Anti-Arrhythmics

Pharmacologic stress agent (Adenoscan®): Continuous I.V. infusion: 140 mcg/kg/minute for 6 minutes using syringe or columetric infusion pump; total dose: 0.84 mg/kg. Thallium-201 is injected at midpoint (3 minutes) of infusion.

Mechanism of Action
Adenosine is a potent vasodilator in most vascular beds, except in renal afferent arterioles and hepatic veins where it produces vasoconstriction. Adenosine is thought to exert its pharmacological effects through activation of purine receptors (cell-surface A1 and A2 adenosine receptors). Although the exact mechanism by which adenosine receptor activation relaxes vascular smooth muscle is not known, there is evidence to support both inhibition of the slow inward calcium current reducing calcium uptake, and activation of adenylate cyclase through A2 receptors in smooth muscle cells. Adenosine may also lessen vascular tone by modulating sympathetic neurotransmission. The intracellular uptake of adenosine is mediated by a specific transmembrane nucleoside transport system. Once inside the cell, adenosine is rapidly phosphorylated by adenosine kinase to adenosine monophosphate, or deaminated by adenosine deaminase to inosine. These intracellular metabolites of adenosine are not vasoactive.

Supplied: Adenocard®: 3 mg/ml (2 ml, 4 ml)
Adenoscan®: 3 mg/ml (20 ml, 30 ml)

Amiodarone: I.V. DOSE RECOMMENDATIONS -- FIRST 24 HOURS -- Loading infusions. The recommended starting dose of Cordarone I.V. is about 1000 mg over the first 24 hours of therapy, delivered by the following infusion regimen:

First Rapid: 150 mg over the FIRST - 10 minutes (15 mg/min). Add 3 ml of Cordarone I.V. (150 mg) to 100 ml D 5 W. Infuse 100 ml over 10 minutes.
Followed by Slow: 360 mg over the NEXT 6 hours (1 mg/min). Add 18 ml of Cordarone I.V. (900 mg) to 500 ml D 5 W (conc = 1.8 mg/ml).
Maintenance infusion: 540 mg over the REMAINING 18 hours (0.5 mg/min).

After the first 24 hours, the maintenance infusion rate of 0.5 mg/min (720 mg/24 hours) should be continued utilizing a concentration of 1 to 6 mg/ml (Cordarone I.V. concentrations greater than 2 mg/ml should be administered via a central venous catheter). In the event of breakthrough episodes of VF or hemodynamically unstable VT, Give 150-mg/100 ml D5W over 10 minutes to minimize potential for hypotension. The rate of the maintenance infusion may be increased to achieve effective arrhythmia suppression. The initial infusion rate should not exceed 30 mg/min. The maintenance infusion of up to 0.5 mg/min can be cautiously continued for 2 to 3 weeks regardless of the patient's age, renal function, or Left-ventricular function. There is limited experience in patients receiving Cordarone I.V. > 3 weeks.

RECOMMENDATIONS FOR ORAL DOSAGE AFTER I.V. INFUSION
Duration of Cordarone I.V. Infusion*: <1 week
Initial Daily Dose of Oral Cordarone : 800-1600 mg

Duration of Cordarone I.V. Infusion: 1 to 3 weeks
Initial Daily Dose of Oral Cordarone : 600-800 mg

Duration of Cordarone I.V. Infusion: >3 weeks
Initial Daily Dose of Oral Cordarone : 400 mg
*Assuming a 720 mg/day infusion (0.5 mg/min). Cordarone I.V is not intended for maint therapy.

Restated: Duration of IV infusion < 1 week: 800-1600mg/day po initially x 1-2 weeks or complete current week; 1-3 weeks: 600-800mg/day po initially - total therapy ~ 1 month counting IV infusion ; >3 weeks: 400mg po qd initially.

Oral Loading - Half-life elimination: 40-55 days (range: 26-107 days);
Administration of Cordarone in divided doses with meals is suggested for total daily doses of 1,000 mg or higher, or when gastrointestinal intolerance occurs.) If side effects become excessive, the dose should be reduced.
Loading Dose (Daily): (Ventricular Arrhythmias) 800 to 1,600 mg x 1-3 weeks, then 600 to 800 mg x ~1 month, then start maintenance of 400mg/day.

Recommendations for conversion to intravenous amiodarone after oral administration: During long-term amiodarone therapy (ie, 4 months), the mean plasma-elimination half-life of the active metabolite of amiodarone is 61 days. Replacement therapy may not be necessary in such patients if oral therapy is discontinued for a period <2 weeks, since any changes in serum amiodarone concentrations during this period may not be clinically significant.

Bradycardia: 0.5 mg I.V every 5 minutes, not to exceed a total of 3 mg or 0.04 mg/kg; may give intratracheal in 1 mg/10 ml dilution only, intratracheal dose should be 2-2.5 times the I.V. dose. (Doses <0.5 mg have been associated with paradoxical bradycardia.)

Inhibit salivation and secretions (preanesthesia):
0.4-0.6 mg (IM, IV, SQ) 30 to 60 minutes preop - repeat every 4-6 hours as needed.
Oral: 0.4 mg, may repeat every 4 to 6 hours.

Organophosphate or carbamate poisoning:
2 mg IV, followed by 2 mg every 15 minutes until adequate response (initial doses of up to 6 mg may be used in life-threatening cases).

A-fib: 10 to 15 mcg/kg IBW given as above. (If given IVPush-admin over at least 5 min).
PSVT: (For patients not on digoxin): 0.25 to 0.5 mg IV. May follow with 0.125 to 0.25 mg IV q2-6h until 0.75 to 1.5 mg is given over 24hrs. [Loading: 10 to 15 mcg/kg IBW in divided doses (q4-8h) over 12-24hrs.] Digoxin is considered to be a 3rd line drug in stable patients who fail to respond to adenosine/verapamil/esmolol. Not preferred drug for PSVT because it is not rapidly effective (may take up to 60 minutes).

Maintenance dose: Digoxin clearance= [CRCL + 40] x 1.44 (add 20 instead of 40 if pt has CHF). Predicted Css= (Dose) (0.65 to 0.8)/ Digoxin clearance. Alternatively, maint dose= Loading dose x [0.14 x crcl / 500 ] Avoid IM injections-can lead to severe pain (If it must be given by this route, give deep IM followed by massage).
Monitoring: Obtain blood samples at least 4 hrs after IV dose and 6-8hrs after oral dose.

Serum levels: 0.5 to 2.0 ng/ml. Obtain first level within 24 hours of digitalization. Monitor BUN and serum creatinine q2days (qd if unstable). Monitor apical pulse daily.. Onset/peak: IV: 5-30min/ 1-4hrs Oral: 1-2hrs/ 2-8 hrs. Time to steady state: 5-7 days (average) ESRD: 15-20 days. Half-life: 38-48 hrs. (anephric: 4-6 days).

Conversion from oral to IV: Decrease IV dose by 20 to 25%. When the maintenance dose is given IV, the onset and peak will occur earlier, however the duration of action is the same. Patients' on the "floors" may receive once daily IV maintenance doses, however, IV loading regimens (multiple doses) are restricted to pts on a monitor- ICU's. [Oral bioavailability (tablets): 70 to 80%].

Factors that increase likelihood of digoxin toxicity: Hypokalemia, hypomagnesaemia, hypothyroidism, renal dysfunction, interacting drugs (eg quinidine, verapamil).

Adverse reactions: sinus bradyarrhythmias; AV block; N/V/D; yellow vision and hallucinations; supra and ventricular arrhythmias. Contraindications: V-fibrillation; hypokalemia; WPW syndrome with wide complex.

CLINICAL PHARMACOLOGY
After intravenous injection of Digoxin Immune Fab (Ovine) in the baboon, digoxin-specific Fab fragments are excreted in the urine with a biological half-life of about 9 to 13 hours.1 In humans with normal renal function, the half-life appears to be 15 to 20 hours.2 Experimental studies in animals indicate that these antibody fragments have a large volume of distribution in the extracellular space, unlike whole antibody which distributes in a space only about twice the plasma volume.1 Ordinarily, following administration of DIGIBIND, improvement in signs and symptoms of digitalis intoxication begins within one-half hour or less.2,3,4,5

The affinity of DIGIBIND for digoxin is in the range of 109 to 1011 M-1, which is greater than the affinity of digoxin for (sodium, potassium) ATPase, the presumed receptor for its toxic effects. The affinity of DIGIBIND for digitoxin is about 108 to 109 M-1.

DIGIBIND binds molecules of digoxin, making them unavailable for binding at their site of action on cells in the body. The Fab fragment-digoxin complex accumulates in the blood, from which it is excreted by the kidney. The net effect is to shift the equilibrium away from binding of digoxin to its receptors in the body, thereby reversing its effects.

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INDICATIONS AND USAGE
DIGIBIND, Digoxin Immune Fab (Ovine), is indicated for treatment of potentially life-threatening digoxin intoxication.3 Although designed specifically to treat life-threatening digoxin overdose, it has also been used successfully to treat life-threatening digitoxin overdose.3 Since human experience is limited and the consequences of repeated exposures are unknown, DIGIBIND is not indicated for milder cases of digitalis toxicity.

Manifestations of life-threatening toxicity include severe ventricular arrhythmias such as ventricular tachycardia or ventricular fibrillation, or progressive bradyarrhythmias such as severe sinus bradycardia or second or third degree heart block not responsive to atropine.

Ingestion of more than 10 mg of digoxin in previously healthy adults or 4 mg of digoxin in previously healthy children, or ingestion causing steady-state serum concentrations greater than 10 ng/mL, often results in cardiac arrest. Digitalis-induced progressive elevation of the serum potassium concentration also suggests imminent cardiac arrest. If the potassium concentration exceeds 5 mEq/L in the setting of severe digitalis intoxication, therapy with DIGIBIND is indicated.

CONTRAINDICATIONS
There are no known contraindications to the use of DIGIBIND

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Dosage
Each vial of Digibind® 38 mg or DigiFab™ 40 mg will bind ~0.5 mg of digoxin or digitoxin.
Estimation of the dose is based on the body burden of digitalis. This may be calculated if the amount ingested is known or the postdistribution serum drug level is known (round dose to the nearest whole vial). See table.
Fab dose based on serum drug level postdistribution:

Digoxin Immune Fab

Fab dose based on serum drug level postdistribution:
Digoxin: No. of vials = level (ng/mL) x body weight (kg) divided by 100

Digitoxin: No. of vials = digitoxin (ng/mL) x body weight (kg) divided by 1000

 If neither amount ingested nor drug level are known, dose empirically as follows:
For acute toxicity: 20 vials, administered in 2 divided doses to decrease the possibility of a febrile reaction, and to avoid fluid overload in small children.

For chronic toxicity: 6 vials; for infants and small children </=( 20kg), a single vial may be sufficient
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Administration
Continuous I.V. infusion over >/= 30 minutes is preferred. May give by bolus injection if cardiac arrest is imminent. Small doses (infants/small children) may be administered using tuberculin syringe. Stopping the infusion and restarting at a slower rate may help if infusion-related reactions occur.
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Supplied:
Injection, powder for reconstitution:
Digibind®: 38 mg

DigiFab™: 40 mg

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Dilution: Prescribed dose/ 50 ml NS. (Must use 0.22 micron filter) Improvement in signs and symptoms usually begins in 30 minutes or less.
Stability: Use promptly after mixing (may refrigerate up to 4 hours).
Reconstitution: Dissolve each vial with 4 ml sterile water (do not shake). May be further diluted with normal saline. Infuse over 30 minutes-- must use 0.22 micron filter. If cardiac arrest is imminent, may give as a bolus.

Number of vials needed =[(steady state serum digoxin level (ng/ml) x weight (kg)] / 100. Each vial contains 38 mg which will bind approximately 0.5 mg of digoxin. Dosage for acute ingestion of unknown amount: 20 vials (760mg) of Digibind is adequate to treat most life-threatening ingestions. May consider giving 10 vials, observing the patient's response, and following with an additional 10 vials.
Dosage for toxicity during chronic therapy : for adults, 6 vials (228mg) usually is adequate to reverse most cases of toxicity. This dose can be used in patients in acute distress or when a serum concentration is not available.

>50 kg: 150 mg every 6 hours or 300 mg every 12 hours (controlled release); if no response, may increase to 200 mg every 6 hours; maximum dose required for patients with severe refractory ventricular tachycardia is 400 mg every 6 hours.

Renal Dosing:
CRCL 30-40 ml/minute: 100mg every 8 hours
CRCL 15-30 ml/minute: 100mg every 12 hours
CRCL <15 ml/minute: 100mg every 24 hours

Supplied:
(Norpace®): Capsule 100 mg, 150 mg
(Norpace® CR): Capsule (controlled release) 100 mg, 150 mg

A-fib/Flutter: Dosing (adults)::
Usual initial dose: 500 mcg orally twice daily. Dosage modification: c interval should be measured 2-3 hours after the initial dose. If the QTc >15% of baseline, or if the QTc is >500 msec (550 msec in patients with ventricular conduction abnormalities), dofetilide should be adjusted.
If the starting dose is 500 mcg twice daily, then adjust to 250 mcg twice daily. If the starting dose was 250 mcg twice daily, then adjust to 125 mcg twice daily. If the starting dose was 125 mcg twice daily, then adjust to 125 mcg every day.

Continued monitoring for doses 2-5: QTc interval must be determined 2-3 hours after each subsequent dose of dofetilide for in-hospital doses 2-5. If the measured QTc is >500 msec (550 msec in patients with ventricular conduction abnormalities) dofetilide should be stopped.

Renal Dosing:
CRCL >60 ml/min: Administer 500 mcg twice daily.
CRCL 40-60 ml/min: Administer 250 mcg twice daily.
CRCL 20-39 ml/min: Administer 125 mcg twice daily.
CRCL <20 ml/min: Contraindicated in this group

Supplied: 125 mcg, 250 mcg, 500 mcg capsule

In a placebo-controlled study in patients with severe heart failure requiring recent hospitalization or referral to a specialized heart failure clinic for worsening symptoms (the ANDROMEDA Study), patients given dronedarone had a greater than two-fold increase in mortality. Such patients should not be given dronedarone.

INDICATIONS AND USAGE
MULTAQ® is indicated to reduce the risk of cardiovascular hospitalization in patients with paroxysmal or persistent atrial fibrillation (AF) or atrial flutter (AFL), with a recent episode of AF/AFL and associated cardiovascular risk factors (i.e., age >70, hypertension, diabetes, prior cerebrovascular accident, left atrial diameter ≥50 mm or left ventricular ejection fraction [LVEF] <40%), who are in sinus rhythm or who will be cardioverted

DOSAGE AND ADMINISTRATION
The only recommended dosage of MULTAQ is 400 mg twice daily in adults. MULTAQ should be taken as one tablet with the morning meal and one tablet with the evening meal.

Treatment with Class I or III antiarrhythmics (e.g., amiodarone, flecainide, propafenone, quinidine, disopyramide, dofetilide, sotalol) or drugs that are strong inhibitors of CYP3A (e.g., ketoconazole) must be stopped before starting MULTAQ

HOW SUPPLIED
MULTAQ 400-mg tablets are provided as white film-coated tablets for oral administration, oblong-shaped, engraved with a double wave marking on one side and "4142" code on the other side in:Bottles of 60 tablets, NDC 0024-4142-60
Bottles of 180 tablets, NDC 0024-4142-18
Bottles of 500 tablets NDC 0024-4142-50
Box of 10 blisters (10 tablets per blister) NDC 0024-4142-10

Bronchospasm: 0.1-0.5 mg IM, SQ (1:1000): every 10-15 minutes to 4 hours.

Hypotension (refractory to dopamine/dobutamine): Initial (continuous infusion): 1 mcg/minute (range: 1-10 mcg/minute); titrate to desired effect; severe cardiac dysfunction may require doses >10 mcg/minute (up to 0.1 mcg/kg/minute).

Hypersensitivity reaction: 0.2-0.5 mg IM, SQ every 20 minutes to 4 hours (maximum single dose: 1 mg)

Intraoperative tachycardia and/or hypertension (immediate control): Initial bolus: 80 mg IV (~1 mg/kg) over 30 seconds, followed by a 150 mcg/kg/minute infusion, if necessary. Adjust infusion rate as needed to maintain desired heart rate and/or blood pressure, up to 300 mcg/kg/minute.
For control of postoperative hypertension, as many as one-third of patients may require higher doses (250-300 mcg/kg/minute) to control blood pressure; the safety of doses >300 mcg/kg/minute has not been studied.

Half life: 9 minutes. Onset of action: 2-10 minutes. Contraindicated in: sinus bradycardia; > 1st degree heart block; overt cardiac failure.
Adverse reactions: dose related hypotension; ventricular arrhythmias; heart failure. Drip preparation: Add 2.5 grams/ 250 ml D5W or NS
[Drip rate (ml/hr)= wt(kg) x mcg/min x 0.006 ]

Renal Dosing: CRCL <10 ml/minute: Decrease usual dose by 25% to 50% in severe renal impairment.
Supplied: 50 mg, 100 mg, 150 mg tablet.

Major adverse reactions: proarrhythmic events: VT, PVC's, BC, AV block, torsades de pointes, etc.
Dosing (adults):
IVPB: 0 to 1 mg/50 ml D5W or NS over 10 minutes. If patient is < 60kg give 0.01 mg/kg over 10 minutes. May repeat x 1

Supplied: 0.02 mg/ml (10 ml); 0.2 mg/ml (1:5000) (1 ml, 5 ml).

Prevention of ventricular fibrillation: Initial bolus: 0.5 mg/kg; repeat every 5-10 minutes to a total dose of 2 mg/kg. Refractory ventricular fibrillation: Repeat 1.5 mg/kg bolus may be given 3-5 minutes after initial dose.
E.T. (loading dose only): 2 to 2.5 times the IV dose

Note: Decrease dose in patients with CHF, elderly, hepatic disease.

Dosing (adults):  Arrhythmias: Oral: Initial: 200 mg every 8 hours with food (may load with 400 mg if necessary); adjust dose every 2-3 days; usual dose: 200-300 mg every 8 hours; maximum: 1.2 g/day (some patients respond to every 12-hour dosing). When switching from another antiarrhythmic, initiate a 200 mg dose 6-12 hours after stopping former agents, 3-6 hours after stopping procainamide.

Supplied: 150 mg, 200 mg, 250 mg capsule.

Supplied: 200 mg, 250 mg, 300 mg tablet

Oral: 250-500 mg/dose every 3-6 hours or 500 mg to 1 g every 6 hours extended release; usual dose: 50 mg/kg/24 hours; maximum: 4 g/24 hours.

Renal Dosing:
crcl 10-50 ml/minute: Administer every 6-12 hours.
crcl <10 ml/minute: Administer every 8-24 hours.
Hepatic impairment: Reduce dose by 50%.

Supplied: 250 mg, 500 mg capsule.
ER Tab: 500 mg, 750 mg, 1000 mg.
Injection: 100 mg/ml (10 ml); 500 mg/ml (2 ml).

Supplied: 225 mg, 325 mg, 425 mg extended release cap. 150 mg, 225 mg, 300 mg tablet.

( 267 mg of quinidine gluconate = 275 mg of quinidine polygalacturonate = 200 mg of quinidine sulfate. )

Renal Dosing Crcl <10 ml/minute: Administer 75% of normal dose.

Supplied: 200 mg, 300 mg tab (sulfate). 300mg extended release tablet (sulfate). 324 mg extended release tab (gluconate). Injection: 80 mg/ml (10 ml) (gluconate)

Renal Dosing
Ventricular arrhythmias (Betapace®):
Crcl >60 ml/min: Administer every 12 hours.
Crcl 30-60 ml/min: Administer every 24 hours.
Crcl 10-30 ml/min: Administer every 36-48 hours.
Crcl <10 ml/min: Individualize dose.

Atrial fibrillation/flutter (Betapace AF®):
Crcl >60 ml/min: Administer every 12 hours.
Crcl 40-60 ml/min: Administer every 24 hours.
Crcl <40 ml/min: Use is contraindicated.

Supplied: 80 mg, 120 mg, 160 mg, 240 mg tablet
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Drug UPDATES:  SOTYLIZE ™  (sotalol hydrochloride) oral solution
Initial U.S. Approval: 1992
[Drug information  /  PDF]  
Dosing:  Click (+) next to Dosage and Administration section (drug info link)

U.S. Approval:  2014

Mechanism of Action: 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 two isomers, both of which 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 an oral dose of 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.

In children, a Class III electrophysiological effect can be seen at daily doses of 210 mg/m2 body surface area (BSA). A reduction of the resting heart rate due to the beta-blocking effect of sotalol is observed at daily doses >/=90 mg/m2 in children.

INDICATIONS AND USAGE: 
SOTYLIZE is an antiarrhythmic indicated for:
The treatment of life-threatening ventricular arrhythmias.
The maintenance of normal sinus rhythm in patients with highly symptomatic atrial fibrillation/flutter (AFIB/AFL)
HOW SUPPLIED: 5 mg/mL oral solution

Renal Dosing: Crcl <30 ml/min: Administer 50% of normal dose or 600 mg once daily. Hepatic impairment: Maximum daily dose: 1200 mg

Supplied: 400, 600mg tab.

Decrease dose by 30-50% in hepatic insufficiency.

Adverse reactions: Severe hypotension; bradycardia; ventricular standstill in digitalized patients; asystole; respiratory failure.