreme caution in patients with sick sinus syndrome associated with symptomatic arrhythmias, because it may cause sinus bradycardia, sinus pauses or sinus arrest. In patients with AFIB and sinus node dysfunction, the risk of Torsade de Pointes with Sotalol AF therapy is increased, especially after cardioversion. Bradycardia following cardioversion in these patients is associated with QT c interval prolongation which is augmented due to the reverse use dependence of the Class III effects of Sotalol AF. Patients with AFIB/AFL associated with the sick sinus syndrome may be treated with Sotalol AF if they have an implanted pacemaker for control of bradycardia symptoms. Thyrotoxicosis Beta-blockade may mask certain clinical signs (e.g., tachycardia) of hyperthyroidism. Patients suspected of developing thyrotoxicosis should be managed carefully to avoid abrupt withdrawal of beta-blockade which might be followed by an exacerbation of symptoms of hyperthyroidism, including thyroid storm. The beta-blocking effects of Sotalol AF may be useful in controlling heart rate in AFIB associated with thyrotoxicosis but no study has been conducted to evaluate this. --- BOXED WARNING: To minimize the risk of induced arrhythmia, patients initiated or re-initiated on Sotalol Hydrochloride Tablets (AF) should be placed for a minimum of three days (on their maintenance dose) in a facility that can provide cardiac resuscitation, continuous electrocardiographic monitoring and calculations of creatinine clearance. For detailed instructions regarding dose selection, and special cautions for people with renal impairment, see DOSAGE AND ADMINISTRATION . Sotalol is also indicated for the treatment of documented life threatening ventricular arrhythmias and is marketed under the brand name Betapace (R) (sotalol hydrochloride tablets). Sotalol hydrochloride tablets, however, should not be substituted for sotalol hydrochloride tablets (AF) because of significant differences in labeling (i.e., patient package insert, dosing administration and safety information). | This summary contains important patient information that has been reviewed and approved by the U.S. Food and Drug Administration. This summary is not meant to take the place of your doctor's instructions. Read this patient information carefully before you start taking Sotalol AF. Each time you get a refill, you will receive patient information. Be sure to read it because it may contain new information that you need to know.
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.