DRUGS & SUPPLEMENTS

Sota-Gry

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INDICATIONS AND USAGE

Oral Sota-Gry hydrochloride 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 Sota-Gry (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 Sota-Gry 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 Sota-Gry.

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 by 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 Sota-Gry 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.

Sota-Gry 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®. Sota-Gry Hydrochloride Tablets are 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.

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CONTRAINDICATIONS

Sota-Gry hydrochloride 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 congestive heart failure, and previous evidence of hypersensitivity to Sota-Gry.

WARNINGS

Mortality

The National Heart, Lung, and Blood Institute’s Cardiac Arrhythmia Suppression Trial I was a long-term, multi-center, double-blind study in patients with asymptomatic, 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 associated with 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. Sota-Gry hydrochloride 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, Sota-Gry hydrochloride did not produce increased mortality at doses up to 320 mg/day (see Clinical  Studies ). 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, Sota-Gry 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 (QTc 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 Sota-Gry, occurring in about 4% of high risk (history of sustained VT/VF) patients. The risk of torsade de pointes progressively increases with prolongation of the QT interval, and is worsened also by reduction in heart rate and reduction in serum potassium (see Electrolyte Disturbances ).

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 QTc.) 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 WARNINGS: Mortality ) 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 Sota-Gry, 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. In patients with a history of sustained ventricular tachycardia, the incidence of torsade de pointes was 4% and worsened VT in about 1%; in patients with other, less serious, ventricular arrhythmias and supraventricular arrhythmias, the incidence of torsade de pointes was 1% and 1.4%, respectively.

Torsade de pointes arrhythmias were dose related, as is the prolongation of QT (QTc) interval, as shown in the table below.

Daily Dose (mg)     Incidence of Torsade de Pointes     Mean QTc a (msec)
    80 0 (69)b      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)  

aHighest on-therapy value

bNumber 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 QTc 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 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 Sota-Gry therapy was discontinued in most patients experiencing torsade de pointes, 17% were continued on a lower dose.

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

 On-Therapy QTc Interval (msec)  Incidence of Torsade de Pointes  Change in QTc Interval From Baseline (msec)  Incidence of Torsade de Pointes
 <500  1.3% (1787)  <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 130  5.2% (115)
     >130  7.1% (99)

( ) Number of patients assessed

Proarrhythmic events must be anticipated not only on initiating therapy, but with every upward dose adjustment. Proarrhythmic events most often occur within 7 days of initiating therapy or of an increase in dose; 75% of serious proarrhythmias (torsade de pointes and worsened VT) occurred within 7 days of initiating Sota-Gry therapy, while 60% of such events occurred within 3 days of initiation or a dosage change. Initiating therapy at 80 mg BID with gradual upward dose titration and appropriate evaluations for efficacy (e.g., PES or Holter) and safety (e.g., QT interval, heart rate and electrolytes) prior to dose escalation, should reduce the risk of proarrhythmia. Avoiding excessive accumulation of Sota-Gry in patients with diminished renal function, by appropriate dose reduction, should also reduce the risk of proarrhythmia (see DOSAGE AND ADMINISTRATION ).

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, Sota-Gry should be administered cautiously. Both digitalis and Sota-Gry 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 occurred in 3.3% (n = 3257) of patients and led to discontinuation in approximately 1% of patients receiving Sota-Gry. 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 Sota-Gry (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

Sota-Gry 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 can promote serious arrhythmias and should be avoided (see Proarrhythmia above). Sinus bradycardia (heart rate less than 50 bpm) occurred in 13% of patients receiving Sota-Gry 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 2nd- or 3rd-degree AV block is approximately 1%.

Recent Acute MI

Sota-Gry 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 Sota-Gry 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 WARNINGS: Mortality ). 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 Sota-Gry.

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 Sota-Gry, 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 Sota-Gry hydrochloride 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 Sota-Gry, 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. It is prudent, if Sota-Gry hydrochloride is to be administered, to use the smallest effective dose, so that inhibition of bronchodilation produced by endogenous or exogenous catecholamine stimulation of beta2 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 or with a history of episodes of spontaneous hypoglycemia, Sota-Gry should be given with caution since beta-blockade may mask some important premonitory signs of acute hypoglycemia; e.g., tachycardia.

Sick Sinus Syndrome

Sota-Gry 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.

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PRECAUTIONS

Renal Impairment

Sota-Gry hydrochloride is mainly eliminated 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 Sota-Gry. Guidance for dosing in conditions of renal impairment can be found under DOSAGE AND ADMINISTRATION .

Drug Interactions

Drugs undergoing CYP450 metabolism

Sota-Gry is primarily eliminated by renal excretion; therefore, drugs that are metabolized by CYP450 are not expected to alter the pharmacokinetics of Sota-Gry. Sota-Gry 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.

Antiarrhythmics

Class Ia antiarrhythmic drugs, such as disopyramide, quinidine and procainamide and other Class III drugs are not recommended as concomitant therapy with Sota-Gry, because of their potential to prolong refractoriness (see WARNINGS ). 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 Sota-Gry.

Digoxin

Single and multiple doses of Sota-Gry do not substantially affect serum digoxin levels. Proarrhythmic events were more common in Sota-Gry treated patients also receiving digoxin; it is not clear whether this represents an interaction or is related to the presence of CHF, a known risk factor for proarrhythmia, in the patients receiving digoxin. Both digitalis glycosides and beta-blockers slow atrioventricular conduction and decrease heart rate. Concomitant use can increase the risk of bradycardia.

Calcium-blocking drugs

Sota-Gry should be administered with caution in conjunction with calcium-blocking drugs because of possible additive effects on atrioventricular conduction or ventricular function. Additionally, concomitant use of these drugs may have additive effects on blood pressure, possibly leading to hypotension.

Catecholamine-depleting agents

Concomitant use of catecholamine-depleting drugs, such as reserpine and guanethidine, with a beta-blocker may produce an excessive reduction of resting sympathetic nervous tone. Patients treated with Sota-Gry plus a catecholamine depletor should therefore be closely monitored for evidence of hypotension and/or marked bradycardia which may produce syncope.

Insulin and oral antidiabetics

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

Beta-2-receptor stimulants

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

Clonidine

Beta-blocking drugs may potentiate the rebound hypertension sometimes observed after discontinuation of clonidine; therefore, caution is advised when discontinuing clonidine in patients receiving Sota-Gry.

Other

No pharmacokinetic interactions were observed with hydrochlorothiazide or warfarin.

Antacids

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

Drugs prolonging the QT interval

Sota-Gry 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.

Drug/Laboratory Test Interactions

The presence of Sota-Gry 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 Sota-Gry, a specific method, such as a high performance liquid chromatographic assay with solid phase extraction (e.g., J. Chromatogr. 385:241, 1987) should be employed in determining levels of catecholamines.

Carcinogenesis, Mutagenesis, Impairment of Fertility

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

Sota-Gry 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.

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/m2), respectively, did not reveal any teratogenic potential associated with Sota-Gry HCl. In rabbits, a high dose of Sota-Gry HCl (160 mg/kg/day) at 16 times the MRHD as mg/kg (6 times the MRHD as mg/m2) 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/m2) did not result in an increased incidence of fetal deaths. In rats, 1000 mg/kg/day Sota-Gry HCl, 100 times the MRHD (18 times the MRHD as mg/m2), increased the number of early resorptions, while at 14 times the maximum dose (2.5 times the MRHD as mg/m2), 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, Sota-Gry HCl has been shown to cross the placenta, and is found in amniotic fluid. There has been a report of subnormal birth weight with Sota-Gry. Therefore, Sota-Gry hydrochloride should be used during pregnancy only if the potential benefit outweighs the potential risk.

Nursing Mothers

Sota-Gry 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 Sota-Gry, 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 Sota-Gry in children have not been established. However, the Class III electrophysiologic and beta-blocking effects, the pharmacokinetics, and the relationship between the effects (QTc interval and resting heart rate) and drug concentrations have been evaluated in children aged between 3 days and 12 years old (see CLINICAL PHARMACOLOGY ).

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ADVERSE REACTIONS

During premarketing trials, 3186 patients with cardiac arrhythmias (1363 with sustained ventricular tachycardia) received oral Sota-Gry, 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 Sota-Gry 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 Sota-Gry therapy but no cause and effect relationship has been established. One case of peripheral neuropathy which resolved on discontinuation of Sota-Gry 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.

 DAILY DOSE
Body

System 

160 mg

(n=832)

240 mg

(n=263)

320 mg

(n=835)

480 mg

(n=459)

640 mg

(n=324)


Any Dosea

(n=1292)

% Patients

Discontinued

(n=1292) 

Body as

a whole

infection <1 
fever <1 
localized pain <1 

Cardiovascular

dyspnea 11  15  15  21 
bradycardia  16 
chest pain 10  10  14  16  <1 
palpitation 12  14  <1 
edema
ECG abnormal   2
hypotension  3
proarrhythmia <1  <1   5
syncope  5
heart failure  2
presyncope  3 <1 
peripheral vascular

   disorder

2 <1 
cardiovascular

   disorder

<1   2 <1 
vasodilation <1   1 <1 
AICD discharge <1   2 <1 
hypertension <1  <1 

Nervous

fatigue 12  12  13  20  2
dizziness 11  11  14  20   1
asthenia 10  13   1
light-headed 12   1
headache  <1
sleep problem  <1
perspiration  <1
altered

   consciousness

 <1
depression  <1
paresthesia  <1
anxiety  <1
mood change <1  <1   <1
appetite disorder  <1
stroke <1  <1  <1   <1

Digestive

nausea/vomiting 10   1
diarrhea  <1
dyspepsia  <1
abdominal pain <1  <1  2  <1
colon problem <1   <1
flatulence <1   <1

Respiratory

pulmonary problem  <1
upper respiratory

   tract problem

 <1
asthma <1   <1

Urogenital


genitourinary

   disorder

 <1
sexual dysfunction  <1   <1

Metabolic

abnormal lab value  <1
weight change <1   <1

Musculoskeletal

extremity pain  <1
back pain <1   <1

Skin and Appendages

rash  <1

Hematologic

bleeding <1  <1  2  <1

Special Senses

visual problem  5  <1

a Because patients are counted at each dose level tested, the Any Dose column cannot be determined by adding across the doses.

In an unblinded multicenter trial of 25 patients with SVT and/or VT receiving daily doses of 30, 90 and 210 mg/m2 with dosing every 8 hours for a total of 9 doses, no torsade de pointes or other serious new arrhythmias were observed. One (1) patient, receiving 30 mg/m2 daily, was discontinued because of increased frequency of sinus pauses/bradycardia. Additional cardiovascular AEs were seen at the 90 and 210 mg/m2 daily dose levels. They included QT prolongations (2 patients), sinus pauses/bradycardia (1 patient), increased severity of atrial flutter and reported chest pain (1 patient). Values for QTc ≥ 525 msec were seen in 2 patients at the 210 mg/m2 daily dose level. Serious adverse events including death, torsade 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 Sota-Gry 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, pruritis, alopecia.

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

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OVERDOSAGE

Intentional or accidental overdosage with Sota-Gry hydrochloride has rarely resulted in death.

Symptoms and Treatment of Overdosage

The most common signs to be expected are bradycardia, congestive heart failure, hypotension, bronchospasm and hypoglycemia. In cases of massive intentional overdosage (2 to 16 grams) of Sota-Gry hydrochloride the following clinical findings were seen: hypotension, bradycardia, cardiac asystole, prolongation of QT interval, torsade de pointes, ventricular tachycardia, and premature ventricular complexes. If overdosage occurs, therapy with Sota-Gry should be discontinued and the patient observed closely. Because of the lack of protein binding, hemodialysis is useful for reducing Sota-Gry plasma concentrations. Patients should be carefully observed until QT intervals are normalized and the heart rate returns to levels >50 bpm. The occurrence of hypotension following an overdose may be associated with an initial slow drug elimination phase (half-life of 30 hours) thought to be due to a temporary reduction of renal function caused by hypotension. In addition, if required, the following therapeutic measures are suggested:

Bradycardia or Cardiac Asystole: Atropine, another anticholinergic drug, a beta-adrenergic agonist or transvenous cardiac pacing.

Heart Block: (second and third degree) transvenous cardiac pacemaker.

Hypotension: (depending on associated factors) epinephrine rather than isoproterenol or norepinephrine may be useful.

Bronchospasm: Aminophylline or aerosol beta-2-receptor stimulant.

Torsade de pointes: DC cardioversion, transvenous cardiac pacing, epinephrine, magnesium sulfate.

DOSAGE AND ADMINISTRATION

As with other antiarrhythmic agents, Sota-Gry hydrochloride should be initiated and doses increased in a hospital with facilities for cardiac rhythm monitoring and assessment. Sota-Gry should be administered only after appropriate clinical assessment (see INDICATIONS AND USAGE ), and the dosage of Sota-Gry hydrochloride 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

Dosage of Sota-Gry hydrochloride should be adjusted gradually, allowing 3 days between dosing increments in order to attain steady-state plasma concentrations, and to allow monitoring of QT intervals. Graded dose adjustment will help prevent the usage of doses which are higher than necessary to control the arrhythmia. The recommended initial dose is 80 mg twice daily. This dose may be increased, if necessary, after appropriate evaluation to 240 or 320 mg/day (120 to 160 mg twice daily). In most patients, a therapeutic response is obtained at a total daily dose of 160 to 320 mg/day, given in two or three divided doses. Some patients with life-threatening refractory ventricular arrhythmias may require doses as high as 480 to 640 mg/day; however, these doses should only be prescribed when the potential benefit outweighs the increased risk of adverse events, in particular proarrhythmia. Because of the long terminal elimination half-life of Sota-Gry, dosing on more than a BID regimen is usually not necessary.

Children

As in adults the following precautionary measures should be considered when initiating Sota-Gry 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 QTc 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 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/m2 three times a day (90 mg/m2 total daily dose) is approximately equivalent to the initial 160 mg total daily dose for adults. Subsequent titration to a maximum of 60 mg/m2 (approximately equivalent to the 360 mg total daily dose for adults) can then occur. Titration should be guided by clinical response, heart rate and QTc, 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 Sota-Gry 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/m2, 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/m2, 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/m2. Similar calculations should be made for increased doses as titration proceeds. Since the half-life of Sota-Gry 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 Sota-Gry hydrochloride should be used with particular caution in children if the QTc is greater than 500 msec on therapy, and serious consideration should be given to reducing the dose or discontinuing therapy when QTc exceeds 550 msec.

Dosage in Renal Impairment

Adults

Because Sota-Gry is excreted predominantly in urine and its terminal elimination half-life is prolonged in conditions of renal impairment, the dosing interval of Sota-Gry should be modified (when creatinine clearance is lower than 60 mL/min) according to the following table.

Creatinine

Clearance

mL/min

Dosinga

Interval

(hours)

 >60  12
 30 to 59  24
 10 to 29  36 to 48
 <10  Dose should be individualized

aThe initial dose of 80 mg and subsequent doses should be administered at these intervals. See following paragraph for dosage escalations.

Since the terminal elimination half-life of Sota-Gry hydrochloride 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 to 6 doses at appropriate intervals. Extreme caution should be exercised in the use of Sota-Gry in patients with renal failure undergoing hemodialysis. The half-life of Sota-Gry is prolonged (up to 69 hours) in anuric patients. Sota-Gry, 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.

Children

The use of Sota-Gry hydrochloride in children with renal impairment has not been investigated. Sota-Gry elimination is predominantly via the kidney in the unchanged form. Use of Sota-Gry in any age group with decreased renal function should be at lower doses or at increased intervals between doses. Monitoring of heart rate and QTc is more important and it will take much longer to reach steady-state with any dose and/or frequency of administration.

Transfer to Sota-Gry

Before starting Sota-Gry, 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. Treatment has been initiated in some patients receiving I.V. lidocaine without ill effect. After discontinuation of amiodarone, Sota-Gry should not be initiated until the QT interval is normalized (see WARNINGS ).

Preparation of Extemporaneous Oral Solution

Sota-Gry hydrochloride syrup 5 mg/mL can be compounded using Simple Syrup containing 0.1% sodium benzoate (Syrup, NF) available from Humco Laboratories as follows:

  • Measure 120 mL of Simple Syrup.
  • Transfer the syrup to a 6-ounce 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) Sota-Gry hydrochloride 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 at least 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 Sota-Gry HCI. The fine solid particles are the water-insoluble inactive ingredients of the tablets.

This extemporaneously prepared oral solution of Sota-Gry HCI (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 for three months when stored at controlled room temperature (20°-25°C/68°-77°F) and ambient humidity.

Transfer to Betapace AF® from Sota-Gry

Patients with a history of symptomatic AFIB/AFL who are currently receiving Sota-Gry 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).

HOW SUPPLIED

Sota-Gry hydrochloride; capsule-shaped bisected light-blue scored tablets, are available as follows:

80 mg strength imprinted “58/75” on one side and “V” on the reverse side available in the following configurations:

  • Bottles of 10: NDC 0603-5769-10
  • Bottles of 100: NDC 0603-5769-21
  • Bottles of 500: NDC 0603-5769-28
  • Bottles of 1000: NDC 0603-5769-32
  • Unit dose packs of 100: NDC 0603-5769-29

120 mg strength imprinted “58/76” on one side and “V” on the reverse side available in the following configurations:

  • Bottles of 10: NDC 0603-5770-10
  • Bottles of 100: NDC 0603-5770-21
  • Bottles of 300: NDC 0603-5770-25
  • Bottles of 500: NDC 0603-5770-28
  • Bottles of 1000: NDC 0603-5770-32
  • Unit dose packs of 100: NDC 0603-5770-29

160 mg strength imprinted “58/77” on one side and “V” on the reverse side available in the following configurations:

  • Bottles of 10: NDC 0603-5771-10
  • Bottles of 100: NDC 0603-5771-21
  • Bottles of 500: NDC 0603-5771-28
  • Bottles of 1000: NDC 0603-5771-32
  • Unit dose packs of 100: NDC 0603-5771-29

240 mg strength imprinted “58/78” on one side and “V” on the reverse side available in the following configurations:

  • Bottles of 100: NDC 0603-5772-21
  • Bottles of 500: NDC 0603-5772-28
  • Bottles of 1000: NDC 0603-5772-32
  • Unit dose packs of 100: NDC 0603-5772-29

Store at 20° to 25°C (68° to 77°F).

Betapace AF® is a registered trademark of Berlex Laboratories.

Manufactured for:

QUALITEST PHARMACEUTICALS

Huntsville, AL 35811

8182127

R9/11-R4

Sota-Gry 80mg Tablet

This is an image of the structural formula of Sota-Gry Hydrochloride. This is a graph of age plotted on a logarithmic scale in months.

Sota-Gry pharmaceutical active ingredients containing related brand and generic drugs:

infoActive ingredient is the part of the drug or medicine which is biologically active. This portion of the drug is responsible for the main action of the drug which is intended to cure or reduce the symptom or disease. The other portions of the drug which are inactive are called excipients; there role is to act as vehicle or binder. In contrast to active ingredient, the inactive ingredient's role is not significant in the cure or treatment of the disease. There can be one or more active ingredients in a drug.


Sota-Gry available forms, composition, doses:

infoForm of the medicine is the form in which the medicine is marketed in the market, for example, a medicine X can be in the form of capsule or the form of chewable tablet or the form of tablet. Sometimes same medicine can be available as injection form. Each medicine cannot be in all forms but can be marketed in 1, 2, or 3 forms which the pharmaceutical company decided based on various background research results.
Composition is the list of ingredients which combinedly form a medicine. Both active ingredients and inactive ingredients form the composition. The active ingredient gives the desired therapeutic effect whereas the inactive ingredient helps in making the medicine stable.
Doses are various strengths of the medicine like 10mg, 20mg, 30mg and so on. Each medicine comes in various doses which is decided by the manufacturer, that is, pharmaceutical company. The dose is decided on the severity of the symptom or disease.


Sota-Gry destination | category:

infoDestination is defined as the organism to which the drug or medicine is targeted. For most of the drugs what we discuss, human is the drug destination.
Drug category can be defined as major classification of the drug. For example, an antihistaminic or an antipyretic or anti anginal or pain killer, anti-inflammatory or so.


Sota-Gry Anatomical Therapeutic Chemical codes:

infoA medicine is classified depending on the organ or system it acts [Anatomical], based on what result it gives on what disease, symptom [Therapeutical], based on chemical composition [Chemical]. It is called as ATC code. The code is based on Active ingredients of the medicine. A medicine can have different codes as sometimes it acts on different organs for different indications. Same way, different brands with same active ingredients and same indications can have same ATC code.


Sota-Gry pharmaceutical companies:

infoPharmaceutical companies are drug manufacturing companies that help in complete development of the drug from the background research to formation, clinical trials, release of the drug into the market and marketing of the drug.
Researchers are the persons who are responsible for the scientific research and is responsible for all the background clinical trials that resulted in the development of the drug.


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References

  1. Dailymed."SOTALOL HYDROCHLORIDE TABLET [BRYANT RANCH PREPACK]". https://dailymed.nlm.nih.gov/dailym... (accessed August 28, 2018).
  2. "sotalol". https://pubchem.ncbi.nlm.nih.gov/co... (accessed August 28, 2018).
  3. "sotalol". http://www.drugbank.ca/drugs/DB0048... (accessed August 28, 2018).

Frequently asked Questions

Can i drive or operate heavy machine after consuming Sota-Gry?

Depending on the reaction of the Sota-Gry after taken, if you are feeling dizziness, drowsiness or any weakness as a reaction on your body, Then consider Sota-Gry not safe to drive or operate heavy machine after consumption. Meaning that, do not drive or operate heavy duty machines after taking the capsule if the capsule has a strange reaction on your body like dizziness, drowsiness. As prescribed by a pharmacist, it is dangerous to take alcohol while taking medicines as it exposed patients to drowsiness and health risk. Please take note of such effect most especially when taking Primosa capsule. It's advisable to consult your doctor on time for a proper recommendation and medical consultations.

Is Sota-Gry addictive or habit forming?

Medicines are not designed with the mind of creating an addiction or abuse on the health of the users. Addictive Medicine is categorically called Controlled substances by the government. For instance, Schedule H or X in India and schedule II-V in the US are controlled substances.

Please consult the medicine instruction manual on how to use and ensure it is not a controlled substance.In conclusion, self medication is a killer to your health. Consult your doctor for a proper prescription, recommendation, and guidiance.

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Review

sDrugs.com conducted a study on Sota-Gry, and the result of the survey is set out below. It is noteworthy that the product of the survey is based on the perception and impressions of the visitors of the website as well as the views of Sota-Gry consumers. We, as a result of this, advice that you do not base your therapeutic or medical decisions on this result, but rather consult your certified medical experts for their recommendations.

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The information was verified by Dr. Arunabha Ray, MD Pharmacology

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