SOTALOL HYDROCHLORIDE

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Overview

What is SOTALOL HYDROCHLORIDE?

Sotalol is an antiarrhythmic drug with Class II (beta-adrenoreceptor blocking) and Class III (cardiac action potential duration prolongation) properties. It is supplied as a light-blue, 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-[l-hydroxy-2-[(l-methylethyl)amino]ethyl]phenyl]methane-sulfonamide monohydrochloride. The molecular formula is CHN0S•HCl and is represented by the following structural formula:

Each tablet for oral administration contains 80 mg, 120 mg, 160 mg or 240 mg of sotalol hydrochloride. In addition, each tablet contains the following inactive ingredients: anhydrous lactose, colloidal silicon dioxide, corn starch, magnesium stearate, microcrystalline cellulose, pregelatinized starch, sodium starch glycolate, stearic acid, FD&C Blue #2 Aluminum Lake.

What does SOTALOL HYDROCHLORIDE look like?

What are the available doses of SOTALOL HYDROCHLORIDE?

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What should I talk to my health care provider before I take SOTALOL HYDROCHLORIDE?

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How should I use SOTALOL HYDROCHLORIDE?

Sotalol is 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 ), 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 sotalol 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 multicenter open-label long-term study of sotalol in patients with life-threatening ventricular arrhythmias which had proved 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™. Sotalol 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.

As with other antiarrhythmic agents, sotalol should be initiated and doses increased in a hospital with facilities for cardiac rhythm monitoring and assessment (see ). Sotalol should be administered only after appropriate clinical assessment (see ), and the dosage of sotalol 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.

What interacts with SOTALOL HYDROCHLORIDE?

Sotalol is 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 heart failure, and previous evidence of hypersensitivity to sotalol.

What are the warnings of SOTALOL HYDROCHLORIDE?

Mortality

The National Heart, Lung, And Blood Institute's Cardiac Arrhythmia Suppression Trial I (CAST I) was a long-term, multi-center double-blind study in patients with symptomatic, non-life-threatening ventricular arrhythmias, 1 to 103 weeks after acute myocardial infarction. Patients in CAST I were randomized to receive placebo or individually optimized doses of encainide, flecainide, or moricizine. The Cardiac Arrhythmia Suppression Trial II (CAST II) was similar, except that the recruited patients had had their index infarction 4 to 90 days before randomization, patients with left ventricular ejection fractions greater than 40% were not admitted, and the randomized regimens were limited to placebo and moricizine.

CAST I was discontinued after an average time-on-treatment of 10 months, and CAST II was discontinued after an average time-on-treatment of 18 months. As compared to placebo treatment, all three active therapies were associated with increases in short-term (14 day) mortality, and encainide and flecainide were associated with significant increases in longer-term mortality as well. The longer-term mortality rate associated with moricizine treatment could not be statistically distinguished from that of placebo.

The applicability of these results to other populations (e.g., those without recent myocardial infarction) and to other than Class I antiarrhythmic agents is uncertain. Sotalol is devoid of Class I effects, and in a large (n=1,456) controlled trial in patients with a recent myocardial infarction, who did not necessarily have ventricular arrhythmias, sotalol did not produce increased mortality at doses up to 320 mg/day (see ). On the other hand, in the large post-infarction study using a non-titrated initial dose of 320 mg once daily and in a second small randomized trial in high-risk post-infarction patients treated with high doses (320 mg BID), there have been suggestions of an excess of early sudden deaths.

Proarrhythmia

Like other antiarrhythmic agents, sotalol can provoke new or worsened ventricular arrhythmias in some patients, including sustained ventricular tachycardia or ventricular fibrillation, with potentially fatal consequences. Because of its effect on cardiac repolarization (QT interval prolongation), torsade de pointes, a polymorphic ventricular tachycardia with prolongation of the QT interval and a shifting electrical axis is the most common form of proarrhythmia associated with sotalol, occurring in about 4% of high risk (history of sustained VT/VF) patients. The risk of torsade de pointes progressively increases with prolongation of QT interval, and is worsened also by reduction in heart rate and reduction in serum potassium (See .)

Because of the variable temporal recurrence of arrhythmias, it is not always possible to distinguish between a new or aggravated arrhythmic event and the patient's underlying rhythm disorder. (Note, however, that torsade de pointes is usually a drug-induced arrhythmia in people with an initially normal QT). Thus, the incidence of drug-related events cannot be precisely determined, so that the occurrence rates provided must be considered approximations. Note also that drug-induced arrhythmias may often not be identified, particularly if they occur long after starting the drug, due to less frequent monitoring. It is clear from the NIH-sponsored CAST (see ) that some antiarrhythmic drugs can cause increased sudden death mortality, presumably due to new arrhythmias or asystole, that do not appear early in treatment but that represent a sustained increased risk.

Overall in clinical trials with sotalol, 4.3% of 3257 patients experienced a new or worsened ventricular arrhythmia. Of this 4.3%, there was new or worsened sustained ventricular tachycardia in approximately 1% of patients and torsade de pointes in 2.4%. 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 were dose related, as is the prolongation of QT (QT) interval, as shown in the table below.

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 interval (see table below) 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 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 ). 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.

Nonetheless, sotalol should be used with particular caution if the QT is greater than 500 msec on-therapy and serious consideration should be given to reducing the dose or discontinuing therapy when the QT exceeds 550 msec. Due to the multiple risk factors associated with torsade de pointes, however, caution should be exercised regardless of the QT interval. The table below relates the incidence of torsade de pointes to on-therapy QT and change in QT from baseline. It should be noted, however, that the highest on-therapy QT 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.

**Percent Incidence of Torsade de Pointes and Mean QT Interval by Dose For Patients With Sustained VT/VF**
Daily Dose (mg)	Incidence of Torsade de Pointes	Mean QT (msec)
( ) number of patients assessed
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
On-Therapy QT Interval (msec)	Incidence of Torsade de Pointes		Change in QT Interval From Baseline (msec)	Incidence of Torsade de Pointes
<500	1.3% (1787)		<65	1.6% (1516)
500-525	3.4% (236)		65-80	3.2% (158)
525-550	5.6% (125)		80-100	4.1% (146)
>550	10.8% (157)		100-130	5.2% (115)
			>130	7.1% (99)

Proarrhythmic events must be anticipated not only on initiating therapy, but with every upward dose adjustment.

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 congestive heart failure controlled by digitalis and/or diuretics, sotalol 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 premarketing 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 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.

Conduction Disturbances

Excessive prolongation of the QT interval (>550 msec) can promote serious arrhythmias and should be avoided (see above). Sinus bradycardia (heart rate less than 50 bpm) occurred in 13% of patients receiving sotalol in clinical trials, and led to discontinuation in about 3% of patients. Bradycardia itself increases the risk of torsade de pointes. Sinus pause, sinus arrest and sinus node dysfunction occur in less than 1% of patients. The incidence of 2- or 3-degree AV block is approximately 1%.

Recent Acute MI

Sotalol can be used safely and effectively in the long-term treatment of life-threatening ventricular arrhythmias following a myocardial infarction. However, experience in the use of sotalol to treat cardiac arrhythmias in the early phase of recovery from acute MI is limited and at least at high initial doses is not reassuring. (See .) In the first 2 weeks post-MI caution is advised and careful dose titration is especially important, particularly in patients with markedly impaired ventricular function.

The following warnings are related to the beta-blocking activity of sotalol.

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, 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 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, abrupt discontinuation in patients with arrhythmias may unmask latent coronary insufficiency.

Non-Allergic Bronchospasm

PATIENTS WITH BRONCHOSPASTIC DISEASES SHOULD IN GENERAL NOT RECEIVE BETA-BLOCKERS.

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.

Anesthesia

The management of patients undergoing major surgery who are being treated with beta-blockers is controversial. Protracted severe hypotension and difficulty in restoring and maintaining normal cardiac rhythm after anesthesia have been reported in patients receiving beta-blockers.

Diabetes

In patients with diabetes (especially labile diabetes) or with a history of episodes of spontaneous hypoglycemia, sotalol should be given with caution since beta-blockade may mask some important premonitory signs of acute hypoglycemia; e.g., tachycardia.

Sick Sinus Syndrome

Sotalol 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.

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.

What are the precautions of SOTALOL HYDROCHLORIDE?

Renal Impairment

Sotalol is mainly eliminated principally via the kidneys through glomerular filtration and to a small degree by tubular secretion. There is a direct relationship between renal function, as measured by serum creatinine or creatinine clearance, and the elimination rate of sotalol. Guidance for dosing in conditions of renal impairment can be found under

Drug Interactions

Sotalol is primarily eliminated by renal excretion; therefore, drugs that are metabolized by CYP450 are not expected to alter the pharmacokinetics of sotalol. Sotalol is not expected to inhibit or induce any CYP450 enzymes; therefore, it is not expected to alter the PK of drugs that are metabolized by these enzymes.

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, because of their potential to prolong refractoriness (see ). There is only limited experience with the concomitant use of Class Ib or Ic antiarrhythmics. Additive Class II effects would also be anticipated with the use of other beta-blocking agents concomitantly with sotalol.

Single and multiple doses of sotalol do not substantially affect serum digoxin levels. 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.

Sotalol 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.

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 plus a catecholamine depletor should therefore be closely monitored for evidence of hypotension and or marked bradycardia which may produce syncope.

Hyperglycemia may occur, and the dosage of insulin or antidiabetic drugs may require adjustment. Symptoms of hypoglycemia may be masked.

Beta-agonists such as salbutamol, terbutaline and isoprenaline may have to be administered in increased dosages when used concomitantly with sotalol.

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.

No pharmacokinetic interactions were observed with hydrochlorothiazide or warfarin.

Administration of sotalol within 2 hours of antacids containing aluminum oxide and magnesium hydroxide should be avoided because it may result in a reduction in C 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 has no effect on the pharmacokinetics or pharmacodynamics of sotalol.

Sotalol should be administered with caution in conjunction with other drugs known to prolong the QT interval such as Class I and Class III antiarrhythmic agents, phenothiazines, tricyclic antidepressants, astemizole, bepridil, certain oral macrolides, and certain quinolone antibiotics (see ).

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, Mutagenicity, Impairment of Fertility

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/m) 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/m).

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) 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), respectively, did not reveal any teratogenic potential associated with sotalol HCl. In rabbits, a high dose of sotalol HCl (160 mg/kg/day) at 16 times the MRHD as mg/kg (6 times the MRHD as mg/m) produced a slight increase in fetal death likely due to maternal toxicity. Eight times the maximum dose (80 mg/kg/day or 3 times the MRHD as mg/m) did not result in an increased incidence of fetal deaths. In rats, 1000 mg/kg/day sotalol HCl, 100 times the MRHD (18 times the MRHD as mg/m), increased the number of early resorptions, while at 14 times the maximum dose (2.5 times the MRHD as mg/m), no increase in early resorptions was noted. However, animal reproduction studies are not always predictive of human response.

Although there are no adequate and well-controlled studies in pregnant women, sotalol HCl has been shown to cross the placenta, and is found in amniotic fluid. There has been a report of subnormal birth weight with sotalol. Therefore, sotalol should be used during pregnancy only if the potential benefit outweighs the potential risk.

Nursing Mothers

Sotalol is excreted in the milk of laboratory animals and has been reported to be present in human milk. Because of the potential for adverse reactions in nursing infants from sotalol, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

The safety and effectiveness of sotalol in pediatric patients have not been established. However, information relating to the clinical pharmacology in pediatric patients is approved for Berlex Laboratories' sotalol hydrochloride tablets. Due to Berlex's marketing exclusivity rights, this drug product is not labeled for pediatric use.

What are the side effects of SOTALOL HYDROCHLORIDE?

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 ), 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 lists 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 multicenter trial of 25 patients with SVT and/or VT receiving daily doses of 30, 90 and 210 mg/m 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/m daily, was discontinued because of increased frequency of sinus pauses/bradycardia. Additional cardiovascular AEs were seen at the 90 and 210 mg/m 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≥525 msec were seen in 2 patients at the 210 mg/m 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.

**Incidence (%) of Adverse Events and Discontinuations**

	BodySystem	160 mg(n=832)	240 mg(n=263)	320 mg(n=835)	480 mg(n=459)	640 mg(n=324)	Any Dose(n=1292)	% PatientsDiscontinued(n=1292)
Body as a whole
infection	1	2	2	2	3	4	<1
fever	1	2	3	2	2	4	<1
localized pain	1	1	2	2	2	3	<1
Cardiovascular
dyspnea	5	8	11	15	15	21	2
bradycardia	8	8	9	7	5	16	2
chest pain	4	3	10	10	14	16	<1
palpitation	3	3	8	9	12	14	<1
edema	2	2	5	3	5	8	1
ECG abnormal	4	2	4	2	2	7	1
hypotension	3	4	3	2	3	6	2
proarrhythmia	<1	<1	2	4	5	5	3
syncope	1	1	3	2	5	5	1
heart failure	2	3	2	2	2	5	1
presyncope	1	2	2	4	3	4	<1
peripheral vascular disorder	1	2	1	1	2	3	<1
cardiovascular disorder	1	<1	2	2	2	3	<1
vasodilation	1	<1	1	2	1	3	<1
AICD discharge	<1	2	2	2	2	3	<1
hypertension	<1	1	1	1	2	2	<1
Nervous
fatigue	5	8	12	12	13	20	2
dizziness	7	6	11	11	14	20	1
asthenia	4	5	7	8	10	13	1
light-headed	4	3	6	6	9	12	1
headache	3	2	4	4	4	8	<1
sleep problem	1	1	5	5	6	8	<1
perspiration	1	2	3	4	5	6	<1
altered consciousness	2	3	1	2	3	4	<1
depression	1	2	2	2	3	4	<1
paresthesia	1	1	2	3	2	4	<1
anxiety	2	2	2	3	2	4	<1
mood change	<1	<1	1	3	2	3	<1
appetite disorder	1	2	2	1	3	3	<1
stroke	<1	<1	1	1	<1	1	<1
Digestive
nausea/vomiting	5	4	4	6	6	10	1
diarrhea	2	3	3	3	5	7	<1
dyspepsia	2	3	3	3	3	6	<1
abdominal pain	<1	<1	2	2	2	3	<1
colon problem	2	1	1	<1	2	3	<1
flatulence	1	<1	1	1	2	2	<1
Respiratory
pulmonary problem	3	3	5	3	4	8	<1
upper respiratory tract problem	1	1	3	4	3	5	<1
asthma	1	<1	1	1	1	2	<1
Urogenital
genitourinary disorder	1	0	1	1	2	3	<1
sexual dysfunction	<1	1	1	1	3	2	<1
Metabolic
abnormal lab value	1	2	3	2	1	4	<1
weight change	1	1	1	<1	2	2	<1
Musculoskeletal
extremity pain	2	2	4	5	3	7	<1
back pain	1	<1	2	2	2	3	<1
Skin and Appendages
rash	2	3	2	3	4	5	<1
Hematologic
bleeding	1	<1	1	<1	2	2	<1
Special Senses
visual problem	1	1	2	4	5	5	<1

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 (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.

What should I look out for while using SOTALOL HYDROCHLORIDE?

Sotalol is 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 heart failure, and previous evidence of hypersensitivity to sotalol.

What might happen if I take too much SOTALOL HYDROCHLORIDE?

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

How should I store and handle SOTALOL HYDROCHLORIDE?

SOTALOL HYDROCHLORIDE TABLETS are available as follows:Sotalol hydrochloride tablets, 80 mg, light blue, capsule shaped, scored, debossed MP 514Bottles of 50 NDC 53489-288-02Bottles of 100 NDC 53489-288-01Bottles of 250 NDC 53489-288-03Bottles of 500 NDC 53489-288-05Bottles of 1000 NDC 53489-288-10Sotalol hydrochloride tablets, 120 mg, light blue, capsule shaped, scored, debossed MP 515Bottles of 50 NDC 53489-289-02Bottles of 100 NDC 53489-289-01Bottles of 250 NDC 53489-289-03Bottles of 500 NDC 53489-289-05Bottles of 1000 NDC 53489-289-10Sotalol hydrochloride tablets, 160 mg, light blue, capsule shaped, scored, debossed MP 516Bottles of 50 NDC 53489-290-02Bottles of 100 NDC 53489-290-01Bottles of 250 NDC 53489-290-03Bottles of 500 NDC 53489-290-05Bottles of 1000 NDC 53489-290-10Sotalol hydrochloride tablets, 240 mg, light blue, capsule shaped, scored, debossed MP 517Bottles of 50 NDC 53489-291-02Bottles of 100 NDC 53489-291-01Bottles of 250 NDC 53489-291-03Bottles of 500 NDC 53489-291-05Bottles of 1000 NDC 53489-291-10Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature]DISPENSE IN TIGHT, LIGHT-RESISTANT CONTAINER.SOTALOL HYDROCHLORIDE TABLETS are available as follows:Sotalol hydrochloride tablets, 80 mg, light blue, capsule shaped, scored, debossed MP 514Bottles of 50 NDC 53489-288-02Bottles of 100 NDC 53489-288-01Bottles of 250 NDC 53489-288-03Bottles of 500 NDC 53489-288-05Bottles of 1000 NDC 53489-288-10Sotalol hydrochloride tablets, 120 mg, light blue, capsule shaped, scored, debossed MP 515Bottles of 50 NDC 53489-289-02Bottles of 100 NDC 53489-289-01Bottles of 250 NDC 53489-289-03Bottles of 500 NDC 53489-289-05Bottles of 1000 NDC 53489-289-10Sotalol hydrochloride tablets, 160 mg, light blue, capsule shaped, scored, debossed MP 516Bottles of 50 NDC 53489-290-02Bottles of 100 NDC 53489-290-01Bottles of 250 NDC 53489-290-03Bottles of 500 NDC 53489-290-05Bottles of 1000 NDC 53489-290-10Sotalol hydrochloride tablets, 240 mg, light blue, capsule shaped, scored, debossed MP 517Bottles of 50 NDC 53489-291-02Bottles of 100 NDC 53489-291-01Bottles of 250 NDC 53489-291-03Bottles of 500 NDC 53489-291-05Bottles of 1000 NDC 53489-291-10Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature]DISPENSE IN TIGHT, LIGHT-RESISTANT CONTAINER.SOTALOL HYDROCHLORIDE TABLETS are available as follows:Sotalol hydrochloride tablets, 80 mg, light blue, capsule shaped, scored, debossed MP 514Bottles of 50 NDC 53489-288-02Bottles of 100 NDC 53489-288-01Bottles of 250 NDC 53489-288-03Bottles of 500 NDC 53489-288-05Bottles of 1000 NDC 53489-288-10Sotalol hydrochloride tablets, 120 mg, light blue, capsule shaped, scored, debossed MP 515Bottles of 50 NDC 53489-289-02Bottles of 100 NDC 53489-289-01Bottles of 250 NDC 53489-289-03Bottles of 500 NDC 53489-289-05Bottles of 1000 NDC 53489-289-10Sotalol hydrochloride tablets, 160 mg, light blue, capsule shaped, scored, debossed MP 516Bottles of 50 NDC 53489-290-02Bottles of 100 NDC 53489-290-01Bottles of 250 NDC 53489-290-03Bottles of 500 NDC 53489-290-05Bottles of 1000 NDC 53489-290-10Sotalol hydrochloride tablets, 240 mg, light blue, capsule shaped, scored, debossed MP 517Bottles of 50 NDC 53489-291-02Bottles of 100 NDC 53489-291-01Bottles of 250 NDC 53489-291-03Bottles of 500 NDC 53489-291-05Bottles of 1000 NDC 53489-291-10Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature]DISPENSE IN TIGHT, LIGHT-RESISTANT CONTAINER.SOTALOL HYDROCHLORIDE TABLETS are available as follows:Sotalol hydrochloride tablets, 80 mg, light blue, capsule shaped, scored, debossed MP 514Bottles of 50 NDC 53489-288-02Bottles of 100 NDC 53489-288-01Bottles of 250 NDC 53489-288-03Bottles of 500 NDC 53489-288-05Bottles of 1000 NDC 53489-288-10Sotalol hydrochloride tablets, 120 mg, light blue, capsule shaped, scored, debossed MP 515Bottles of 50 NDC 53489-289-02Bottles of 100 NDC 53489-289-01Bottles of 250 NDC 53489-289-03Bottles of 500 NDC 53489-289-05Bottles of 1000 NDC 53489-289-10Sotalol hydrochloride tablets, 160 mg, light blue, capsule shaped, scored, debossed MP 516Bottles of 50 NDC 53489-290-02Bottles of 100 NDC 53489-290-01Bottles of 250 NDC 53489-290-03Bottles of 500 NDC 53489-290-05Bottles of 1000 NDC 53489-290-10Sotalol hydrochloride tablets, 240 mg, light blue, capsule shaped, scored, debossed MP 517Bottles of 50 NDC 53489-291-02Bottles of 100 NDC 53489-291-01Bottles of 250 NDC 53489-291-03Bottles of 500 NDC 53489-291-05Bottles of 1000 NDC 53489-291-10Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature]DISPENSE IN TIGHT, LIGHT-RESISTANT CONTAINER.SOTALOL HYDROCHLORIDE TABLETS are available as follows:Sotalol hydrochloride tablets, 80 mg, light blue, capsule shaped, scored, debossed MP 514Bottles of 50 NDC 53489-288-02Bottles of 100 NDC 53489-288-01Bottles of 250 NDC 53489-288-03Bottles of 500 NDC 53489-288-05Bottles of 1000 NDC 53489-288-10Sotalol hydrochloride tablets, 120 mg, light blue, capsule shaped, scored, debossed MP 515Bottles of 50 NDC 53489-289-02Bottles of 100 NDC 53489-289-01Bottles of 250 NDC 53489-289-03Bottles of 500 NDC 53489-289-05Bottles of 1000 NDC 53489-289-10Sotalol hydrochloride tablets, 160 mg, light blue, capsule shaped, scored, debossed MP 516Bottles of 50 NDC 53489-290-02Bottles of 100 NDC 53489-290-01Bottles of 250 NDC 53489-290-03Bottles of 500 NDC 53489-290-05Bottles of 1000 NDC 53489-290-10Sotalol hydrochloride tablets, 240 mg, light blue, capsule shaped, scored, debossed MP 517Bottles of 50 NDC 53489-291-02Bottles of 100 NDC 53489-291-01Bottles of 250 NDC 53489-291-03Bottles of 500 NDC 53489-291-05Bottles of 1000 NDC 53489-291-10Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature]DISPENSE IN TIGHT, LIGHT-RESISTANT CONTAINER.SOTALOL HYDROCHLORIDE TABLETS are available as follows:Sotalol hydrochloride tablets, 80 mg, light blue, capsule shaped, scored, debossed MP 514Bottles of 50 NDC 53489-288-02Bottles of 100 NDC 53489-288-01Bottles of 250 NDC 53489-288-03Bottles of 500 NDC 53489-288-05Bottles of 1000 NDC 53489-288-10Sotalol hydrochloride tablets, 120 mg, light blue, capsule shaped, scored, debossed MP 515Bottles of 50 NDC 53489-289-02Bottles of 100 NDC 53489-289-01Bottles of 250 NDC 53489-289-03Bottles of 500 NDC 53489-289-05Bottles of 1000 NDC 53489-289-10Sotalol hydrochloride tablets, 160 mg, light blue, capsule shaped, scored, debossed MP 516Bottles of 50 NDC 53489-290-02Bottles of 100 NDC 53489-290-01Bottles of 250 NDC 53489-290-03Bottles of 500 NDC 53489-290-05Bottles of 1000 NDC 53489-290-10Sotalol hydrochloride tablets, 240 mg, light blue, capsule shaped, scored, debossed MP 517Bottles of 50 NDC 53489-291-02Bottles of 100 NDC 53489-291-01Bottles of 250 NDC 53489-291-03Bottles of 500 NDC 53489-291-05Bottles of 1000 NDC 53489-291-10Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature]DISPENSE IN TIGHT, LIGHT-RESISTANT CONTAINER.SOTALOL HYDROCHLORIDE TABLETS are available as follows:Sotalol hydrochloride tablets, 80 mg, light blue, capsule shaped, scored, debossed MP 514Bottles of 50 NDC 53489-288-02Bottles of 100 NDC 53489-288-01Bottles of 250 NDC 53489-288-03Bottles of 500 NDC 53489-288-05Bottles of 1000 NDC 53489-288-10Sotalol hydrochloride tablets, 120 mg, light blue, capsule shaped, scored, debossed MP 515Bottles of 50 NDC 53489-289-02Bottles of 100 NDC 53489-289-01Bottles of 250 NDC 53489-289-03Bottles of 500 NDC 53489-289-05Bottles of 1000 NDC 53489-289-10Sotalol hydrochloride tablets, 160 mg, light blue, capsule shaped, scored, debossed MP 516Bottles of 50 NDC 53489-290-02Bottles of 100 NDC 53489-290-01Bottles of 250 NDC 53489-290-03Bottles of 500 NDC 53489-290-05Bottles of 1000 NDC 53489-290-10Sotalol hydrochloride tablets, 240 mg, light blue, capsule shaped, scored, debossed MP 517Bottles of 50 NDC 53489-291-02Bottles of 100 NDC 53489-291-01Bottles of 250 NDC 53489-291-03Bottles of 500 NDC 53489-291-05Bottles of 1000 NDC 53489-291-10Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature]DISPENSE IN TIGHT, LIGHT-RESISTANT CONTAINER.SOTALOL HYDROCHLORIDE TABLETS are available as follows:Sotalol hydrochloride tablets, 80 mg, light blue, capsule shaped, scored, debossed MP 514Bottles of 50 NDC 53489-288-02Bottles of 100 NDC 53489-288-01Bottles of 250 NDC 53489-288-03Bottles of 500 NDC 53489-288-05Bottles of 1000 NDC 53489-288-10Sotalol hydrochloride tablets, 120 mg, light blue, capsule shaped, scored, debossed MP 515Bottles of 50 NDC 53489-289-02Bottles of 100 NDC 53489-289-01Bottles of 250 NDC 53489-289-03Bottles of 500 NDC 53489-289-05Bottles of 1000 NDC 53489-289-10Sotalol hydrochloride tablets, 160 mg, light blue, capsule shaped, scored, debossed MP 516Bottles of 50 NDC 53489-290-02Bottles of 100 NDC 53489-290-01Bottles of 250 NDC 53489-290-03Bottles of 500 NDC 53489-290-05Bottles of 1000 NDC 53489-290-10Sotalol hydrochloride tablets, 240 mg, light blue, capsule shaped, scored, debossed MP 517Bottles of 50 NDC 53489-291-02Bottles of 100 NDC 53489-291-01Bottles of 250 NDC 53489-291-03Bottles of 500 NDC 53489-291-05Bottles of 1000 NDC 53489-291-10Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature]DISPENSE IN TIGHT, LIGHT-RESISTANT CONTAINER.SOTALOL HYDROCHLORIDE TABLETS are available as follows:Sotalol hydrochloride tablets, 80 mg, light blue, capsule shaped, scored, debossed MP 514Bottles of 50 NDC 53489-288-02Bottles of 100 NDC 53489-288-01Bottles of 250 NDC 53489-288-03Bottles of 500 NDC 53489-288-05Bottles of 1000 NDC 53489-288-10Sotalol hydrochloride tablets, 120 mg, light blue, capsule shaped, scored, debossed MP 515Bottles of 50 NDC 53489-289-02Bottles of 100 NDC 53489-289-01Bottles of 250 NDC 53489-289-03Bottles of 500 NDC 53489-289-05Bottles of 1000 NDC 53489-289-10Sotalol hydrochloride tablets, 160 mg, light blue, capsule shaped, scored, debossed MP 516Bottles of 50 NDC 53489-290-02Bottles of 100 NDC 53489-290-01Bottles of 250 NDC 53489-290-03Bottles of 500 NDC 53489-290-05Bottles of 1000 NDC 53489-290-10Sotalol hydrochloride tablets, 240 mg, light blue, capsule shaped, scored, debossed MP 517Bottles of 50 NDC 53489-291-02Bottles of 100 NDC 53489-291-01Bottles of 250 NDC 53489-291-03Bottles of 500 NDC 53489-291-05Bottles of 1000 NDC 53489-291-10Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature]DISPENSE IN TIGHT, LIGHT-RESISTANT CONTAINER.SOTALOL HYDROCHLORIDE TABLETS are available as follows:Sotalol hydrochloride tablets, 80 mg, light blue, capsule shaped, scored, debossed MP 514Bottles of 50 NDC 53489-288-02Bottles of 100 NDC 53489-288-01Bottles of 250 NDC 53489-288-03Bottles of 500 NDC 53489-288-05Bottles of 1000 NDC 53489-288-10Sotalol hydrochloride tablets, 120 mg, light blue, capsule shaped, scored, debossed MP 515Bottles of 50 NDC 53489-289-02Bottles of 100 NDC 53489-289-01Bottles of 250 NDC 53489-289-03Bottles of 500 NDC 53489-289-05Bottles of 1000 NDC 53489-289-10Sotalol hydrochloride tablets, 160 mg, light blue, capsule shaped, scored, debossed MP 516Bottles of 50 NDC 53489-290-02Bottles of 100 NDC 53489-290-01Bottles of 250 NDC 53489-290-03Bottles of 500 NDC 53489-290-05Bottles of 1000 NDC 53489-290-10Sotalol hydrochloride tablets, 240 mg, light blue, capsule shaped, scored, debossed MP 517Bottles of 50 NDC 53489-291-02Bottles of 100 NDC 53489-291-01Bottles of 250 NDC 53489-291-03Bottles of 500 NDC 53489-291-05Bottles of 1000 NDC 53489-291-10Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature]DISPENSE IN TIGHT, LIGHT-RESISTANT CONTAINER.SOTALOL HYDROCHLORIDE TABLETS are available as follows:Sotalol hydrochloride tablets, 80 mg, light blue, capsule shaped, scored, debossed MP 514Bottles of 50 NDC 53489-288-02Bottles of 100 NDC 53489-288-01Bottles of 250 NDC 53489-288-03Bottles of 500 NDC 53489-288-05Bottles of 1000 NDC 53489-288-10Sotalol hydrochloride tablets, 120 mg, light blue, capsule shaped, scored, debossed MP 515Bottles of 50 NDC 53489-289-02Bottles of 100 NDC 53489-289-01Bottles of 250 NDC 53489-289-03Bottles of 500 NDC 53489-289-05Bottles of 1000 NDC 53489-289-10Sotalol hydrochloride tablets, 160 mg, light blue, capsule shaped, scored, debossed MP 516Bottles of 50 NDC 53489-290-02Bottles of 100 NDC 53489-290-01Bottles of 250 NDC 53489-290-03Bottles of 500 NDC 53489-290-05Bottles of 1000 NDC 53489-290-10Sotalol hydrochloride tablets, 240 mg, light blue, capsule shaped, scored, debossed MP 517Bottles of 50 NDC 53489-291-02Bottles of 100 NDC 53489-291-01Bottles of 250 NDC 53489-291-03Bottles of 500 NDC 53489-291-05Bottles of 1000 NDC 53489-291-10Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature]DISPENSE IN TIGHT, LIGHT-RESISTANT CONTAINER.

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Clinical Information

Chemical Structure

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Clinical Pharmacology

Sotalol has both beta-adrenoreceptor blocking (Vaughan Williams Class II) and cardiac action potential duration prolongation (Vaughan Williams Class III) antiarrhythmic properties. Sotalol hydrochloride is a racemic mixture of d- and l-sotalol. Both isomers have similar Class III antiarrhythmic effects, while the l-isomer is responsible for virtually all of the beta-blocking activity. The beta-blocking effect of sotalol is non-cardioselective, half maximal at about 80 mg/day and maximal at doses between 320 and 640 mg/day. Sotalol does not have partial agonist or membrane stabilizing activity. Although significant beta-blockade occurs at oral doses as low as 25 mg, significant Class III effects are seen only at daily doses of 160 mg and above.

Information related to an electrophysiologic effect in pediatric patients is approved for Berlex Laboratories' sotalol hydrochloride tablets. However, due to Berlex's marketing exclusivity rights, this drug product is not labeled for pediatric use.

Non-Clinical Toxicology

Sotalol is 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 heart failure, and previous evidence of hypersensitivity to sotalol.

Sotalol is mainly eliminated principally via the kidneys through glomerular filtration and to a small degree by tubular secretion. There is a direct relationship between renal function, as measured by serum creatinine or creatinine clearance, and the elimination rate of sotalol. Guidance for dosing in conditions of renal impairment can be found under

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 ), 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 lists 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 multicenter trial of 25 patients with SVT and/or VT receiving daily doses of 30, 90 and 210 mg/m 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/m daily, was discontinued because of increased frequency of sinus pauses/bradycardia. Additional cardiovascular AEs were seen at the 90 and 210 mg/m 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≥525 msec were seen in 2 patients at the 210 mg/m 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.

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Reference

This information is obtained from the National Institute of Health's Standard Packaging Label drug database.
"https://dailymed.nlm.nih.gov/dailymed/"

While we update our database periodically, we cannot guarantee it is always updated to the latest version.

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Clonazepam Description Each single-scored tablet, for oral administration, contains 0.5 mg, 1 mg, or 2 mg Clonazepam, USP, a benzodiazepine. Each tablet also contains corn starch, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and povidone. Clonazepam tablets USP 0.5 mg contain Yellow D&C No. 10 Aluminum Lake. Clonazepam tablets USP 1 mg contain Yellow D&C No. 10 Aluminum Lake, as well as FD&C Blue No. 1 Aluminum Lake. Chemically, Clonazepam, USP is 5-(o-chlorophenyl)-1,3-dihydro-7-nitro-2H-1,4-benzodiazepin-2-one. It is a light yellow crystalline powder. It has the following structural formula: C15H10ClN3O3 M.W. 315.72

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Interactions

A total of 440 drugs (1549 brand and generic names) are known to interact with Imbruvica (ibrutinib). 228 major drug interactions (854 brand and generic names) 210 moderate drug interactions (691 brand and generic names) 2 minor drug interactions (4 brand and generic names) Show all medications in the database that may interact with Imbruvica (ibrutinib).

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