Drug interactions- summary

 + Dofetilide-

Amiloride-                                                                                                                           inhibitors of dofetilide elimination of renal cationic secretion are Metformin contraindicated Megestrol Use caution when coadministering drugs actively secreted Prochlorperazine via cationic secetion as they might increase dofetilide levels

Triameterene, Antiarrhthmic agents-                                                                           withhold class I or class III antiarrhythmics agents for > 3plasma Class I or Class III half lives prior to dofetilide dosing

Cimetidine-                                                                                                                     concomittant use of cimetidine is contraindicated. Cimetidine increased dofetilide plasma levels by 58% Use omiprezole , ranitidine or antacids as an alternative to cimetidine

Dogoxin-                                                                                                                                   a higher occurrence of torsades de pointes was associated in patients concomittantly administered digoxin with dofetilide

 Ketoconazole-                                                                                                                concomittant use of ketoconazole is contraindicated. Ketoconazole increased dofetilide Cmax and AUC by 53% and 41% in males 97% and 69% in females respy. 

Potassium depleting-                                                                                                    hypokalemia or hypomagnesemia may occur with administration diuretics of pot-depleting diuretics, increasing the potential for torsades de pointes. Pot. levels should be withinn normal range prior to admin of dofetilide and maintained in the normal range during dofetilide administration

Trimethoprin-                                                                                                           concomittant use of trimethoprin alone or in combination is Trimethoprin/ contraindicated sulfamethoxazole C0-admin. increased dofetilide AUC by 103% and max by 93%

Verapramil-                                                                                                                 Concomittant use of verapramil is contraindicated Dofetilide peak conc. increased by 42% when co-administered verapramil, although overal exposure to dofetilide was not significantly increased. Concomittant adminstration was associated with higher occurence of torsades de pointes 

Most important adverse reaction- headache, chest pain and dizziness.

Concomittant use with verapramil, or the cation transport system inhibotors, cimetidine, trimethoprin alone or in combination with sulphamethaxzole or ketoconazole or other known inhibiotors of the renal cation system such as prochloroperazine

Special precautions-

Ventricular arrhythmias- dofetilide can cause serious ventricular arrhythmias primarrily torsades de pointes Treatment with dofetilide must therefore be started only in patients placed for minimum 3 days in facility that can provide electrocardiographic monitoring and presence of personal trained in management of serious ventricular arrhythmias

Renal functional impairment- The overal systemic clearance of dofetilide is decreased and plasma concentration increased with decreasing creatine clearance. The dose of dofetilide must be adjusted based on creatine clearance.

Hepatic function impairment- After adjustment for creatine clearance no additional dosage adjustment is required for patients with mild or moderate hepatic impairment

Indication-

Conversion of atrial fibrillation/flutter

Dosage-

Prior to administration of first dose, patients creatinine level mus be calculated Calculated creatinine clearance

Dofetilide dose > 60mL/min 500mcg twice daily 40 to 60mL/min 250 mcg twice daily 20 to < 40 mL/min 125mcg twice daily > 20mL/min Dofetilide is contraindicated in these patients

Patient should be fully instructed on the need for compliance with the recommended dosing schedule of dofetilide and the potential for drugb interactions

Pharmacology-

The mechaanism of action is blockade of the cardiac ion channel carrying the rapid component of delayed rectifier-potassium current.

Pharmacokinetics-

The oral bioavailability of dofetilide is more than 90% with maximum plasma concentration occuring at about 2 to 3 hours in the fasted state. oralbioavailabity is unaffected by food The terminal half life of dofetilide is approx. 10 hours. Steady state plasma is obtained within 2 to 3 days. Approximately 80% of the single dose of dofetilide is excreted in urine.

Oral bioavailabity is unaffected by food or antacid

Pregnancy-

To be aministered only if benefit justifies the potential risk to the fetus.

Lactation-

No information on the presence of deofetilde in breast milk. patients adviced not to breast feed an infant if they are taking dofetilide

Children-

Safety and effectiveness of dofetilide in children ( age below 18 years) not established