Eurythmic

Uses

Because of its life-threatening side effects and the substantial management difficulties associated with its use, Eurythmic is used only for the treatment of the following documented, life threatening recurrent ventricular arrhythmias when these have not responded to documented adequate doses of other available antiarrhythmics or when alternative agents could not be tolerated.

• Recurrent ventricular fibrillation.
• Recurrent hemodynamically unstable ventricular tachycardia.

As is the case for other antiarrhythmic agents, there is no evidence from controlled trials that the use of Eurythmic Tablets favorably affects survival.Eurythmic should be used only by physicians familiar with and with access to (directly or through referral) the use of all available modalities for treating recurrent life threatening ventricular arrhythmias, and who have access to appropriate monitoring facilities, including in-hospital and ambulatory continuous electrocardiographic monitoring and electrophysiologictechniques. Because of the life-threatening nature of the arrhythmias treated, potential interactions with prior therapy, and potential exacerbation of the arrhythmia, initiation of therapy with Eurythmic should be carried out in the hospital.

Eurythmic is also used to associated treatment for these conditions: Atrial Fibrillation, Tachycardia, Supraventricular, Recurrent Ventricular fibrillation, Recurrent hemodynamically unstable Ventricular tachycardia

How Eurythmic works

Eurythmic is considered a class III anti-arrhythmic drug. It blocks potassium currents that cause repolarization of the heart muscle during the third phase of the cardiac action potential. As a result amiodarone increases the duration of the action potential as well as the effective refractory period for cardiac cells (myocytes). Therefore, cardiac muscle cell excitability is reduced, preventing and treating abnormal heart rhythms.

Unique from other members of the class III anti-arrhythmic drug class, amiodarone also interferes with the functioning of beta-adrenergic receptors, sodium channels, and calcium channels channels. These actions, at times, can lead to undesirable effects, such as hypotension, bradycardia, and Torsades de pointes (TdP). In addition to the above, amiodarone may increase activity of peroxisome proliferator-activated receptors, leading to steatogenic changes in the liver or other organs. Finally, amiodarone has been found to bind to the thyroid receptor due to its iodine content, potentially leading to amiodarone induced hypothyroidism or thyrotoxicosis.

Dosage

Eurythmic dosage

Oral dose is 200 mg 3 times daily for 1 week reduced to 200 mg twice daily or the minimum required to control arrhythmia.

Side Effects

The most severe side effects are any symptoms of cough, fever, or painful breathing, reversible corneal microdeposits, impaired vision due to optic neuritis, peripheral neuropathy, bradycardia and conduction disturbances, phototoxicity and rarely persistent skin discoloration, hypothyroidism, hyperthyroidism, raised serum transaminases, jaundice, hepatitis and cirrhosis etc.

Toxicity

The LD50 of oral amiodarone in mice and rats exceeds 3,000 mg/kg. An overdose with amiodarone can have a fatal outcome due to its potential to cause arrhythmia. Signs or symptoms of an overdose may include, hypotension, shock, bradycardia, AV block, and liver toxicity. In cases of an overdose, initiate supportive treatment and, if needed, use fluids, vasopressors, or positive inotropic agents. Temporary pacing may be required for heart block. Ensure to monitor liver function regularly. Eurythmic and its main metabolite, DEA, are not removable by dialysis.

Interaction

Eurythmic may interact with β- blockers, calcium channel blockers, digoxin, flecainide, procainamide, quinidine, tricyclic antidepressants, warfarin and dextromethorphan.

Food Interaction

• Avoid grapefruit products. Grapefruit inhibits CYP3A4 metabolism, which may increase the serum concentration of amiodarone.
• Avoid St. John's Wort. This herb induces the CYP3A4 metabolism of amiodarone. Therefore it may reduce the serum concentration and effectiveness of amiodarone.
• Take with or without food. The absorption is unaffected by food.

[Major] GENERALLY AVOID: Grapefruit juice may significantly increase the plasma concentrations of orally administered amiodarone.

The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits.

In 11 nonsmoking, healthy volunteers, grapefruit juice (300 mL with drug administration, then 3 hours and 9 hours later) increased the mean peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) of amiodarone (17 mg

Formation of the pharmacologically active metabolite, N-desethylamiodarone (N-DEA), was completely inhibited.

Clinically, this interaction can lead to altered efficacy of amiodarone, since antiarrhythmic properties of amiodarone and N-DEA appear to differ.

In the study, mean increases in PR and QTc intervals of 17.9% and 11.3%, respectively, were observed 6 hours postdose with water, while increases of 10.2% and 3.3%, respectively, were observed after administration with grapefruit juice.

ADJUST DOSING INTERVAL: Food increases the rate and extent of absorption of amiodarone.

The mechanism appears to involve the effect of food-induced physiologic changes on drug release from its formulation.

In 30 healthy volunteers, administration of a single 600 mg dose of amiodarone following a high-fat meal resulted in a Cmax and AUC that were 3.8 and 2.4 times the respective values under fasting conditions.

The time to reach peak plasma concentration (Tmax) was decreased by 37%, indicating an increased rate of absorption.

Mean Cmax and AUC for the active metabolite, N-DEA, also increased by 32% and 55%, respectively, but there was no change in the Tmax.

MANAGEMENT: Patients treated with oral amiodarone should avoid consumption of grapefruits and grapefruit juice.

In addition, oral amiodarone should be administered consistently with regard to meals.

Eurythmic Drug Interaction

Major: furosemide, furosemideModerate: apixaban, apixaban, atorvastatin, atorvastatin, metoprolol, metoprolol, metoprolol, metoprolol, clopidogrel, clopidogrel, rivaroxaban, rivaroxabanUnknown: aspirin, aspirin, cyanocobalamin, cyanocobalamin, cholecalciferol, cholecalciferol

Eurythmic Disease Interaction

Major: dialysis, pulmonary dysfunction, sinus node dysfunction, visual impairment, cardiovascular dysfunction, proarrhythmic effectsModerate: hepatic impairment, neurologic dysfunction, thyroid dysfunction, electrolyte imbalance

Volume of Distribution

In a pharmacokinetic study of 3 healthy individuals and 3 patients diagnosed with supraventricular tachycardia (SVT), the volume of distribution was found to be 9.26-17.17 L/kg in healthy volunteers and 6.88-21.05 L/kg in the SVT patients. Prescribing information mentions that the volume of distribution of amiodarone varies greatly, with a mean distribution of approximately 60 L/kg. It accumulates throughout the body, especially in adipose tissue and highly vascular organs including the lung, liver, and spleen. One major metabolite of amiodarone, desethylamiodarone (DEA), is found in even higher proportions in the same tissues as amiodarone.

Elimination Route

The Cmax of amiodarone in the plasma is achieved about 3 to 7 hours after administration. The general time to onset of action of amiodarone after one dose given by the intravenous route is between 1 and 30 minutes, with therapeutic effects lasting from 1-3 hours. Steady-state concentrations of amiodarone in the plasma ranges between 0.4 to 11.99 μg/ml; it is advisable that steady-state levels are generally maintained between 1.0 and 2.5 μg/ml in patients with arrhythmias.

Interestingly, its onset of action may sometimes begin after 2 to 3 days, but frequently takes 1 to 3 weeks, despite the administration of higher loading doses. The bioavailability of amiodarone varies in clinical studies, averaging between 35 and 65%.

Effect of food

In healthy subjects who were given a single 600-mg dose immediately after consuming a meal high in fat, the AUC of amiodarone increased by 2.3 and the Cmax by 3.8 times. Food also enhances absorption, reducing the Tmax by about 37%.

Half Life

The terminal half-life of amiodarone varies according to the patient, but is long nonetheless, and ranges from about 9-100 days. The half-life duration varies according to different sources. According to the prescribing information for amiodarone, the average apparent plasma terminal elimination half-life of amiodarone is of 58 days (ranging from 15 to 142 days). The terminal half-life range was between 14 to 75 days for the active metabolite, (DEA). The plasma half-life of amiodarone after one dose ranges from 3.2 to 79.7 hours, according to one source.

Clearance

The clearance of amiodarone after intravenous administration in patients with ventricular fibrillation and ventricular tachycardia ranged from 220 to 440 ml/hr/kg in one clinically study. Another study determined that the total body clearance of amiodarone varies from 0.10 to 0.77 L/min after one intravenous dose. Renal impairment does not appear to affect the clearance of amiodarone, but hepatic impairment may reduce clearance. Patients with liver cirrhosis exhibited significantly lower Cmax and mean amiodarone concentration for DEA, but not for amiodarone. Severe left ventricular dysfunction prolongs the half-life of DEA.

A note on monitoring

No guidelines have been developed for adjusting the dose of amiodarone in renal, hepatic, or cardiac abnormalities. In patients on chronic amiodarone treatment, close clinical monitoring is advisable, especially for elderly patients and those with severe left ventricular dysfunction.

Elimination Route

Eurythmic is eliminated primarily by hepatic metabolism and biliary excretion. A small amount of desethylamiodarone (DEA) is found in the urine.

Pregnancy & Breastfeeding use

Should not be administered during pregnancy and lactation.

Contraindication

Eurythmic is contraindicated in patients with cardiogenic shock; severe sinus-node dysfunction, causing marked sinus bradycardia; second- or third degree atrioventricular block; and when episodes of bradycardia have caused syncope (except when used in conjunction with a pacemaker). Eurythmic is contraindicated in patients with a known hypersensitivity to the drug or to any of its components, including iodine.

Special Warning

Pediatric Use: The safety and effectiveness of Eurythmic HCl tablets in pediatric patients have not been established.

Geriatric Use: Clinical studies of Eurythmic HCl tablets did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Acute Overdose

There have been cases, some fatal, of Eurythmic overdose. In addition to general supportive measures, the patient's cardiac rhythm and blood pressure should be monitored, and if bradycardia ensues, a β-adrenergic agonist or a pacemaker may be used. Hypotension with inadequate tissue perfusion should be treated with positive inotropic and/or vasopressor agents. Neither Eurythmic nor its metabolite is dialyzable. The acute oral LD50 of Eurythmic HCl in mice and rats is greater than 3,000 mg/kg.

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