Digoxin and Diltiazem: Interaction Details

a) During pharmacokinetic studies, coadministration of oral digoxin and dilTIAZem resulted in a 20% increase in digoxin exposures ¹²³.

b) A reduction in digoxin renal clearance was observed with the concurrent use of dilTIAZem. Eight volunteers received oral digoxin 0.25 mg/day alone for 13 days; and then, on day 14, dilTIAZem 30 mg four times daily was added and therapy continued for 15 more days. Trough blood samples were obtained throughout the study for digoxin concentration determination. Following the digoxin dose on days 13 and 28, urine was collected for 24 hours. The coadministration of dilTIAZem resulted in a significant elevation of the mean steady-state digoxin trough concentration from 0.32 to 0.48 nanogram (ng/mL; 0.41 to 0.615 nanomol/L). Seven subjects displayed elevated digoxin concentrations, one demonstrating a 0.3 mg/mL (0.38 mmol/L) increase. Elevations became evident within one week of concurrent therapy. Mean renal clearances significantly decreased from 223 to 153 mL/min. No change in CrCl was observed among the subjects between the two phases. The authors attributed the interaction to decreased tubular secretion since digoxin renal clearance decreased but creatinine clearance remained constant. However, the determination of only trough concentrations does not allow for full determination of total body clearance and Vd, which would permit a better analysis ⁴.

c) The effect of dilTIAZem on digoxin steady-state concentrations was studied in 11 patients with congestive heart failure. All patients were receiving a chronic stable oral dose of digoxin (nine were receiving 0.25 mg and two were receiving 0.125 mg) for at least 14 days. Prior to initiating dilTIAZem therapy (60 mg three times daily), blood samples were obtained immediately prior to and 3, 6, and 24 hours after a dose of digoxin. Similar blood levels were drawn after 3 days of concurrent dilTIAZem therapy. Additionally, digoxin trough samples were obtained following the first and seventh doses of digoxin during combined therapy. A significant increase (36%) in digoxin concentration was observed during the third day of concurrent therapy. Trough concentrations increased significantly from 1.1 nanogram/mL (ng/mL; 1.41 nanomol/L) with digoxin alone to 1.5 ng/mL (1.92 nanomol/L) on the seventh day of combined therapy. None of the patients demonstrated digoxin toxicity. The authors concluded that an interaction exists between dilTIAZem and digoxin, but is of minor clinical importance unless digoxin concentrations are initially at the upper limit of normal ⁵.

d) Not all investigators have observed an elevation in digoxin concentrations with the addition of dilTIAZem. Nine patients with organic heart disease (five with congestive heart failure (CHF); four with atrial fibrillation) who were receiving chronic oral digoxin 0.25 mg daily were studied. Prior to dilTIAZem therapy, a 24-hour urine collection and a mid-interval blood sample were obtained. Patients then received dilTIAZem 30 mg four times daily for 4 to 11 days (mean 7 days), which was eventually increased to 60 mg four times daily for an additional 5 to 20 days (mean 11 days). Blood and urine were collected for digoxin analysis at each dilTIAZem dose. No significant change in mean, midpoint digoxin concentrations or digoxin renal clearance were observed during either dilTIAZem phase. Only one patient demonstrated a clinically significant rise in digoxin concentration. The authors concluded that no interaction exists between digoxin and dilTIAZem ⁶.

e) A lack of change in digoxin trough concentrations following the concurrent administration of several different doses of dilTIAZem was reported. Eight subjects received digoxin 0.25 mg for one week at which time a trough blood sample was obtained. DilTIAZem 30 mg four times daily was then coadministered for seven days before a second trough blood sample was obtained. This procedure was repeated for dilTIAZem 60 mg four times daily and 90 mg four times daily. No significant difference from baseline (0.85 nanogram/mL (ng/mL) or 1.088 nanomol/L) in any of the digoxin trough concentration with the addition of dilTIAZem was noted (0.86, 0.84, and 0.90 ng/mL or 1.101, 1.076, and 1.152 nanomol/L, respectively) ⁷.

f) It was of the opinion of the authors that dilTIAZem did not elevate digoxin concentrations. The results of another study might explain the conflicting results observed among the trials described above. Twelve patients with congestive heart failure who were receiving a stable oral dose of beta-acetyldigoxin (0.1 to 0.3 mg daily) for several weeks were entered into a trial. Trough blood samples for digoxin determination were obtained prior to the initiation of dilTIAZem (60 mg three times daily) and during dilTIAZem therapy. Urine was collected for a 24-hour period prior to and on several occasions during dilTIAZem therapy in nine patients. Mean digoxin concentrations did not increase with the coadministration of dilTIAZem overall. However, when looking at individual data, 8 of 12 patients displayed significant increases ranging from 24% to 70% (mean 46%) in digoxin plasma concentrations with the coadministration of dilTIAZem. In these individuals, total body clearance was reduced 28% (oral absorption was assumed to be 80%), but renal clearance remained unchanged, suggesting the interaction in these individuals occurred through nonrenal mechanisms. Mean total body clearance and renal clearance for the total study group was not reported. It should be noted that the calculation of total body clearance and renal clearance of digoxin was not optimal in this trial since only single trough samples were used ⁸.