Dofetilide

Mechanism of effect

Vaughan Williams Class III antiarrhythmic activity. Blockade of the cardiac ion channel carrying the rapid component of the delayed rectifier potassium current. Dofetilide has no effect on sodium channels, adrenergic alpha-receptors, or adrenergic beta-receptors. It increases the monophasic action potential duration due to delayed repolarization. The increase in the QT interval is a function of prolongation of both effective and functional refractory periods in the His-Purkinje system and the ventricles. Changes in cardiac conduction velocity and sinus node function have not been observed in patients with or without structural heart disease. PR and QRS width remain the same in patients with preexisting heart block and or sick sinus syndrome.

Pharmacokinetics

Absorption:

Well absorbed

Distribution:

V_d: 3 L/kg

Metabolism:

Hepatic via CYP3A4 (low affinity); metabolites formed by N-dealkylation and N-oxidation

Excretion:

Urine (80%; ~80% as unchanged drug, 20% as inactive or minimally active metabolites); renal elimination consists of glomerular filtration and active tubular secretion via cationic transport system

Time to Peak:

Serum: Fasting: 2 to 3 hours

Half-Life Elimination:

~10 hours; prolonged with renal impairment

Protein Binding:

60% to 70%

Drug indications

Labeled Indications

Atrial fibrillation/atrial flutter: Maintenance of normal sinus rhythm in patients with chronic atrial fibrillation/atrial flutter of longer than 1-week duration who have been converted to normal sinus rhythm; conversion of atrial fibrillation and atrial flutter to normal sinus rhythm.

Dosage

Adult

Note: CrCl and QTc interval (or QT interval if heart rate is <60 beats/minute) must be determined prior to first dose. If QTc >440 msec (>500 msec in patients with ventricular conduction abnormalities), dofetilide is contraindicated. Adjust initial dosage in patients with estimated CrCl <60 mL/minute (see dosage adjustment in renal impairment). Dofetilide may be initiated at lower doses than recommended based on physician discretion; however, if the lower dose is increased, the patient will require rehospitalization for 3 days.

Atrial fibrillation/atrial flutter: Oral: Initial: 500 mcg twice daily (maximum dose: 500 mcg twice daily)*

Supraventricular tachycardia (ongoing management) (off-label use): Oral: Initial: 500 mcg every 12 hours .

Modification of dosage in response to initial dose: QTc interval should be measured 2 to 3 hours after the initial dose. If the QTc interval increases to more than 15% above baseline QTc or if the QTc is >500 msec (>550 msec in patients with ventricular conduction abnormalities), dofetilide dose should be reduced by 50%. If the starting dose was 500 mcg twice daily, then reduce to 250 mcg twice daily. If the starting dose was 250 mcg twice daily, then reduce to 125 mcg twice daily. If the starting dose was 125 mcg twice daily, then reduce to 125 mcg once daily. QTc interval should be measured 2 to 3 hours after each subsequent dose (in-hospital doses 2 through 5). If at any time after the second dose the QTc is >500 msec (>550 msec in patients with ventricular conduction abnormalities), dofetilide should be discontinued.

Maintenance therapy: No further down titration of dose based on QTc is recommended following modification of initial dose. Renal function and QTc should be re-evaluated every 3 months or as medically warranted. If QTc >500 msec (>550 msec in patients with ventricular conduction abnormalities), discontinue therapy. If renal function deteriorates, adjust dose as described in dosage adjustment in renal impairment.

Administration

Oral: Administer with or without food.

Drug contraindications

Hypersensitivity to dofetilide or any component of the formulation; congenital or acquired long QT syndromes; patients with baseline QT interval or QTc >440 msec (500 msec in patients with ventricular conduction abnormalities); severe renal impairment (CrCl <20 mL/minute); concurrent use with cimetidine, dolutegravir, hydrochlorothiazide (alone or in combinations), itraconazole (according to itraconazole prescribing information), ketoconazole, megestrol, prochlorperazine, trimethoprim (alone or in combination), or verapamil

Side effects

Side effects requiring immediate medical attention:

Along with its needed effects, dofetilide may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur while taking dofetilide:

More common

Dizziness
fainting
fast heartbeat

Less common

Chest pain
confusion
facial or flaccid paralysis
numbness or tingling of the hands, feet, or face
paralysis
pounding, slow heartbeat
slurred speech
swelling of the ankles, arms, face, feet, fingers, legs, lips, tongue, or throat
troubled breathing
unexplained shortness of breath
unusual tiredness or weakness
weight gain
yellow eyes or skin

Side effects not requiring immediate medical attention:

Some side effects of dofetilide may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects.

Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

Less common

Abdominal or stomach pain
accidental injury
back pain
chills
cough
diarrhea
fever
flu-like symptoms
general feeling of discomfort or illness
headache
joint pain
loss of appetite
migraine
muscle aches and pains
nausea
rash
runny nose
shivering
sneezing
sore throat
sweating
trouble sleeping
vomiting

You should not take dofetilide if you have severe kidney disease or a history of Long QT syndrome.

Serious drug interactions can occur when certain medicines are used together with dofetilide. Tell each of your healthcare providers about all medicines you use now, and any medicine you start or stop using.

You will need to spend at least 3 days in a hospital setting when you first start taking dofetilide. This is so your heart rhythm and kidney function can be monitored in case the medicine causes serious side effects.

You should not take dofetilide if you are allergic to it, or if you have:

severe kidney disease (or if you are on dialysis); or
a history of Long QT syndrome.

Some medicines can cause unwanted or dangerous effects when used with dofetilide, and should not be used at the same time. Your doctor may need to change your treatment plan if you use any of the following drugs:

cimetidine;
dolutegravir;
ketoconazole;
megestrol;
prochlorperazine;
trimethoprim(Proloprim, Trimpex, Bactrim, Septra);
verapamil; or
a diuretic (water pill) that contains hydrochlorothiazide(HCTZ), such as Accuretic, Aldactazide, Atacand HCT, Benicar HCT, Diovan HCT, Dyazide, Exforge HCT, Hyzaar, Lopressor HCT, Maxzide, Micardis HCT, Monopril HCT, Prinzide, Tekturna HCT, Vaseretic, and others.

To make sure dofetilide is safe for you, tell your doctor if you have:

heart disease, high blood pressure;
liver or kidney disease;
depression, mental illness;
asthmaor allergies;
any active infection;
skin problems; or
an electrolyte imbalance (such as low levels of potassium or magnesium in your blood).

Interactions

Megestrol , Chlorpromazine , Methazolamide , Buprenorphine , saquinavir , Palonosetron , vandetanib , Droperidol , sparfloxacin , Procainamide , Mefloquine , Atomoxetine , Amphotericin B , Amitriptyline , Amiodarone , Epirubicin , Adenosine , ozogamicin , dichlorphenamide , lefamulin , lofexidine , macimorelin , methotrimeprazine , osilodrostat , selpercatinib , Romidepsin , bosutinib , Methyclothiazide , Pasireotide , levomethadyl acetate , ozanimod , Siponimod , Rucaparib , Lomefloxacin , Ceritinib , Nilutamide , norfloxacin , Triclabendazole , ivosidenib , Crizotinib , Telavancin , Deutetrabenazine , Cabozantinib , Degarelix , Sodium Polystyrene Sulfonate , Foscarnet , lenvatinib , encorafenib , midostaurin , Amisulpride , Paliperidone , Pazopanib , Bendroflumethiazide , ezogabine , Iloperidone , Abiraterone , Efavirenz , Capreomycin , Gatifloxacin , Trimeprazine , Triflupromazine , Inotuzumab‎ , Idarubicin , Anagrelide , Bumetanide , Torsemide , probucol , Polyethylene glycol , Panobinostat , Ribociclib , Indapamide , Eribulin , Halothane , vemurafenib , Osimertinib , Quinine , Chloroquine , Mesoridazine , Ivabradine , Fenoldopam , Mifepristone , Dolasetron , Liposomal Amphotericin-B , Telithromycin , cortisone , dronedarone , Mirtazapine , primaquine , valbenazine , Arsenic , Amoxapine , Ziprasidone , Histrelin , propoxyphene , protriptyline , ISOPROTERENOL , Chlorothiazide , Toremifene , Tamoxifen , Metaproterenol , Prochlorperazine , Quinidine , astemizole , ethacrynic acid , Trimethoprim , Pentamidine , Quetiapine , lithium , Bicalutamide , ritodrine , Leuprolide acetate , escitalopram , Clofazimine , Ranolazine , Clarithromycin , Clozapine , Clomipramine , Solifenacin , Enzalutamide , Flecainide , Hydrocortisone , Vardenafil , Verapamil , Venlafaxine , Voriconazole , Ketoconazole , Moxifloxacin , Nortriptyline , Nilotinib , Haloperidol , Hydroxychloroquine , Hydrochlorothiazide , Lamotrigine , Lapatinib , Lidocaine , Methadone , Metolazone , Mexiletine , Fluoxetine , Fluconazole , Phenytoin , Furosemide , Fingolimod , Granisetron , Ciprofloxacin , Cisapride , Cisplatin , Flutamide , Fludrocortisone , Fluphenazine , Sunitinib , Cimetidine , Sertraline , Sotalol , Sorafenib , Sevoflurane , Desipramine , Doxepin , Doxorubicin , Disopyramide , Digoxin , Risperidone , Terbutaline , Triptorelin , Trimipramine , Thioridazine , Gemifloxacin , Daunorubicin , Posaconazole , Pimozide , Tacrolimus , Tetrabenazine , Trazodone , Tramadol , Itraconazole , Imipramine , Papaverine , perphenazine , Propafenone , Promethazine , Erythromycin , Acetazolamide , Ofloxacin , Oxaliplatin , Ondansetron , Oxytocin , Ibutilide , Goserelin , Promazine , Vasopressin , Chlorthalidone , Arsenic trioxide , Dolutegravir , Panitumumab , Halofantrine , Grepafloxacin , Terfenadine , Asenapine , Alfuzosin , Perflutren , Pimavanserin , Tafenoquine , Pitolisant , Entrectinib , Bretylium , gilteritinib , glasdegib , Eliglustat , Bepridil , bedaquiline , Dasatinib , Gemtuzumab , vemurafenib , Bictegravir , Halaven

amphotericin b cholesteryl sulfate , amphotericin b lipid complex , digoxin immune fab , doxepin topical ,ethacrynic acid , fostemsavir , hydroflumethiazide , ibutilide , polythiazide , tocainide ,trichlormethiazide

Alerts

You will need to spend at least 3 days in a hospital setting when you first start taking dofetilide. This is so your heart rhythm and kidney function can be monitored in case the medicine causes serious side effects.

You should not take dofetilide if you are allergic to it, or if you have:

severe kidney disease (or if you are on dialysis); or
a history of Long QT syndrome.

Some medicines can cause unwanted or dangerous effects when used with dofetilide, and should not be used at the same time. Your doctor may need to change your treatment plan if you use any of the following drugs:

cimetidine;
dolutegravir;
ketoconazole;
megestrol;
prochlorperazine;
trimethoprim(Proloprim, Trimpex, Bactrim, Septra);
verapamil; or
a diuretic (water pill) that contains hydrochlorothiazide(HCTZ), such as Accuretic, Aldactazide, Atacand HCT, Benicar HCT, Diovan HCT, Dyazide, Exforge HCT, Hyzaar, Lopressor HCT, Maxzide, Micardis HCT, Monopril HCT, Prinzide, Tekturna HCT, Vaseretic, and others.

To make sure dofetilide is safe for you, tell your doctor if you have:

heart disease, high blood pressure;
liver or kidney disease;
depression, mental illness;
asthmaor allergies;
any active infection;
skin problems; or
an electrolyte imbalance (such as low levels of potassium or magnesium in your blood).

Points of recommendation

It is not known whether dofetilide will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant while using this medicine.

It is not known whether dofetilide passes into breast milk or if it could harm a nursing baby. You should not breast-feed while you are using dofetilide.

Dofetilide is available only from a hospital or specialty pharmacy.

You will need to spend at least 3 days in a hospital setting when you first start taking dofetilide. This is so your heart rhythm and kidney function can be monitored in case the medicine causes serious side effects.

Follow all directions on your prescription label. Do not take this medicine in larger or smaller amounts or for longer than recommended.

You may take dofetilide with or without food.

You should not skip doses or stop using dofetilide suddenly. Stopping suddenly may make your condition worse. Follow your doctor's instructions about tapering your dose.

Tell your doctor if you have a prolonged illness that causes severe diarrhea, vomiting, or heavy sweating. These conditions can cause an electrolyte imbalance, making it dangerous for you to use dofetilide.

Your blood pressure will need to be checked often. Your kidney function may also need to be checked with frequent blood tests.

Store at room temperature away from moisture and heat.

Skip the missed dose and take your next dose at the usual time to stay on schedule. Do not take extra medicine to make up the missed dose.

Storage

Store at 15°C to 30°C (59°F to 86°F). Protect from moisture and humidity.

Pregnancy level

C

Animal studies have revealed adversely affected in utero growth and survival. There are no controlled data in human pregnancy.

This drug should be used during pregnancy only if the benefit outweighs the risk to the fetus.

US FDA pregnancy category: C

Breast feeding warning

Breastfeeding is not recommended during use of this drug.

Excreted into human milk: Unknown
Excreted into animal milk: Unknown

Comments: The effects in the nursing infant are unknown.

GENERIC DRUG INFO

suppliment

Drug information of Dofetilide