DOFETILIDE Drug Interactions: What You Need to Know

Drug-Drug Interactions Cimetidine: (see WARNINGS , CONTRAINDICATIONS ) 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 CONTRAINDICATIONS ) 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 WARNINGS , CONTRAINDICATIONS ) 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 max 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 WARNINGS , CONTRAINDICATIONS ) 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 max by 93%. Hydrochlorothiazide (HCTZ) Alone or in Combination with Triamterene: (see CONTRAINDICATIONS ) 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 max 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 max 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.

CONTRAINDICATIONS Dofetilide capsules are contraindicated in patients with congenital or acquired long QT syndromes. Dofetilide capsules should not be used in patients with a baseline QT interval or QTc >440 msec (500 msec in patients with ventricular conduction abnormalities). Dofetilide capsules are 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 capsules are contraindicated (see WARNINGS and PRECAUTIONS , Drug-Drug Interactions ), 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 capsules. The concomitant use of hydrochlorothiazide (alone or in combinations such as with triamterene) with dofetilide capsules are contraindicated (see PRECAUTIONS , Drug-Drug Interactions ) because this has been shown to significantly increase dofetilide plasma concentrations and QT interval prolongation. Dofetilide capsules are also contraindicated in patients with a known hypersensitivity to the drug.

WARNINGS Ventricular Arrhythmia Dofetilide capsules 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 capsules-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 capsules dose (see Figures 1 and 2 in CLINICAL PHARMACOLOGY and Dose-Response and Concentration Response for Increase in QT Interval ). 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.

Table

4: Summary of Torsade de Pointes in Patients Randomized to Dofetilide by Dose; Patients with Supraventricular Arrhythmias Dofetilide Capsules 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%) As shown in Table 5, the rate of TdP was reduced when patients were dosed according to their renal function (see CLINICAL PHARMACOLOGY, Pharmacokinetics in Special Populations, Renal Impairment and DOSAGE AND ADMINISTRATION ).

Table

5: Incidence of Torsade de Pointes Before and After Introduction of Dosing According to Renal Function Population: Total Before After n/N % n/N % n/N % Supraventricular Arrhythmias 11/1346 (0.8%) 6/193 (3.1%) 5/1153 (0.4%) DIAMOND CHF 25/762 (3.3%) 7/148 (4.7%) 18/614 (2.9%) DIAMOND MI 7/749 (0.9%) 3/101 (3.0%) 4/648 (0.6%) DIAMOND AF 4/249 (1.6%) 0/43 (0%) 4/206 (1.9%) The majority of the episodes of TdP occurred within the first three days of dofetilide capsules 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). 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 capsules 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 capsules/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 capsules 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 capsules was 31% vs. 32% on placebo (see CLINICAL STUDIES ). Because of the small number of events, an excess mortality due to dofetilide capsules 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 capsules-treated patients than in patients given placebo (see CLINICAL STUDIES ). 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 capsules and maintained in the normal range during administration of dofetilide capsules (see DOSAGE AND ADMINISTRATION ). Use with Drugs that Prolong QT Interval and Antiarrhythmic Agents The use of dofetilide capsules 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 capsules. In clinical trials, dofetilide capsules were administered to patients previously treated with oral amiodarone only if serum amiodarone levels were below 0.3 mg/L or amiodarone had been withdrawn for at least three months.