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Dofetilide
Overview
What is Dofetilide?
Dofetilide is an antiarrhythmic drug with Class III (cardiac action potential duration prolonging) properties. Its empirical formula is CHNOS and it has a molecular weight of 441.6. The structural formula is
The chemical name for dofetilide is:
N
Dofetilide is a white to off-white powder. It is very slightly soluble in water and propan-2-ol and is soluble in 0.1M aqueous sodium hydroxide, acetone, and aqueous 0.1M hydrochloric acid.
Dofetilide capsules contain the following inactive ingredients: microcrystalline cellulose, corn starch, colloidal silicon dioxide and magnesium stearate. The capsule shells contain gelatin, titanium dioxide, FD&C yellow 6 and black imprint ink. The black imprint ink contains shellac, alcohol, isopropyl alcohol, butyl alcohol, propylene glycol, ammonia solution, black iron oxide and potassium hydroxide. Dofetilide capsules are supplied for oral administration in three dosage strengths: 125 mcg (0.125 mg) orange and white capsules, 250 mcg (0.25 mg) peach capsules, and 500 mcg (0.5 mg) peach and white capsules.
What does Dofetilide look like?
What are the available doses of Dofetilide?
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What should I talk to my health care provider before I take Dofetilide?
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How should I use Dofetilide?
Dofetilide is indicated for the maintenance of normal sinus rhythm (delay in time to recurrence of atrial fibrillation/atrial flutter [AF/AFl]) in patients with atrial fibrillation/atrial flutter of greater than one week duration who have been converted to normal sinus rhythm. Because Dofetilide can cause life threatening ventricular arrhythmias, it should be reserved for patients in whom atrial fibrillation/atrial flutter is highly symptomatic.
In general, antiarrhythmic therapy for atrial fibrillation/atrial flutter aims to prolong the time in normal sinus rhythm. Recurrence is expected in some patients (see ).
Therapy with Dofetilide must be initiated (and, if necessary, re-initiated) in a setting that provides continuous electrocardiographic (ECG) monitoring and in the presence of personnel trained in the management of serious ventricular arrhythmias. Patients should continue to be monitored in this way for a minimum of three days. Additionally, patients should not be discharged within 12 hours of electrical or pharmacological conversion to normal sinus rhythm.
The dose of Dofetilide must be individualized according to calculated creatinine clearance and QTc. (QT interval should be used if the heart rate is <60 beats per minute. There are no data on use of Dofetilide when the heart rate is <50 beats per minute.)
Special Considerations
Serum potassium should be maintained within the normal range before Dofetilide treatment is initiated and should be maintained within the normal range while the patient remains on Dofetilide therapy. (See ). In clinical trials, potassium levels were generally maintained above 3.6-4.0 m Eq/L.
Patients with atrial fibrillation should be anticoagulated according to usual medical practice prior to electrical or pharmacological cardioversion. Anticoagulant therapy may be continued after cardioversion according to usual medical practice for the treatment of people with AF. Hypokalemia should be corrected before initiation of Dofetilide therapy (see ).
Patients to be discharged on Dofetilide therapy from an inpatient setting as described above must have an adequate supply of Dofetilide, at the patient’s individualized dose, to allow uninterrupted dosing until the patient can fill a Dofetilide prescription.
What interacts with Dofetilide?
Dofetilide is contraindicated in patients with congenital or acquired long QT syndromes. Dofetilide should not be used in patients with a baseline QT interval or QTc >440 msec (500 msec in patients with ventricular conduction abnormalities). Dofetilide is also contraindicated in patients with severe renal impairment (calculated creatinine clearance <20 mL/min).
The concomitant use of verapamil or the cation transport system inhibitors cimetidine, trimethoprim (alone or in combination with sulfamethoxazole), or ketoconazole with Dofetilide is contraindicated (see ), as each of these drugs cause a substantial increase in dofetilide plasma concentrations. In addition, other known inhibitors of the renal cation transport system such as prochlorperazine, dolutegravir and megestrol should not be used in patients on Dofetilide.
The concomitant use of hydrochlorothiazide (alone or in combinations such as with triamterene) with Dofetilide is contraindicated (see ) because this has been shown to significantly increase Dofetilide plasma concentrations and QT interval prolongation.
Dofetilide is also contraindicated in patients with a known hypersensitivity to the drug.
What are the warnings of Dofetilide?
Ventricular Arrhythmia
Dofetilide can cause serious ventricular arrhythmias, primarily Torsade de Pointes (TdP) type ventricular tachycardia, a polymorphic ventricular tachycardia associated with QT interval prolongation. QT interval prolongation is directly related to dofetilide plasma concentration. Factors such as reduced creatinine clearance or certain dofetilide drug interactions will increase dofetilide plasma concentration. The risk of TdP can be reduced by controlling the plasma concentration through adjustment of the initial dofetilide dose according to creatinine clearance and by monitoring the ECG for excessive increases in the QT interval.
Treatment with dofetilide must therefore be started only in patients placed for a minimum of three days in a facility that can provide electrocardiographic monitoring and in the presence of personnel trained in the management of serious ventricular arrhythmias. Calculation of the creatinine clearance for all patients must precede administration of the first dose of dofetilide. For detailed instructions regarding dose selection, see DOSAGE AND ADMINISTRATION.
The risk of dofetilide induced ventricular arrhythmia was assessed in three ways in clinical studies: 1) by description of the QT interval and its relation to the dose and plasma concentration of dofetilide; 2) by observing the frequency of TdP in Dofetilide-treated patients according to dose; 3) by observing the overall mortality rate in patients with atrial fibrillation and in patients with structural heart disease.
Relation of QT Interval to Dose
The QT interval increases linearly with increasing Dofetilide dose (see Figures 1 and 2 in ).
Frequency of Torsade de Pointes
In the supraventricular arrhythmia population (patients with AF and other supraventricular arrhythmias), the overall incidence of Torsade de Pointes was 0.8%. The frequency of TdP by dose is shown in Table 4. There were no cases of TdP on placebo.
As shown in Table 5, the rate of TdP was reduced when patients were dosed according to their renal function (see and ).
The majority of the episodes of TdP occurred within the first three days of Dofetilide therapy (10/11 events in the studies of patients with supraventricular arrhythmias; 19/25 and 4/7 events in DIAMOND CHF and DIAMOND MI, respectively; 2/4 events in the DIAMOND AF subpopulation).
| Dofetilide Dose | |||||
|---|---|---|---|---|---|
| <250 mcg BID | 250 mcg BID | >250-500 mcg BID | >500 mcg BID | All Doses | |
| Number of Patients | 217 | 388 | 703 | 38 | 1346 |
| Torsade de Pointes | 0 | 1 (0.3%) | 6 (0.9%) | 4 (10.5%) | 11(0.8%) |
| Total | Before | After | |||
| Population | n/N% | n/N% | n/N% | ||
| Supraventricular Arrhythamias | 11/1346 (0.8%) | 6/193 (3.1%) | 5/1153 (0.4%) | ||
| DAIMOND CHF | 25/762 (3.3%) | 7/148 (4.7%) | 18/614 (2.9%) | ||
| DAIMOND MI | 7/749 (0.9%) | 3/101 (3.0%) | 4/648 (0.6%) | ||
| DAIMOND AF | 4/249 (1.6%) | 0/43 (0%) | 4/206 (1.9%) |
Mortality
In a pooled survival analysis of patients in the supraventricular arrhythmia population (low prevalence of structural heart disease), deaths occurred in 0.9% (12/1346) of patients receiving Dofetilide and 0.4% (3/677) in the placebo group. Adjusted for duration of therapy, primary diagnosis, age, gender, and prevalence of structural heart disease, the point estimate of the hazard ratio for the pooled studies (Dofetilide /placebo) was 1.1 (95% CI: 0.3, 4.3). The DIAMOND CHF and MI trials examined mortality in patients with structural heart disease (ejection fraction ≤35%). In these large, double-blind studies, deaths occurred in 36% (541/1511) of Dofetilide patients and 37% (560/1517) of placebo patients. In an analysis of 506 DIAMOND patients with atrial fibrillation/flutter at baseline, one year mortality on Dofetilide was 31% vs. 32% on placebo (see ).
Because of the small number of events, an excess mortality due to Dofetilide cannot be ruled out with confidence in the pooled survival analysis of placebo-controlled trials in patients with supraventricular arrhythmias. However, it is reassuring that in two large placebo-controlled mortality studies in patients with significant heart disease (DIAMOND CHF/MI), there were no more deaths in Dofetilide-treated patients than in patients given placebo (see ).
Drug-Drug Interactions
(see CONTRAINDICATIONS)
Because there is a linear relationship between dofetilide plasma concentration and QTc, concomitant drugs that interfere with the metabolism or renal elimination of dofetilide may increase the risk of arrhythmia (Torsade de Pointes). Dofetilide is metabolized to a small degree by the CYP3A4 isoenzyme of the cytochrome P450 system and an inhibitor of this system could increase systemic dofetilide exposure. More important, dofetilide is eliminated by cationic renal secretion, and three inhibitors of this process have been shown to increase systemic dofetilide exposure. The magnitude of the effect on renal elimination by cimetidine, trimethoprim, and ketoconazole (all contraindicated concomitant uses with dofetilide) suggests that all renal cation transport inhibitors should be contraindicated.
Hypokalemia and Potassium-Depleting Diuretics
Hypokalemia or hypomagnesemia may occur with administration of potassium-depleting diuretics, increasing the potential for Torsade de Pointes. Potassium levels should be within the normal range prior to administration of Dofetilide and maintained in the normal range during administration of Dofetilide (see ).
Use with Drugs that Prolong QT Interval and Antiarrhythmic Agents
The use of Dofetilide in conjunction with other drugs that prolong the QT interval has not been studied and is not recommended. Such drugs include phenothiazines, cisapride, bepridil, tricyclic antidepressants, certain oral macrolides, and certain fluoroquinolones. Class I or Class III antiarrhythmic agents should be withheld for at least three half-lives prior to dosing with Dofetilide. In clinical trials, Dofetilide was administered to patients previously treated with oral amiodarone only if serum amiodarone levels were below 0.3mg/L or amiodarone had been withdrawn for at least three months.
What are the precautions of Dofetilide?
Renal Impairment
The overall systemic clearance of dofetilide is decreased and plasma concentration increased with decreasing creatinine clearance. The dose of Dofetilide must be adjusted based on creatinine clearance (see ). Patients undergoing dialysis were not included in clinical studies, and appropriate dosing recommendations for these patients are unknown. There is no information about the effectiveness of hemodialysis in removing dofetilide from plasma.
Hepatic Impairment
After adjustment for creatinine clearance, no additional dose adjustment is required for patients with mild or moderate hepatic impairment. Patients with severe hepatic impairment have not been studied. Dofetilide should be used with particular caution in these patients.
Cardiac Conduction Disturbances
Animal and human studies have not shown any adverse effects of dofetilide on conduction velocity. No effect on AV nodal conduction following Dofetilide treatment was noted in normal volunteers and in patients with 1 degree heart block. Patients with sick sinus syndrome or with 2 or 3 degree heart block were not included in the Phase 3 clinical trials unless a functioning pacemaker was present. Dofetilide has been used safely in conjunction with pacemakers (53 patients in DIAMOND studies, 136 in trials in patients with ventricular and supraventricular arrhythmias).
Information for Patients
Please refer patient to the Medication Guide.
Prior to initiation of Dofetilide therapy, the patient should be advised to read the Medication Guide and reread it each time therapy is renewed in case the patient’s status has changed. The patient should be fully instructed on the need for compliance with the recommended dosing of Dofetilide and the potential for drug interactions, and the need for periodic monitoring of QTc and renal function to minimize the risk of serious abnormal rhythms.
Medications and Supplements
Assessment of patients' medication history should include all over-the-counter, prescription, and herbal/natural preparations with emphasis on preparations that may affect the pharmacokinetics of Dofetilide such as cimetidine (see ), trimethoprim alone or in combination with sulfamethoxazole (see ), prochlorperazine (see ), megestrol (see ), ketoconazole (see ), dolutegravir (see ), hydrochlorothiazide (alone or in combinations such as with triamterene) (see ), other cardiovascular drugs (especially verapamil – see ), phenothiazines, and tricyclic antidepressants (see ). If a patient is taking Dofetilide and requires anti-ulcer therapy, omeprazole, ranitidine, or antacids (aluminum and magnesium hydroxides) should be used as alternatives to cimetidine, as these agents have no effect on the pharmacokinetics of Dofetilide. Patients should be instructed to notify their health care providers of any change in over-the-counter, prescription, or supplement use. If a patient is hospitalized or is prescribed a new medication for any condition, the patient must inform the healthcare provider of ongoing Dofetilide therapy. Patients should also check with their health care provider and/or pharmacist prior to taking a new over-the-counter preparation.
Electrolyte Imbalance
If patients experience symptoms that may be associated with altered electrolyte balance, such as excessive or prolonged diarrhea, sweating, or vomiting or loss of appetite or thirst, these conditions should immediately be reported to their healthcare provider.
Dosing Schedule
Patients should be instructed NOT to double the next dose if a dose is missed. The next dose should be taken at the usual time.
Drug/Laboratory Test Interactions
None known.
Drug-Drug Interactions
Cimetidine
(see ) Concomitant use of cimetidine is contraindicated. Cimetidine at 400 mg BID (the usual prescription dose) co-administered with Dofetilide (500 mcg BID) for 7 days has been shown to increase dofetilide plasma levels by 58%. Cimetidine at doses of 100 mg BID (OTC dose) resulted in a 13% increase in dofetilide plasma levels (500 mcg single dose). No studies have been conducted at intermediate doses of cimetidine. If a patient requires Dofetilide and anti-ulcer therapy, it is suggested that omeprazole, ranitidine, or antacids (aluminum and magnesium hydroxides) be used as alternatives to cimetidine, as these agents have no effect on the pharmacokinetic profile of Dofetilide.
Verapamil
(see ) Concomitant use of verapamil is contraindicated. Co-administration of Dofetilide with verapamil resulted in increases in dofetilide peak plasma levels of 42%, although overall exposure to dofetilide was not significantly increased. In an analysis of the supraventricular arrhythmia and DIAMOND patient populations, the concomitant administration of verapamil with dofetilide was associated with a higher occurrence of Torsade de Pointes.
Ketoconazole
(see ) Concomitant use of ketoconazole is contraindicated. Ketoconazole at 400 mg daily (the maximum approved prescription dose) co-administered with Dofetilide (500 mcg BID) for 7 days has been shown to increase dofetilide C by 53% in males and 97% in females, and AUC by 41% in males and 69% in females.
Trimethoprim Alone or in Combination with Sulfamethoxazole
(see ) Concomitant use of trimethoprim alone or in combination with sulfamethoxazole is contraindicated. Trimethoprim 160 mg in combination with 800 mg sulfamethoxazole co-administered BID with Dofetilide (500 mcg BID) for 4 days has been shown to increase Dofetilide AUC by 103% and C by 93%.
Hydrochlorothiazide (HCTZ) Alone or in Combination with Triamterene
(see ) Concomitant use of HCTZ alone or in combination with triamterene is contraindicated. HCTZ 50 mg QD or HCTZ/triamterene 50/100 mg QD was co-administered with Dofetilide (500 mcg BID) for 5 days (following 2 days of diuretic use at half dose). In patients receiving HCTZ alone, dofetilide AUC increased by 27% and C by 21%. However, the pharmacodynamic effect increased by 197% (QTc increase over time) and by 95% (maximum QTc increase). In patients receiving HCTZ in combination with triamterene, dofetilide AUC increased by 30% and C by 16%. However, the pharmacodynamic effect increased by 190% (QTc increase over time) and by 84% (maximum QTc increase). The pharmacodynamic effects can be explained by a combination of the increase in dofetilide exposure and the reductions in serum potassium. In the DIAMOND trials, 1252 patients were treated with Dofetilide and diuretics concomitantly, of whom 493 died compared to 508 deaths among the 1248 patients receiving placebo and diuretics. Of the 229 patients who had potassium depleting diuretics added to their concomitant medications in the DIAMOND trials, the patients on Dofetilide had a non-significantly reduced relative risk for death of 0.68 (95% CI: 0.376, 1.230).
Potential Drug Interactions
Dofetilide is eliminated in the kidney by cationic secretion. Inhibitors of renal cationic secretion are contraindicated with Dofetilide. In addition, drugs that are actively secreted via this route (e.g., triamterene, metformin, and amiloride) should be co-administered with care as they might increase dofetilide levels.
Dofetilide is metabolized to a small extent by the CYP3A4 isoenzyme of the cytochrome P450 system. Inhibitors of the CYP3A4 isoenzyme could increase systemic dofetilide exposure. Inhibitors of this isoenzyme (e.g., macrolide antibiotics, azole antifungal agents, protease inhibitors, serotonin reuptake inhibitors, amiodarone, cannabinoids, diltiazem, grapefruit juice, nefazadone, norfloxacin, quinine, zafirlukast) should be cautiously co-administered with Dofetilide as they can potentially increase dofetilide levels. Dofetilide is not an inhibitor of CYP3A4 nor of other cytochrome P450 isoenzymes (e.g., CYP2C9, CYP2D6) and is not expected to increase levels of drugs metabolized by CYP3A4.
Other Drug Interaction Information
Digoxin
Studies in healthy volunteers have shown that Dofetilide does not affect the pharmacokinetics of digoxin. In patients, the concomitant administration of digoxin with dofetilide was associated with a higher occurrence of Torsade de Pointes. It is not clear whether this represents an interaction with Dofetilide or the presence of more severe structural heart disease in patients on digoxin; structural heart disease is a known risk factor for arrhythmia. No increase in mortality was observed in patients taking digoxin as concomitant medication.
Other Drugs
In healthy volunteers, amlodipine, phenytoin, glyburide, ranitidine, omeprazole, hormone replacement therapy (a combination of conjugated estrogens and medroxyprogesterone), antacid (aluminum and magnesium hydroxides), and theophylline did not affect the pharmacokinetics of Dofetilide. In addition, studies in healthy volunteers have shown that Dofetilide does not affect the pharmacokinetics or pharmacodynamics of warfarin, or the pharmacokinetics of propranolol (40 mg twice daily), phenytoin, theophylline, or oral contraceptives.
Population pharmacokinetic analyses were conducted on plasma concentration data from 1445 patients in clinical trials to examine the effects of concomitant medications on clearance or volume of distribution of dofetilide. Concomitant medications were grouped as ACE inhibitors, oral anticoagulants, calcium channel blockers, beta blockers, cardiac glycosides, inducers of CYP3A4, substrates and inhibitors of CYP3A4, substrates and inhibitors of P‑glycoprotein, nitrates, sulphonylureas, loop diuretics, potassium sparing diuretics, thiazide diuretics, substrates and inhibitors of tubular organic cation transport, and QTc-prolonging drugs. Differences in clearance between patients on these medications (at any occasion in the study) and those off medications varied between -16% and +3%. The mean clearances of dofetilide were 16% and 15% lower in patients on thiazide diuretics and inhibitors of tubular organic cation transport, respectively.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Dofetilide had no genotoxic effects, with or without metabolic activation, based on the bacterial mutation assay and tests of cytogenetic aberrations in mouse bone marrow and in human lymphocytes. Rats and mice treated with dofetilide in the diet for two years showed no evidence of an increased incidence of tumors compared to controls. The highest dofetilide dose administered for 24 months was 10 mg /kg /day to rats and 20 mg/kg/day to mice. Mean dofetilide AUCs at these doses were about 26 and 10 times, respectively, the maximum likely human AUC.
There was no effect on mating or fertility when dofetilide was administered to male and female rats at doses as high as 1.0 mg /kg /day, a dose that would be expected to provide a mean dofetilide AUC about 3 times the maximum likely human AUC. Increased incidences of testicular atrophy and epididymal oligospermia and a reduction in testicular weight were, however, observed in other studies in rats. Reduced testicular weight and increased incidence of testicular atrophy were also consistent findings in dogs and mice. The no effect doses for these findings in chronic administration studies in these 3 species (3, 0.1, and 6 mg/kg/day) were associated with mean dofetilide AUCs that were about 4, 1.3, and 3 times the maximum likely human AUC, respectively.
Pregnancy Category C
Dofetilide has been shown to adversely affect growth and survival of rats and mice when orally administered during organogenesis at doses of 2 or more mg/kg/day. Other than an increased incidence of non-ossified 5 metacarpal, and the occurrence of hydroureter and hydronephroses at doses as low as 1 mg /kg/day in the rat, structural anomalies associated with drug treatment were not observed in either species at doses below 2 mg/kg/day. The clearest drug-effect associations were for sternebral and vertebral anomalies in both species; cleft palate, adactyly, levocardia, dilation of cerebral ventricles, hydroureter, hydronephroses, and unossified metacarpal in the rat; and increased incidence of unossified calcaneum in the mouse. The "no observed adverse effect dose" in both species was 0.5 mg/kg/day. The mean dofetilide AUCs at this dose in the rat and mouse are estimated to be about equal to the maximum likely human AUC and about half the likely human AUC, respectively. There are no adequate and well controlled studies in pregnant women. Therefore, dofetilide should only be administered to pregnant women where the benefit to the patient justifies the potential risk to the fetus.
Nursing Mothers
There is no information on the presence of dofetilide in breast milk. Patients should be advised not to breast-feed an infant if they are taking Dofetilide.
Geriatric Use
Of the total number of patients in clinical studies of Dofetilide, 46% were 65 to 89 years old. No overall differences in safety, effect on QTc, or effectiveness were observed between elderly and younger patients. Because elderly patients are more likely to have decreased renal function with a reduced creatinine clearance, care must be taken in dose selection (see ).
Use in Women
Female patients constituted 32% of the patients in the placebo-controlled trials of Dofetilide. As with other drugs that cause Torsade de Pointes, Dofetilide was associated with a greater risk of Torsade de Pointes in female patients than in male patients. During the Dofetilide clinical development program, the risk of Torsade de Pointes in females was approximately 3 times the risk in males. Unlike Torsade de Pointes, the incidence of other ventricular arrhythmias was similar in female patients receiving Dofetilide and patients receiving placebo. Although no study specifically investigated this risk, in post-hoc analyses, no increased mortality was observed in females on Dofetilide compared to females on placebo.
Pediatric Use
The safety and effectiveness of Dofetilide in children (<18 years old) has not been established.
What are the side effects of Dofetilide?
The Dofetilide clinical program involved approximately 8,600 patients in 130 clinical studies of normal volunteers and patients with supraventricular and ventricular arrhythmias. Dofetilide was administered to 5,194 patients, including two large, placebo-controlled mortality trials (DIAMOND CHF and DIAMOND MI) in which 1,511 patients received Dofetilide for up to three years.
In the following section, adverse reaction data for cardiac arrhythmias and non-cardiac adverse reactions are presented separately for patients included in the supraventricular arrhythmia development program and for patients included in the DIAMOND CHF and MI mortality trials (see , for a description of these trials).
In studies of patients with supraventricular arrhythmias, a total of 1,346 and 677 patients were exposed to Dofetilide and placebo for 551 and 207 patient years, respectively. A total of 8.7% of patients in the dofetilide groups were discontinued from clinical trials due to adverse events compared to 8.0% in the placebo groups. The most frequent reason for discontinuation (>1%) was ventricular tachycardia (2.0% on dofetilide vs. 1.3% on placebo). The most frequent adverse events were headache, chest pain, and dizziness.
Serious Arrhythmias and Conduction Disturbances
Torsade de Pointes is the only arrhythmia that showed a dose-response relationship to Dofetilide treatment. It did not occur in placebo treated patients. The incidence of Torsade de Pointes in patients with supraventricular arrhythmias was 0.8% (11/1346) (see ). The incidence of Torsade de Pointes in patients who were dosed according to the recommended dosing regimen (see ) was 0.8% (4/525). Table 6 shows the frequency by randomized dose of serious arrhythmias and conduction disturbances reported as adverse events in patients with supraventricular arrhythmias.
In DIAMOND trials, a total of 1,511 patients were exposed to Dofetilide for 1757 patient years. The incidence of Torsade de Pointes was 3.3% in CHF patients and 0.9% in patients with a recent MI.
Table 7 shows the incidence of serious arrhythmias and conduction disturbances reported as adverse events in the DIAMOND subpopulation that had AF at entry to these trials.
Array
| Dofetilide Dose | Placebo | ||||
|---|---|---|---|---|---|
| Arrhythmia event: | <250 mcg BIDN = 217 | 250 mcg BIDN = 388 | >250-500 mcg BIDN = 703 | >500 mcg BIDN = 38 | N = 677 |
| Ventricular Arrhythmias | 3.7 % | 2.6 % | 3.4 % | 15.8 % | 2.7 % |
| Ventricular fibrillation | 0 | 0.3 % | 0.4 % | 2.6 % | 0.1 % |
| Ventricular tachycardia | 3.7 % | 2.6 % | 3.3 % | 13.2 % | 2.5 % |
| Torsade de Pointes | 0 | 0.3 % | 0.9 % | 10.5 % | 0 |
| Various forms of block | |||||
| AV block | 0.9 % | 1.5 % | 0.4 % | 0 | 0.3 % |
| Bundle branch block | 0 | 0.5 % | 0.1 % | 0 | 0.1 % |
| Heart block | 0 | 0.5 % | 0.1 % | 0 | 0.1 % |
| Dofetilide | Placebo | ||||
| N = 249 | N = 257 | ||||
| Ventricular Arrhythmias | 14.5 % | 13.6 % | |||
| Ventricular fibrillation | 4.8 % | 3.1 % | |||
| Ventricular tachycardia | 12.4 % | 11.3 % | |||
| Torsade de Pointes | 1.6 % | 0 | |||
| Various forms of block | |||||
| AV block | 0.8 % | 2.7 % | |||
| (Left) Bundle branch block | 0 | 0.4 % | |||
| Heart block | 1.2 % | 0.8 % |
Other Adverse Reactions
Table 8 presents other adverse events reported with a frequency of >2% on Dofetilide and reported numerically more frequently on Dofetilide than on placebo in the studies of patients with supraventricular arrhythmias.
Adverse events reported at a rate >2% but no more frequently on Dofetilide than on placebo were: angina pectoris, anxiety, arthralgia, asthenia, atrial fibrillation, complications (application, injection, incision, insertion, or device), hypertension, pain, palpitation, peripheral edema, supraventricular tachycardia, sweating, urinary tract infection, ventricular tachycardia.
The following adverse events have been reported with a frequency of ≤2% and numerically more frequently with Dofetilide than placebo in patients with supraventricular arrhythmias: angioedema, bradycardia, cerebral ischemia, cerebrovascular accident, edema, facial paralysis, flaccid paralysis, heart arrest, increased cough, liver damage, migraine, myocardial infarct, paralysis, paresthesia, sudden death, and syncope.
The incidences of clinically significant laboratory test abnormalities in patients with supraventricular arrhythmias were similar for patients on Dofetilide and those on placebo. No clinically relevant effects were noted in serum alkaline phosphatase, serum GGT, LDH, AST, ALT, total bilirubin, total protein, blood urea nitrogen, creatinine, serum electrolytes (calcium, chloride, glucose, magnesium, potassium, sodium), or creatine kinase. Similarly, no clinically relevant effects were observed in hematologic parameters.
In the DIAMOND population, adverse events other than those related to the post-infarction and heart failure patient population were generally similar to those seen in the supraventricular arrhythmia groups.
| Dofetilide | Placebo | ||
|---|---|---|---|
| Adverse Event | % | % | |
| headache | 11 | 9 | |
| chest pain | 10 | 7 | |
| dizziness | 8 | 6 | |
| respiratory tract infection | 7 | 5 | |
| dyspnea | 6 | 5 | |
| nausea | 5 | 4 | |
| flu syndrome | 4 | 2 | |
| insomnia | 4 | 3 | |
| accidental injury | 3 | 1 | |
| back pain | 3 | 2 | |
| procedure (medical/surgical/health service) | 3 | 2 | |
| diarrhea | 3 | 2 | |
| rash | 3 | 2 | |
| abdominal pain | 3 | 2 |
What should I look out for while using Dofetilide?
Dofetilide is contraindicated in patients with congenital or acquired long QT syndromes. Dofetilide should not be used in patients with a baseline QT interval or QTc >440 msec (500 msec in patients with ventricular conduction abnormalities). Dofetilide is also contraindicated in patients with severe renal impairment (calculated creatinine clearance <20 mL/min).
The concomitant use of verapamil or the cation transport system inhibitors cimetidine, trimethoprim (alone or in combination with sulfamethoxazole), or ketoconazole with Dofetilide is contraindicated (see ), as each of these drugs cause a substantial increase in dofetilide plasma concentrations. In addition, other known inhibitors of the renal cation transport system such as prochlorperazine, dolutegravir and megestrol should not be used in patients on Dofetilide.
The concomitant use of hydrochlorothiazide (alone or in combinations such as with triamterene) with Dofetilide is contraindicated (see ) because this has been shown to significantly increase Dofetilide plasma concentrations and QT interval prolongation.
Dofetilide is also contraindicated in patients with a known hypersensitivity to the drug.
What might happen if I take too much Dofetilide?
There is no known antidote to Dofetilide; treatment of overdose should therefore be symptomatic and supportive. The most prominent manifestation of overdosage is likely to be excessive prolongation of the QT interval.
In cases of overdose, cardiac monitoring should be initiated. Charcoal slurry may be given soon after overdosing but has been useful only when given within 15 minutes of Dofetilide administration. Treatment of Torsade de Pointes or overdose may include administration of isoproterenol infusion, with or without cardiac pacing. Administration of intravenous magnesium sulfate may be effective in the management of Torsade de Pointes. Close medical monitoring and supervision should continue until the QT interval returns to normal levels.
Isoproterenol infusion into anesthetized dogs with cardiac pacing rapidly attenuates the dofetilide - induced prolongation of atrial and ventricular effective refractory periods in a dose‑dependent manner. Magnesium sulfate, administered prophylactically either intravenously or orally in a dog model, was effective in the prevention of dofetilide-induced Torsade de Pointes ventricular tachycardia. Similarly, in man, intravenous magnesium sulfate may terminate Torsade de Pointes, irrespective of cause.
Dofetilide overdose was rare in clinical studies; there were two reported cases of Dofetilide overdose in the oral clinical program. One patient received very high multiples of the recommended dose (28 capsules), was treated with gastric aspiration 30 minutes later, and experienced no events. One patient inadvertently received two 500 mcg doses one hour apart and experienced ventricular fibrillation and cardiac arrest 2 hours after the second dose.
In the supraventricular arrhythmia population, only 38 patients received doses greater than 500 mcg BID, all of whom received 750 mcg BID irrespective of creatinine clearance. In this very small patient population, the incidence of Torsade de Pointes was 10.5% (4/38 patients), and the incidence of new ventricular fibrillation was 2.6% (1/38 patients).
How should I store and handle Dofetilide?
Store under refrigeration at 2°C to 8°C (36°F to 46°F). The product should not be stored at room temperature for more than 48 hours. Vials that develop particulate matter should not be used.Injection vials are single-dose only. After opening, any unused product should be discarded.Store under refrigeration at 2°C to 8°C (36°F to 46°F). The product should not be stored at room temperature for more than 48 hours. Vials that develop particulate matter should not be used.Injection vials are single-dose only. After opening, any unused product should be discarded.Dofetilide 125mcg (0.125mg) capsules are supplied as No. 4 capsules with opaque light orange cap and opaque white body, printed with '125 mcg' in black ink on body and "710" in black ink on cap and are available in:Dofetilide 250 mcg (0.250mg) capsules are supplied as No. 4 capsules with opaque peach cap and opaque peach body, printed with '250 mcg' in black ink on body and "711" in black ink on cap and are available in:Dofetilide 500 mcg (0.500 mg) capsules are supplied as No. 2 capsules with opaque peach cap and opaque white body, printed with '500 mcg' in black ink on body and "712" in black ink on cap and are available in:Store at controlled room temperature, 15° to 30°C (59° to 86°F).PROTECT FROM MOISTURE AND HUMIDITY.Dispense in tight containers (USP).Rx OnlyManufactured For:Dofetilide 125mcg (0.125mg) capsules are supplied as No. 4 capsules with opaque light orange cap and opaque white body, printed with '125 mcg' in black ink on body and "710" in black ink on cap and are available in:Dofetilide 250 mcg (0.250mg) capsules are supplied as No. 4 capsules with opaque peach cap and opaque peach body, printed with '250 mcg' in black ink on body and "711" in black ink on cap and are available in:Dofetilide 500 mcg (0.500 mg) capsules are supplied as No. 2 capsules with opaque peach cap and opaque white body, printed with '500 mcg' in black ink on body and "712" in black ink on cap and are available in:Store at controlled room temperature, 15° to 30°C (59° to 86°F).PROTECT FROM MOISTURE AND HUMIDITY.Dispense in tight containers (USP).Rx OnlyManufactured For:Dofetilide 125mcg (0.125mg) capsules are supplied as No. 4 capsules with opaque light orange cap and opaque white body, printed with '125 mcg' in black ink on body and "710" in black ink on cap and are available in:Dofetilide 250 mcg (0.250mg) capsules are supplied as No. 4 capsules with opaque peach cap and opaque peach body, printed with '250 mcg' in black ink on body and "711" in black ink on cap and are available in:Dofetilide 500 mcg (0.500 mg) capsules are supplied as No. 2 capsules with opaque peach cap and opaque white body, printed with '500 mcg' in black ink on body and "712" in black ink on cap and are available in:Store at controlled room temperature, 15° to 30°C (59° to 86°F).PROTECT FROM MOISTURE AND HUMIDITY.Dispense in tight containers (USP).Rx OnlyManufactured For:Dofetilide 125mcg (0.125mg) capsules are supplied as No. 4 capsules with opaque light orange cap and opaque white body, printed with '125 mcg' in black ink on body and "710" in black ink on cap and are available in:Dofetilide 250 mcg (0.250mg) capsules are supplied as No. 4 capsules with opaque peach cap and opaque peach body, printed with '250 mcg' in black ink on body and "711" in black ink on cap and are available in:Dofetilide 500 mcg (0.500 mg) capsules are supplied as No. 2 capsules with opaque peach cap and opaque white body, printed with '500 mcg' in black ink on body and "712" in black ink on cap and are available in:Store at controlled room temperature, 15° to 30°C (59° to 86°F).PROTECT FROM MOISTURE AND HUMIDITY.Dispense in tight containers (USP).Rx OnlyManufactured For:Dofetilide 125mcg (0.125mg) capsules are supplied as No. 4 capsules with opaque light orange cap and opaque white body, printed with '125 mcg' in black ink on body and "710" in black ink on cap and are available in:Dofetilide 250 mcg (0.250mg) capsules are supplied as No. 4 capsules with opaque peach cap and opaque peach body, printed with '250 mcg' in black ink on body and "711" in black ink on cap and are available in:Dofetilide 500 mcg (0.500 mg) capsules are supplied as No. 2 capsules with opaque peach cap and opaque white body, printed with '500 mcg' in black ink on body and "712" in black ink on cap and are available in:Store at controlled room temperature, 15° to 30°C (59° to 86°F).PROTECT FROM MOISTURE AND HUMIDITY.Dispense in tight containers (USP).Rx OnlyManufactured For:Dofetilide 125mcg (0.125mg) capsules are supplied as No. 4 capsules with opaque light orange cap and opaque white body, printed with '125 mcg' in black ink on body and "710" in black ink on cap and are available in:Dofetilide 250 mcg (0.250mg) capsules are supplied as No. 4 capsules with opaque peach cap and opaque peach body, printed with '250 mcg' in black ink on body and "711" in black ink on cap and are available in:Dofetilide 500 mcg (0.500 mg) capsules are supplied as No. 2 capsules with opaque peach cap and opaque white body, printed with '500 mcg' in black ink on body and "712" in black ink on cap and are available in:Store at controlled room temperature, 15° to 30°C (59° to 86°F).PROTECT FROM MOISTURE AND HUMIDITY.Dispense in tight containers (USP).Rx OnlyManufactured For:Dofetilide 125mcg (0.125mg) capsules are supplied as No. 4 capsules with opaque light orange cap and opaque white body, printed with '125 mcg' in black ink on body and "710" in black ink on cap and are available in:Dofetilide 250 mcg (0.250mg) capsules are supplied as No. 4 capsules with opaque peach cap and opaque peach body, printed with '250 mcg' in black ink on body and "711" in black ink on cap and are available in:Dofetilide 500 mcg (0.500 mg) capsules are supplied as No. 2 capsules with opaque peach cap and opaque white body, printed with '500 mcg' in black ink on body and "712" in black ink on cap and are available in:Store at controlled room temperature, 15° to 30°C (59° to 86°F).PROTECT FROM MOISTURE AND HUMIDITY.Dispense in tight containers (USP).Rx OnlyManufactured For:Dofetilide 125mcg (0.125mg) capsules are supplied as No. 4 capsules with opaque light orange cap and opaque white body, printed with '125 mcg' in black ink on body and "710" in black ink on cap and are available in:Dofetilide 250 mcg (0.250mg) capsules are supplied as No. 4 capsules with opaque peach cap and opaque peach body, printed with '250 mcg' in black ink on body and "711" in black ink on cap and are available in:Dofetilide 500 mcg (0.500 mg) capsules are supplied as No. 2 capsules with opaque peach cap and opaque white body, printed with '500 mcg' in black ink on body and "712" in black ink on cap and are available in:Store at controlled room temperature, 15° to 30°C (59° to 86°F).PROTECT FROM MOISTURE AND HUMIDITY.Dispense in tight containers (USP).Rx OnlyManufactured For:
Clinical Information
Chemical Structure
No Image foundClinical Pharmacology
Dofetilide shows Vaughan Williams Class III antiarrhythmic activity. The mechanism of action is blockade of the cardiac ion channel carrying the rapid component of the delayed rectifier potassium current, I. At concentrations covering several orders of magnitude, dofetilide blocks only I with no relevant block of the other repolarizing potassium currents (e.g., I, I). At clinically relevant concentrations, dofetilide has no effect on sodium channels (associated with Class I effect), adrenergic alpha-receptors, or adrenergic beta-receptors.
Non-Clinical Toxicology
Dofetilide is contraindicated in patients with congenital or acquired long QT syndromes. Dofetilide should not be used in patients with a baseline QT interval or QTc >440 msec (500 msec in patients with ventricular conduction abnormalities). Dofetilide is also contraindicated in patients with severe renal impairment (calculated creatinine clearance <20 mL/min).The concomitant use of verapamil or the cation transport system inhibitors cimetidine, trimethoprim (alone or in combination with sulfamethoxazole), or ketoconazole with Dofetilide is contraindicated (see ), as each of these drugs cause a substantial increase in dofetilide plasma concentrations. In addition, other known inhibitors of the renal cation transport system such as prochlorperazine, dolutegravir and megestrol should not be used in patients on Dofetilide.
The concomitant use of hydrochlorothiazide (alone or in combinations such as with triamterene) with Dofetilide is contraindicated (see ) because this has been shown to significantly increase Dofetilide plasma concentrations and QT interval prolongation.
Dofetilide is also contraindicated in patients with a known hypersensitivity to the drug.
Oral anticoagulants: Heparin sodium may prolong the one-stage prothrombin time. Therefore, when heparin sodium is given with dicumarol or warfarin sodium, a period of at least 5 hours after the last intravenous dose or 24 hours after the last subcutaneous dose should elapse before blood is drawn if a valid prothrombin time is to be obtained.
Platelet inhibitors: Drugs such as acetylsalicylic acid, dextran, phenylbutazone, ibuprofen, indomethacin, dipyridamole, hydroxychloroquine and others that interfere with platelet-aggregation reactions (the main hemostatic defense of heparinized patients) may induce bleeding and should be used with caution in patients receiving heparin sodium.
Other interactions; Digitalis, tetracyclines, nicotine, or antihistamines may partially counteract the anticoagulant action of heparin sodium.
The overall systemic clearance of dofetilide is decreased and plasma concentration increased with decreasing creatinine clearance. The dose of Dofetilide must be adjusted based on creatinine clearance (see ). Patients undergoing dialysis were not included in clinical studies, and appropriate dosing recommendations for these patients are unknown. There is no information about the effectiveness of hemodialysis in removing dofetilide from plasma.
The Dofetilide clinical program involved approximately 8,600 patients in 130 clinical studies of normal volunteers and patients with supraventricular and ventricular arrhythmias. Dofetilide was administered to 5,194 patients, including two large, placebo-controlled mortality trials (DIAMOND CHF and DIAMOND MI) in which 1,511 patients received Dofetilide for up to three years.
In the following section, adverse reaction data for cardiac arrhythmias and non-cardiac adverse reactions are presented separately for patients included in the supraventricular arrhythmia development program and for patients included in the DIAMOND CHF and MI mortality trials (see , for a description of these trials).
In studies of patients with supraventricular arrhythmias, a total of 1,346 and 677 patients were exposed to Dofetilide and placebo for 551 and 207 patient years, respectively. A total of 8.7% of patients in the dofetilide groups were discontinued from clinical trials due to adverse events compared to 8.0% in the placebo groups. The most frequent reason for discontinuation (>1%) was ventricular tachycardia (2.0% on dofetilide vs. 1.3% on placebo). The most frequent adverse events were headache, chest pain, and dizziness.
Reference
This information is obtained from the National Institute of Health's Standard Packaging Label drug database.
"https://dailymed.nlm.nih.gov/dailymed/"
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Clonazepam Description Each single-scored tablet, for oral administration, contains 0.5 mg, 1 mg, or 2 mg Clonazepam, USP, a benzodiazepine. Each tablet also contains corn starch, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and povidone. Clonazepam tablets USP 0.5 mg contain Yellow D&C No. 10 Aluminum Lake. Clonazepam tablets USP 1 mg contain Yellow D&C No. 10 Aluminum Lake, as well as FD&C Blue No. 1 Aluminum Lake. Chemically, Clonazepam, USP is 5-(o-chlorophenyl)-1,3-dihydro-7-nitro-2H-1,4-benzodiazepin-2-one. It is a light yellow crystalline powder. It has the following structural formula: C15H10ClN3O3 M.W. 315.72Tips
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