Dofetilide is a class III
antiarrhythmic agent
Antiarrhythmic agents, also known as cardiac dysrhythmia medications, are a group of pharmaceuticals that are used to suppress abnormally fast rhythms ( tachycardias), such as atrial fibrillation, supraventricular tachycardia and ventricular ta ...
.
It is marketed under the trade name Tikosyn by
Pfizer
Pfizer Inc. ( ) is an American multinational pharmaceutical and biotechnology corporation headquartered on 42nd Street in Manhattan, New York City. The company was established in 1849 in New York by two German entrepreneurs, Charles Pfizer ...
, and is available in the
United States
The United States of America (U.S.A. or USA), commonly known as the United States (U.S. or US) or America, is a country primarily located in North America. It consists of 50 states, a federal district, five major unincorporated territori ...
in capsules containing 125, 250, and 500
µg
In the metric system, a microgram or microgramme is a unit of mass equal to one millionth () of a gram. The unit symbol is μg according to the International System of Units (SI); the recommended symbol in the United States and United Kingdom whe ...
of dofetilide. It is not available in Europe
or Australia. In the United States it is only available by mail order or through specially trained local pharmacies.
[TIKOSYN® (dofetilide). Pfizer. .]
Medical uses
Dofetilide is used for the maintenance of
sinus rhythm
A sinus rhythm is any cardiac rhythm in which depolarisation of the cardiac muscle begins at the sinus node. It is characterised by the presence of correctly oriented P waves on the electrocardiogram (ECG). Sinus rhythm is necessary, but not s ...
in individuals prone to the occurrence of
atrial fibrillation and
flutter arrhythmias, and for chemical
cardioversion
Cardioversion is a medical procedure by which an abnormally fast heart rate ( tachycardia) or other cardiac arrhythmia is converted to a normal rhythm using electricity or drugs. Synchronized electrical cardioversion uses a therapeutic dose ...
to sinus rhythm from
atrial fibrillation and
flutter.
Based on the results of the Danish Investigations of Arrhythmias and Mortality on Dofetilide ("DIAMOND") study, dofetilide does not affect mortality in the treatment of patients post-
myocardial infarction
A myocardial infarction (MI), commonly known as a heart attack, occurs when blood flow decreases or stops to the coronary artery of the heart, causing damage to the heart muscle. The most common symptom is chest pain or discomfort which may ...
with
left ventricular
A ventricle is one of two large chambers toward the bottom of the heart that collect and expel blood towards the peripheral beds within the body and lungs. The blood pumped by a ventricle is supplied by an atrium, an adjacent chamber in the upper ...
dysfunction, however it was shown to decrease all-cause readmissions as well as
CHF-related readmissions.
Because of the results of the DIAMOND study, some physicians use dofetilide in the suppression of atrial fibrillation in individuals with LV dysfunction, however use appears limited: After initially receiving marketing approval in Europe in 1999, Pfizer voluntarily withdrew this approval in 2004 for commercial reasons
and it is not registered in other first world countries.
It has clinical advantages over other class III antiarrhythmics in chemical cardioversion of atrial fibrillation, and maintenance of sinus rhythm, and does not have the pulmonary or hepatotoxicity of amiodarone, however atrial fibrillation is not generally considered life-threatening, and dofetilide causes an increased rate of potentially life-threatening arrhythmias in comparison to other therapies.
Contraindications
Prior to administration of the first dose, the
corrected QT (QTc) must be determined. If the QTc is greater than 440 msec (or 500 msec in patients with
ventricular conduction abnormalities), dofetilide is contraindicated. If heart rate is less than 60 bpm, the uncorrected
QT interval should be used. After each subsequent dose of dofetilide, QTc should be determined and dosing should be adjusted. If at any time after the second dose of dofetilide the QTc is greater than 500 msec (550 msec in patients with ventricular conduction abnormalities), dofetilide should be discontinued.
Adverse effects
Torsades de pointes
''Torsades de pointes, torsade de pointes'' or ''torsades des pointes'' (TdP) (, , translated as "twisting of peaks") is a specific type of abnormal heart rhythm that can lead to sudden cardiac death. It is a polymorphic ventricular tachycardia t ...
is the most serious side effect of dofetilide therapy. The incidence of torsades de pointes is 0.3-10.5% and is dose-related, with increased incidence associated with higher doses. The majority of episodes of torsades de pointes have occurred within the first three days of initial dosing. Patients should be hospitalized and monitored for the first three days after starting dofetilide.
The risk of inducing torsades de pointes can be decreased by taking precautions when initiating therapy, such as hospitalizing individuals for a minimum of three days for serial
creatinine
Creatinine (; ) is a breakdown product of creatine phosphate from muscle and protein metabolism. It is released at a constant rate by the body (depending on muscle mass).
Biological relevance
Serum creatinine (a blood measurement) is an importa ...
measurement, continuous
telemetry
Telemetry is the in situ collection of measurements or other data at remote points and their automatic transmission to receiving equipment (telecommunication) for monitoring. The word is derived from the Greek roots ''tele'', "remote", an ...
monitoring and availability of cardiac resuscitation.
Pharmacology
Mechanism of action
Dofetilide works by selectively blocking the rapid component of the
delayed rectifier outward potassium current (I
Kr).
This causes the refractory period of atrial tissue to increase, hence its effectiveness in the treatment of atrial fibrillation and atrial flutter.
Dofetilide does not affect dV/dT
max (the
slope
In mathematics, the slope or gradient of a line is a number that describes both the ''direction'' and the ''steepness'' of the line. Slope is often denoted by the letter ''m''; there is no clear answer to the question why the letter ''m'' is use ...
of the upstroke of phase 0 depolarization), conduction velocity, or the resting membrane potential.
There is a dose-dependent increase in the QT interval and the corrected QT interval (QTc). Because of this, many practitioners will initiate dofetilide therapy only on individuals under telemetry monitoring or if serial EKG measurements of QT and QTc can be performed.
Pharmacokinetics
Peak plasma concentrations are seen two to three hours after oral dosing when
fasting
Fasting is the abstention from eating and sometimes drinking. From a purely physiological context, "fasting" may refer to the metabolic status of a person who has not eaten overnight (see " Breakfast"), or to the metabolic state achieved after ...
. Dofetilide is well absorbed in its oral form, with a
bioavailability
In pharmacology, bioavailability is a subcategory of absorption and is the fraction (%) of an administered drug that reaches the systemic circulation.
By definition, when a medication is administered intravenously, its bioavailability is 100%. Ho ...
of >90%. Intravenous administration of dofetilide is not available in the United States.
The elimination
half-life
Half-life (symbol ) is the time required for a quantity (of substance) to reduce to half of its initial value. The term is commonly used in nuclear physics to describe how quickly unstable atoms undergo radioactive decay or how long stable at ...
of dofetilide is roughly 10 hours; however, this varies based on many physiologic factors (most significantly
creatinine clearance
Assessment of kidney function occurs in different ways, using the presence of symptoms and signs, as well as measurements using urine tests, blood tests, and medical imaging.
Functions of a healthy kidney include maintaining a person's fluid ...
), and ranges from 4.8 to 13.5 hours. Due to the significant level of renal elimination (80% unchanged, 20% metabolites), the dose of dofetilide must be adjusted to prevent toxicity due to impaired renal function.
Dofetilide is metabolized predominantly by
CYP3A4 enzymes predominantly in the
liver
The liver is a major organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the synthesis of proteins and biochemicals necessary for digestion and growth. In humans, it ...
and
GI tract
The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the digestive system that leads from the mouth to the anus. The GI tract contains all the major organs of the digestive system, in humans ...
. This means that it is likely to interact with drugs that inhibit CYP3A4, such as
erythromycin,
clarithromycin
Clarithromycin, sold under the brand name Biaxin among others, is an antibiotic used to treat various bacterial infections. This includes strep throat, pneumonia, skin infections, '' H. pylori'' infection, and Lyme disease, among others. Clarith ...
, or
ketoconazole, resulting in higher and potentially toxic levels of dofetilide.
Metabolism
A steady-state plasma level of dofetilide is achieved in 2–3 days.
80% of dofetilide is excreted by the
kidney
The kidneys are two reddish-brown bean-shaped organs found in vertebrates. They are located on the left and right in the retroperitoneal space, and in adult humans are about in length. They receive blood from the paired renal arteries; blo ...
s, so the dose of dofetilide should be adjusted in individuals with
chronic kidney disease, based on
creatinine clearance
Assessment of kidney function occurs in different ways, using the presence of symptoms and signs, as well as measurements using urine tests, blood tests, and medical imaging.
Functions of a healthy kidney include maintaining a person's fluid ...
.
In the kidneys, dofetilide is eliminated via cation exchange (secretion). Agents that interfere with the renal cation exchange system, such as
verapamil
Verapamil, sold under various trade names, is a calcium channel blocker medication used for the treatment of high blood pressure, angina (chest pain from not enough blood flow to the heart), and supraventricular tachycardia. It may also be ...
,
cimetidine,
hydrochlorothiazide
Hydrochlorothiazide is a diuretic medication often used to treat high blood pressure and swelling due to fluid build-up. Other uses include treating diabetes insipidus and renal tubular acidosis and to decrease the risk of kidney stones in ...
,
itraconazole
Itraconazole, sometimes abbreviated ITZ, is an antifungal medication used to treat a number of fungal infections. This includes aspergillosis, blastomycosis, coccidioidomycosis, histoplasmosis, and paracoccidioidomycosis. It may be given by mo ...
,
ketoconazole,
prochlorperazine
Prochlorperazine, formerly sold under the brand name Compazine among others, is a medication used to treat nausea, migraines, schizophrenia, psychosis and anxiety. It is a less preferred medication for anxiety. It may be taken by mouth, rectally ...
, and
trimethoprim
Trimethoprim (TMP) is an antibiotic used mainly in the treatment of bladder infections. Other uses include for middle ear infections and travelers' diarrhea. With sulfamethoxazole or dapsone it may be used for ''Pneumocystis'' pneumonia in peo ...
should not be administered to individuals taking dofetilide.
About 20 percent of dofetilide is metabolized in the liver via the
CYP3A4 isoenzyme of the
cytochrome P450
Cytochromes P450 (CYPs) are a superfamily of enzymes containing heme as a cofactor that functions as monooxygenases. In mammals, these proteins oxidize steroids, fatty acids, and xenobiotics, and are important for the clearance of various co ...
enzyme system. Drugs that interfere with the activity of the
CYP3A4 isoenzyme can increase serum dofetilide levels. If the renal cation exchange system is interfered with (as with the medications listed above), a larger percentage of dofetilide is cleared via the
CYP3A4 isoenzyme system.
History
After its initial US FDA approval, due to the pro-arrhythmic potential it was only made available to hospitals and prescribers that had received education and undergone specific training in the risks of treatment with dofetilide; however, this restriction was subsequently removed in 2016.
See also
*
Antiarrhythmic agents
Antiarrhythmic agents, also known as cardiac dysrhythmia medications, are a group of pharmaceuticals that are used to suppress abnormally fast rhythms ( tachycardias), such as atrial fibrillation, supraventricular tachycardia and ventricular ta ...
*
Cardiac action potential
The cardiac action potential is a brief change in voltage ( membrane potential) across the cell membrane of heart cells. This is caused by the movement of charged atoms (called ions) between the inside and outside of the cell, through proteins c ...
*
Electrocardiogram
References
{{Antiarrhythmic agents
Sulfonamides
Pfizer brands
Potassium channel blockers
Phenol ethers