Dofetilide Verapamil

IV Ibutilide Dofetilide Verapamil Diltiazem BepridiP Inhibit the slow inward calcium current, minimal effect (decrease) on ventricular action potential, major effects on the atrioventricular node to slow conduction velocity and increase the ERP. 

Dofetilide See below3 patients must be hospitalized for 3 days during initiation of therapy Cimetidine, hy d roch I o roth iaz i de, ketoconazole, medroxyprogesterone, promethazine, trimethoprim, verapamil (all inhibit dofetilide elimination)... 

Verapamil increases serum dofetilide levels, as do drugs that inhibit cationic renal secretion, such as ketoconazole and cimetidine, raise serum levels. 

Dofetilide is 100% bioavailable. Verapamil increases peak plasma dofetilide concentration by increasing intestinal blood flow. Eighty percent of an oral dose is eliminated by the kidneys unchanged the remainder is eliminated in the urine as inactive metabolites. 

Dofetilide is 100% bioavailable. Verapamil increases peak plasma dofetilide concentration by increasing intestinal blood flow. Eighty percent of an oral dose is eliminated by the kidneys unchanged the remainder is eliminated by the kidneys as inactive metabolites. Inhibitors of the renal cation secretion mechanism, eg, cimetidine, prolong the half-life of dofetilide. Since the QT-prolonging effects and risks of ventricular proarrhythmia are directly related to plasma concentration, dofetilide dose must be based on the estimated creatinine clearance. Treatment with dofetilide should be initiated in hospital after baseline measurement of the QTc and serum electrolytes. A baseline QTC of > 450 ms (500 ms in the presence of an intraventricular conduction delay), bradycardia of < 50 beats/min, and hypokalemia are relative contraindications to its use. 

Pharmacokinetic and pharmacodynamic interactions between dofetihde 0.5 mg bd and verapamil 80 mg tds have been studied in 12 healthy men (62). At steady state verapamil increased the peak plasma concentration of dofetilide from 2.40 to 3.43 ng/ml, without other pharmacokinetic effects. This was accompanied by a small increase in the prolongation of the QTc interval produced by dofetilide alone, from 20 to 26 ms. Although this small effect is unlikely to be of chnical significance, it would be wise to avoid verapamil in patients taking dofetihde. 

Clinically important, potentially hazardous interactions with cyclosporine, diltiazem, dofetilide, erythromycin, grapefruit, ketoconazole, quinidine, ritonavir, simvastatin, sotalol, thioridazine, verapamil, ziprasidone... 

Dofetilide has weak affinity for CYP3A4. Concomitant use of dofetilide with cime-tidine, hydrochlorothiazide (including combination products), verapamil, trimethoprim, prochlorperazine, megestrol, or ketoconazole is contraindicated due to significant increases in dofetilide serum concentrations (see Table 8.3). 

Verapamil transiently increases dofetilide plasma levels and QTc prolongation, and has been associated with an increased risk of torsade de pointes arrhythmia. Its use with dofetilide is contraindicated. 

A study in 12 healthy subjects found that verapamil 80 mg three times daily given with dofetilide 500 micrograms twice daily for 3 days caused a 42% increase in the peak plasma levels of dofetilide from 2.4 to 3.43 nanograms/mL. There was a 26% increase in the AUC0.4, which was associated with a transient simultaneous increase in QTc of 20 milliseconds for dofetilide alone and 26 milliseconds for the combination. However, the AUCo.s was not significantly different. The manufacturer notes that an analysis of clinical trial data for dofetilide revealed a higher occurrence of torsade de pointes when verapamil was used with dofetilide. ... 

Verapamil is postulated to interact with dofetilide by increasing its rate of absorption by increasing hepatic blood flow. There is a linear relationship between plasma dofetilide concentrations and prolongation of the QT interval, which is a risk factor for torsade de pointes. ... 

The use of verapamil with dofetilide appears to be associated with a transient increase in dofetilide plasma concentrations, and an increased risk of torsade de pointes. For this reason, the combination is contraindicated. 

Johnson BF, Cheng SL, Venitz J. Transient kinetic and dynamic interactions between verapamil and dofetilide, a class m antiarrhythmic. J Clin Pharmacol (2001) 41,1248-56. 

Vicente J, Johannesen L, Mason JW et al (2015) Comprehensive T wave morphology assessment in a randomized clinical study of dofetilide, quinidine, ranolazine, and verapamil. J Am Heart... 

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