Digoxin Information
Digoxin (Lanoxin) Description:
Digoxin (Lanoxin) is one of the cardiac (or digitalis) glycosides, a closely related group of drugs having in common specific effects on the myocardium. These drugs are found in a number of plants. Digoxin (Lanoxin) is extracted from the leaves of The term “digitalis” is used to designate the whole group of glycosides. The glycosides are composed of two portions: a sugar and a cardenolide (hence “glycosides”).
Digoxin (Lanoxin) is described chemically as (3β,5β,12β)-3-[(-2,6-dideoxy-β---hexopyranosyl-(1→4)--2,6-dideoxy-β---hexopyranosyl-(1→4)-2,6-dideoxy-β---hexopyranosyl)oxy]-12,14-dihydroxy-card-20(22)-enolide. lts molecular formula is CHO, its molecular weight is 780.95, and its structural formula is:
Digoxin (Lanoxin) exists as odorless white crystals that melt with decomposition above 230°C. The drug is practically insoluble in water and in ether; slightly soluble in diluted (50%) alcohol and in chloroform; and freely soluble in pyridine.
Digoxin (Lanoxin) Tablets are supplied as 125 mcg (0.125 mg) or 250 mcg (0.25 mg) tablets for oral administration. Each tablet contains the labeled amount of Digoxin (Lanoxin) USP and the following inactive ingredients:
Digoxin (Lanoxin) Clinical Pharmacology:
In some patients, orally administered Digoxin (Lanoxin) is converted to inactive reduction products (e.g., dihydroDigoxin (Lanoxin) ) by colonic bacteria in the gut. Data suggest that one in ten patients treated with Digoxin (Lanoxin) Tablets will degrade 40% or more of the ingested dose. As a result, certain antibiotics may increase the absorption of Digoxin (Lanoxin) in such patients. Although inactivation of these bacteria by antibiotics is rapid, the serum Digoxin (Lanoxin) concentration will rise at a rate consistent with the elimination half-life of Digoxin (Lanoxin) . The magnitude of rise in serum Digoxin (Lanoxin) concentration relates to the extent of bacterial inactivation, and may be as much as two-fold in some cases.
Following drug administration, a 6- to 8-hour tissue distribution phase is observed. This is followed by a much more gradual decline in the serum concentration of the drug, which is dependent on the elimination of Digoxin (Lanoxin) from the body. The peak height and slope of the early portion, (absorption/distribution phases) of the serum concentration-time curve are dependent upon the route of administration and the absorption characteristics of the formulation. Clinical evidence indicates that the early high serum concentrations do not reflect the concentration of Digoxin (Lanoxin) at its site of action, but that with chronic use, the steady-state post-distribution serum concentrations are in equilibrium with tissue concentrations and correlate with pharmacologic effects. In individual patients, these post-distribution serum concentrations may be useful in evaluating therapeutic and toxic effects (see ).
Digoxin (Lanoxin) is concentrated in tissues and therefore has a large apparent volume of distribution. Digoxin (Lanoxin) crosses both the blood-brain barrier and the placenta. At delivery, the serum Digoxin (Lanoxin) concentration in the newborn is similar to the serum concentration in the mother. Approximately 25% of Digoxin (Lanoxin) in the plasma is bound to protein. Serum Digoxin (Lanoxin) concentrations are not significantly altered by large changes in fat tissue weight, so that its distribution space correlates best with lean (i.e., ideal) body weight, not total body weight.
Race differences in Digoxin (Lanoxin) pharmacokinetics have not been formally studied. Because Digoxin (Lanoxin) is primarily eliminated as unchanged drug via the kidney and because there are no important differences in creatinine clearance among races, pharmacokinetic differences due to race are not expected.
The clearance of Digoxin (Lanoxin) can be primarily correlated with renal function as indicated by creatinine clearance. The Cockcroft and Gault formula for estimation of creatinine clearance includes age, body weight, and gender. Table 5 that provides the usual daily maintenance dose requirements of Digoxin (Lanoxin) Tablets based on creatinine clearance (per 70 kg) is presented in the section.
Plasma Digoxin (Lanoxin) concentration profiles in patients with acute hepatitis generally fell within the range of profiles in a group of healthy subjects.
Two 12-week, double-blind placebo-controlled studies enrolled 178 (RADIANCE trial) and 88 (PROVED trial) patients with NYHA class II or III heart failure previously treated with Digoxin (Lanoxin) , a diuretic, and an ACE inhibitor (RADIANCE only) and randomized them to placebo or treatment with Digoxin (Lanoxin) Tablets. Both trials demonstrated better preservation of exercise capacity in patients randomized to Digoxin (Lanoxin) Tablets. Continued treatment with Digoxin (Lanoxin) Tablets reduced the risk of developing worsening heart failure, as evidenced by heart failure-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 6801 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 (Lanoxin) , and most were receiving concomitant ACE inhibitor (94%) and diuretic (82%). Patients were randomized to placebo or Digoxin (Lanoxin) Tablets, the dose of which was adjusted for the patient's age, sex, lean body weight, and serum creatinine (see ), and followed for up to 58 months (median 37 months). The median daily dose prescribed 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 (Lanoxin) 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).
Use of Digoxin (Lanoxin) Tablets was associated with a trend to increase in time to all-cause death or hospitalization. The trend was evident in subgroups of patients with mild heart failure as well as more severe disease, as shown in Table 3. Although the effect on all-cause death or hospitalization was not statistically significant, much of the apparent benefit derived from effects on mortality and hospitalization attributed to heart failure.
In situations where there is no statistically significant benefit of treatment evident from a trial's primary endpoint, results pertaining to a secondary endpoint should be interpreted cautiously.
Digoxin (Lanoxin) Contraindications:
Digitalis glycosides are contraindicated in patients with ventricular fibrillation or in patients with a known hypersensitivity to Digoxin (Lanoxin) . A hypersensitivity reaction to other digitalis preparations usually constitutes a contraindication to Digoxin (Lanoxin) .
Digoxin (Lanoxin) Precautions:
In patients with hypokalemia or hypomagnesemia, toxicity may occur despite serum Digoxin (Lanoxin) concentrations below 2 ng/mL, because potassium or magnesium depletion sensitizes the myocardium to Digoxin (Lanoxin) . Therefore, it is desirable to maintain normal serum potassium and magnesium concentrations in patients being treated with Digoxin (Lanoxin) . Deficiencies of these electrolytes may result from malnutrition, diarrhea, or prolonged vomiting, as well as the use of the following drugs or procedures: diuretics, amphotericin B, corticosteroids, antacids, dialysis, and mechanical suction of gastrointestinal secretions.
Hypercalcemia from any cause predisposes the patient to digitalis toxicity. Calcium, particularly when administered rapidly by the intravenous route, may produce serious arrhythmias in digitalized patients. On the other hand, hypocalcemia can nullity the effects of Digoxin (Lanoxin) in humans; thus, Digoxin (Lanoxin) may be ineffective until serum calcium is restored to normal. These interactions are related to the fact that Digoxin (Lanoxin) affects contractility and excitability of the heart in a manner similar to that of calcium.
Potassium-depleting are a major contributing factor to digitalis toxicity. particularly if administered rapidly by the intravenous route, may produce serious arrhythmias in digitalized patients. and raise the serum Digoxin (Lanoxin) concentration due to a reduction in clearance and/or in volume of distribution of the drug, with the implication that digitalis intoxication may result. and (and possibly other ) and may increase Digoxin (Lanoxin) absorption in patients who inactivate Digoxin (Lanoxin) by bacterial metabolism in the lower intestine, so that digitalis intoxication may result (see ). and by decreasing gut motility, may increase Digoxin (Lanoxin) absorption. certain and may interfere with intestinal Digoxin (Lanoxin) absorption, resulting in unexpectedly low serum concentrations. may decrease serum Digoxin (Lanoxin) concentration, especially in patients with renal dysfunction, by increasing the non-renal clearance of Digoxin (Lanoxin) . There have been inconsistent reports regarding the effects of other drugs [e.g., ] on serum Digoxin (Lanoxin) concentration. administration to a digitalized, hypothyroid patient may increase the dose requirement of Digoxin (Lanoxin) . Concomitant use of Digoxin (Lanoxin) and increases the risk of cardiac arrhythmias. may cause a sudden extrusion of potassium from muscle cells, and may thereby cause arrhythmias in digitalized patients. Although and Digoxin (Lanoxin) may be useful in combination to control atrial fibrillation, their additive effects on AV node conduction can result in advanced or complete heart block. Both digitalis glycosides and slow atrioventricular conduction and decrease heart rate. Concomitant use can increase the risk of bradycardia. Digoxin (Lanoxin) concentrations are increased by about 15% when Digoxin (Lanoxin) and cervedilol are administered concomitantly. Therefore, increased monitoring of Digoxin (Lanoxin) is recommended when initiating, adjusting, or discontinuing carvedilol.
Due to the considerable variability of these interactions; the dosage of Digoxin (Lanoxin) should be individualized when patients receive these medications concurrently. Furthermore, caution should be exercised when combining Digoxin (Lanoxin) with any drug that may cause a significant deterioration in renal function, since a decline in glomerular filtration or tubular secretion may impair the excretion of Digoxin (Lanoxin) .
Digoxin (Lanoxin) Adverse Reactions:
In general, the adverse reactions of Digoxin (Lanoxin) are dose-dependent and occur at doses higher than those needed to achieve a therapeutic effect. Hence, adverse reactions are less common when Digoxin (Lanoxin) is used within the recommended dose range or therapeutic serum concentration range and when there is careful attention to concurrent medications and conditions.
Because some patients may be particularly susceptible to side effects with Digoxin (Lanoxin) , the dosage of the drug should always be selected carefully and adjusted as the clinical condition of the patient warrants. In the past, when high doses of Digoxin (Lanoxin) were used and little attention was paid to clinical status or concurrent medications, adverse reactions to Digoxin (Lanoxin) were more frequent and severe. Cardiac adverse reactions accounted for about one-half, gastrointestinal disturbances for about one-fourth, and CNS and other toxicity for about one-fourth of these adverse reactions. However, available evidence suggests that the incidence and severity of Digoxin (Lanoxin) toxicity has decreased substantially in recent years. In recent controlled clinical trials, in patients with predominantly mild to moderate heart failure, the incidence of adverse experiences was comparable in patients taking Digoxin (Lanoxin) and in those taking placebo. In a large mortality trial, the incidence of hospitalization for suspected Digoxin (Lanoxin) toxicity was 2% in patients taking Digoxin (Lanoxin) Tablets compared to 0.9% in patients taking placebo. In this trial, the most common manifestations of Digoxin (Lanoxin) toxicity included gastrointestinal and cardiac disturbances; CNS manifestations were less common.
Digoxin (Lanoxin) Overdosage:
In addition to cardiac monitoring, Digoxin (Lanoxin) should be temporarily discontinued until the adverse reaction resolves and may be all that is required to treat the adverse reaction such as in asymptomatic bradycardia or Digoxin (Lanoxin) -related heart block. Every effort should also be made to correct factors that may contribute to the adverse reaction (such as electrolyte disturbances, thyroid function, or concurrent medications) (see and ). Once the adverse reaction has resolved, therapy with Digoxin (Lanoxin) may be reinstituted, following a careful reassessment of dose.
When the primary manifestation of Digoxin (Lanoxin) overdosage is a cardiac arrhythmia, additional therapy may be needed.
If the rhythm disturbance is a symptomatic bradyarrhythmia or heart block, consideration should be given to the reversal of toxicity with Digoxin (Lanoxin) Immune Fab (Ovine) [Digibindor Digifab] (see subsection), the use of atropine, or the insertion of a temporary cardiac pacemaker. Digoxin (Lanoxin) Immune Fab (Ovine) is a specific antidote for Digoxin (Lanoxin) and may be used to reverse potentially life-threatening ventricular arrhythmias due to Digoxin (Lanoxin) overdosage.
If the rhythm disturbance is a ventricular arrhythmia, consideration should be given to the correction of electrolyte disorders, particularly if hypokalemia (see subsection) or hypomagnesemia is present. Ventricular arrhythmias may respond to lidocaine or phenytoin.
Digoxin (Lanoxin) Dosage And Administration:
In general, the dose of Digoxin (Lanoxin) used should be determined on clinical grounds. However, measurement of serum Digoxin (Lanoxin) concentrations can be helpful to the clinician in determining the adequacy of Digoxin (Lanoxin) therapy and in assigning certain probabilities to the likelihood of Digoxin (Lanoxin) intoxication. About two-thirds of adults considered adequately digitalized (without evidence of toxicity) have serum Digoxin (Lanoxin) concentrations ranging from 0.8 to 2 ng/mL (lower serum trough concentrations of 0.5 to 1 ng/mL may be appropriate in some adult patients, see .) However, Digoxin (Lanoxin) may produce clinical benefits even at serum concentrations below this range. About two-thirds of adult patients with clinical toxicity have serum Digoxin (Lanoxin) concentrations greater than 2 ng/mL. However, since one-third of patients with clinical toxicity have concentrations less than 2 ng/mL, values below 2 ng/mL do not rule out the possibility that a certain sign or symptom is related to Digoxin (Lanoxin) therapy. Rarely, there are patients who are unable to tolerate Digoxin (Lanoxin) at serum concentrations below 0.8 ng/mL. Consequently, the serum concentration of Digoxin (Lanoxin) should always be interpreted in the overall clinical context, and an isolated measurement should not be used alone as the basis for increasing or decreasing the dose of the drug.
To allow adequate time for equilibration of Digoxin (Lanoxin) between serum and tissue, sampling of serum concentrations should be done just before the next scheduled dose of the drug. If this is not possible, sampling should be done at least 6 to 8 hours after the last dose, regardless of the route of administration or the formulation used. On a once-daily dosing schedule, the concentration of Digoxin (Lanoxin) will be 10% to 25% lower when sampled at 24 versus 8 hours, depending upon the patient's renal function. On a twice-daily dosing schedule, there will be only minor differences in serum Digoxin (Lanoxin) concentrations whether sampling is done at 8 or 12 hours after a dose.
If a discrepancy exists between the reported serum concentration and the observed clinical response, the clinician should consider the following possibilities:
Peak Digoxin (Lanoxin) body stores of 8 to 12 mcg/kg should provide therapeutic effect with minimum risk of toxicity in most patients with heart failure and normal sinus rhythm. Because of altered Digoxin (Lanoxin) distribution and elimination, projected peak body stores for patients with renal insufficiency should be conservative (i.e., 6 to 10 mcg/kg) [see ].
The loading dose should be administered in several portions, with roughly half the total given as the first dose. Additional fractions of this planned total dose may be given at 6- to-8-hour intervals,
If the patient's clinical response necessitates a change from the calculated loading dose of Digoxin (Lanoxin) , then calculation of the maintenance dose should be based upon the amount actually given.
A single initial dose of 500 to 750 mcg (0.5 to 0.75 mg) of Digoxin (Lanoxin) Tablets usually produces a detectable effect in 0.5 to 2 hours that becomes maximal in 2 to 6 hours. Additional doses of 125 to 375 mcg (0.125 to 0.375 mg) may be given cautiously at 6- to 8-hour intervals until clinical evidence of an adequate effect is noted. The usual amount of Digoxin (Lanoxin) Tablets that a 70 kg patient requires to achieve 8 to 12 mcg/kg peak body stores is 750 to 1250 mcg (0.75 to 1.25 mg).
Digoxin (Lanoxin) Injection is frequently used to achieve rapid digitalization with conversion to Digoxin (Lanoxin) Tablets for maintenance therapy. If patients are switched from intravenous to oral Digoxin (Lanoxin) formulations, allowances must be made for differences in bioavailability when calculating maintenance dosages (see Table 1, ).
The doses of Digoxin (Lanoxin) used in controlled trials in patients with heart failure have ranged from 125 to 500 mcg (0.125 to 0.5 mg) once daily. In these studies, the Digoxin (Lanoxin) dose has been generally titrated according to the patient's age, lean body weight, and renal function. Therapy is generally initiated at a dose of 250 mcg (0.25 mg) once daily in patients under age 70 with good renal function, at a dose of 125 mcg (0.125 mg) once daily in patients over age 70 or with impaired renal function, and at a dose of 62.5 mcg (0.0625 mg) in patients with marked renal impairment. Doses may be increased every 2 weeks according to clinical response.
In a subset of approximately 1800 patients enrolled in the DIG trial (wherein dosing was based on an algorithm similar to that in Table 5) the mean (± SD) serum Digoxin (Lanoxin) concentrations at 1 month and 12 months were 1.01 ± 0.47 ng/mL and 0.97 ± 0.43 ng/mL, respectively. There are no rigid guidelines as to the range of serum concentrations that are most efficacious. Several post hoc analyses of heart failure patients in the DIG trial suggest that the optimal trough Digoxin (Lanoxin) serum level may be 0.5 ng/mL to 1 ng/mL.
The maintenance dose should be based upon the percentage of the peak body stores lost each day through elimination. The following formula has had wide clinical use:
Table 5 provides average daily maintenance dose requirements of Digoxin (Lanoxin) Tablets for patients with heart failure based upon lean body weight and renal function:
In general, divided daily dosing is recommended for infants and young children (under age 10). In the newborn period, renal clearance of Digoxin (Lanoxin) is diminished and suitable dosage adjustments must be observed. This is especially pronounced in the premature infant. Beyond the immediate newborn period, children generally require proportionally larger doses than adults on the basis of body weight or body surface area. Children over 10 years of age require adult dosages in proportion to their body weight. Some researchers have suggested that infants and young children tolerate slightly higher serum concentrations than do adults.
Daily maintenance doses for each age group are given in Table 6 and should provide therapeutic effects with minimum risk of toxicity in most patients with heart failure and normal sinus rhythm. These recommendations assume the presence of normal renal function:
In children with renal disease, Digoxin (Lanoxin) must be carefully titrated, based upon clinical response.
It cannot be overemphasized that both the adult and pediatric dosage guidelines provided are based upon average patient response and substantial individual variation can be expected. Accordingly, ultimate dosage selection must be based upon clinical assessment of the patient.
The difference in bioavailability between Digoxin (Lanoxin) Injection or Digoxin (Lanoxin) Tablets must be considered when changing patients from one dosage form to another.
Doses of 100 mcg (0.1. mg) and 200 mcg (0.2 mg) of Digoxin (Lanoxin) solution in capsules are approximately equivalent to 125 mcg (0.125 mg) and 250 mcg (0.25 mg) doses of Digoxin (Lanoxin) tablets and Digoxin (Lanoxin) pediatric elixir, respectively (see Table 1 in ).
Digoxin (Lanoxin) How Supplied:
Digoxin (Lanoxin) Tablets USP, 0.125 mg are Yellow, Round, Scored Tablets, Debossed "W 40" on Scored Side and are available as follows:NDC 51079-847-20 - Unit dose blister packages of 100 (10 cards of 10 tablets each).
Digoxin (Lanoxin) Tablets USP, 0.25 mg are White, Round, Scored Tablets, Debossed "WW 41" on Scored Side and are available as follows:NDC 51079-848-20 - Unit dose blister packages of 100 (10 cards of 10 tablets each).
Store at 20º to 25ºC (68º to 77ºF). [See USP Controlled Room Temperature] in a dry place.
Digibind is a registered trademark of GlaxoSmithKline.Digifab is a registered trademark of Prostherics Inc.
Manufactured by:West-ward Pharmaceutical Corp. Eatontown, NJ 07724
Distributed by:UDL Laboratories, Inc.Rockford, IL 61103
S-10318 R111/10
Digoxin (Lanoxin) Principal Display Panel - Mcg (. Mg)
NDC 51079-847-20
100 Tablets (10 x 10)
Each scored tablet contains:Digoxin (Lanoxin) 0.125 mg
Store at 20 - 25ºC (68 - 77ºF).[See USPControlled Room Temperature] in a dry place.
Packaged and Distributed by:
UDL LABORATORIES, INC.
ROCKFORD, IL 61103
This unit dose package is not child resistant.
For institutional use only.
Keep this and all drugs out of the reach of children.
This container provides light-resistance.
See window for lot number and expiration date.
Digoxin (Lanoxin) Principal Display Panel - Mcg (. Mg)
NDC 51079-848-20
100 Tablets (10 x 10)
Each scored tablet contains:Digoxin (Lanoxin) 0.25 mg
Store at 20 - 25ºC (68 - 77ºF).[See USPControlled Room Temperature] in a dry place.
Packaged and Distributed by:
UDL LABORATORIES, INC.
ROCKFORD, IL 61103
This unit dose package is not child resistant.
For institutional use only.
Keep this and all drugs out of the reach of children.
This container provides light-resistance.
See window for lot number and expiration date.
