Digitek

[digoxin]

Continued treatment with digoxin reduced the risk of developing worsening heart failure, as evidenced by heart fail-ure- related hospitalizations and emergency care and the need for concomitant heart failure therapy. The larger study also showed treatment-related benefits in NYHA class and patients' global assessment. In the smaller trial, these trended in favor of a treatment benefit.

The Digitalis Investigation Group (DIG) main trial was a multicenter, randomized, double-blind, placebo-controlled mortality study of 6,801 patients with heart failure and left ventricular ejection fraction 0.45. At randomization, 67% were NYHA class I or II, 71% had heart failure of ischemic etiology, 44% had been receiving digoxin, and most were receiving concomitant ACE inhibitor (94%) and diuretic (82%). Patients were randomized to placebo or digoxin, the dose of which was adjusted for the patient's age, sex, lean body weight, and serum creatinine (see DOSAGE AND ADMINISTRATION), and followed for up to 58 months (median 37 months).

The median daily dose pre-scribed was 0.25 mg. Overall all-cause mortality was 35% with no difference between groups (95% confidence limits for relative risk of 0.91 to 1.07). Digoxin was associated with a 25% reduction in the number of hospitalizations for heart failure, a 28% reduction in the risk of a patient having at least one hospitalization for heart failure, and a 6.5% reduction in total hospitalizations (for any cause).

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Use of digoxin was associated with a trend in reduction in time to all-cause death or hospitalization. The trend was evident in sub-groups of patients with mild heart failure as well as more severe dis-ease, as shown in Table 3. Although the effect on all-cause death or hospitalization was not statistically significant, much of the appar-ent benefit derived from effects on mortality and hospitalization attributed to heart failure.

Table 3: Subgroup Analyses of Mortality and Hospitalization During the First Two Years Following Randomization.
*Number of patients with an event during the first 2 years per 1000 randomized patients. * Relative risk (95% confidence interval). * DIG Ancillary Study.

In situations where there is no statistically significant benefit of treatment evident from a trial's primary endpoint, results pertaining to a secondary end-point should be interpreted cautiously.

Chronic Atrial Fibrillation:

In patients with chronic atrial fibrilla-tion, digoxin slows rapid ventricular response rate in linear dose-response fashion from 0.25 to 0.75 mg/ day. Digoxin should not be used for the treatment of multifocal atrial tachycardia.

Drug/ Laboratory Test Interactions

The use of therapeutic doses of digoxin may cause prolongation of the PR interval and depression of the ST segment on the electrocardiogram. Digoxin may produce false positive ST-T changes on the electrocardiogram during exercise test-ing. These electrophysiologic effects reflect an expected effect of the drug and are not indicative of toxicity.

Carcinogenesis, Mutagenesis, Impairment of Fertility

There have been no long-term studies performed in animals to evaluate carcino-genic potential, nor have studies been conducted to assess the muta-genic potential of digoxin or its potential to affect fertility.

Pregnancy:
Teratogenic Effects:
Pregnancy Category C.

Animal Risk of HF-Related Mortality or HF-Related Hospitalization* n Placebo Digoxin Relative risk * All Patients 0.69 (EF 0.45) 6801 294 217 (0.63-0.76)
0.70 NYHA I/ II 4571 242 178 (0.62-0.80)
0.74 EF 0.25-0.45 4543 244 190 (0.66-0.84) 0.71 CTR 0.55 4455 239 180 (0.63-0.81)
0.65 NYHA III/ IV 2224 402 295 (0.57-0.75)
0.61 EF < 0.25 2258 394 270 (0.53-0.71) 0.65 CTR > 0.55 2346 398 287 (0.57-0.75)
0.72 EF > 0.45 * 987 179 136 (0.53-0.99)

Risk of All-Cause Mortality or All-Cause Hospitalization* n Placebo Digoxin Relative risk * All Patients 0.94 (EF 0.45) 6801 604 593 (0.88-1.00)
0.96 NYHA I/ II 4571 549 541 (0.89-1.04)
0.99 EF 0.25-0.45 4543 568 571 (0.91-1.07) 0.98 CTR 0.55 4455 561 563 (0.91-1.06)
0.88 NYHA III/ IV 2224 719 696 (0.80-0.97)
0.84 EF < 0.25 2258 677 637 (0.76-0.93) 0.85 CTR > 0.55 2346 687 650 (0.77-0.94)
1.04 EF > 0.45 * 987 571 585 (0.88-1.23)
Time to Time to Product Onset of Effect* Peak Effect* Digoxin Tablets 0.5-2 hours 2-6 hours Digoxin Pediatric Elixir 0.5-2 hours 2-6 hours Digoxin Solution in Capsules 0.5-2 hours 2-6 hours Digoxin Injection/ IV 5-30 minutes * 1-4 hours

Absolute Bio-Equivalent Doses( mcg)* Product availability Among Dosage Forms Digoxin Tablets 60-80% 62.5 125 250 500 Digoxin Pediatric Elixir 70-85% 62.5 125 250 500
Digoxin Solution in Capsules 90-100% 50 100 200 400 Digoxin Injection/ IV 100% 50 100 200 400

reproduction studies have not been conducted with digoxin. It is also not known whether digoxin can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. Digoxin should be given to a pregnant woman only if clearly needed.

Nursing Mothers

Studies have shown that digoxin concentrations in the mother's serum and milk are similar. However, the estimated expo-sure of a nursing infant to digoxin via breast feeding will be far below the usual infant maintenance dose. Therefore, this amount should have no pharmacologic effect upon the infant. Nevertheless, caution should be exercised when digoxin is administered to a nursing woman.

Pediatric Use

Newborn infants display considerable variability in their tolerance to digoxin. Premature and immature infants are particularly sensitive to the effects of digoxin, and the dosage of the drug must not only be reduced but must be individualized according to their degree of maturity. Digitalis glycosides can cause poisoning in children due to accidental ingestion.

Geriatric Use:

The majority of clinical experience gained with digoxin has been in the elderly population. This experience has not identified dif-ferences in response or adverse effects between the elderly and younger patients. However, this drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, which should be based on renal function, and it may be use-ful to monitor renal function (see DOSAGE AND ADMINISTRATION).

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