Lanoxin

Lanoxin, Lanoxin Pediatric

• Digoxin is used for treating adults with mild to moderate congestive heart failure and for treating an atrial fibrillation, an abnormal heart rhythm.
• It also is used for increasing myocardial contractility in pediatric patients with heart failure.

Common side effects include

• nausea,
• diarrhea,
• vomiting,
• headache,
• dizziness,
• skin rash, and
• mental changes.

Many digoxin side effects are dose dependent and happen when blood levels are over the narrow therapeutic range. Therefore, digoxin side effects can be avoided by keeping blood levels within the therapeutic level. Serious side effects associated with digoxin include

• heart block,
• rapid heartbeat, and
• slow heart rate.

Digoxin has also been associated with visual disturbance (blurred or yellow vision), abdominal pain, and breast enlargement. Patients with low blood potassium levels can develop digoxin toxicity even when digoxin levels are not considered elevated. Similarly, high calcium and low magnesium blood levels can increase digoxin toxicity and produce serious disturbances in heart rhythm.

The following adverse reactions are included in more detail in the WARNINGS AND PRECAUTIONS section of the label:

• Cardiac arrhythmias [see WARNINGS AND PRECAUTIONS]
• Digoxin Toxicity [see WARNINGS AND PRECAUTIONS]

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

In general, the adverse reactions of LANOXIN are dose-dependent and occur at doses higher than those needed to achieve a therapeutic effect. Hence, adverse reactions are less common when LANOXIN is used within the recommended dose range, is maintained within the therapeutic serum concentration range, and when there is careful attention to concurrent medications and conditions.

In the DIG trial (a trial investigating the effect of digoxin on mortality and morbidity in patients with heart failure), the incidence of hospitalization for suspected digoxin toxicity was 2% in patients taking LANOXIN compared to 0.9% in patients taking placebo [see Clinical Studies].

The overall incidence of adverse reactions with digoxin has been reported as 5 to 20%, with 15 to 20% of adverse events considered serious. Cardiac toxicity accounts for about one-half, gastrointestinal disturbances for about one-fourth, and CNS and other toxicity for about one-fourth of these adverse events.

Gastrointestinal: In addition to nausea and vomiting, the use of digoxin has been associated with abdominal pain, intestinal ischemia, and hemorrhagic necrosis of the intestines.

CNS: Digoxin can cause headache, weakness, dizziness, apathy, confusion, and mental disturbances (such as anxiety, depression, delirium, and hallucination).

Other: Gynecomastia has been occasionally observed following the prolonged use of digoxin. Thrombocytopenia and maculopapular rash and other skin reactions have been rarely observed.

Mechanism of Action

All of digoxin's actions are mediated through its effects on Na-K ATPase. This enzyme, the “sodium pump,” is responsible for maintaining the intracellular milieu throughout the body by moving sodium ions out of and potassium ions into cells. By inhibiting Na-K ATPase, digoxin

• causes increased availability of intracellular calcium in the myocardium and conduction system, with consequent increased inotropy, increased automaticity, and reduced conduction velocity
• indirectly causes parasympathetic stimulation of the autonomic nervous system, with consequent effects on the sino-atrial (SA) and atrioventricular (AV) nodes
• reduces catecholamine reuptake at nerve terminals, rendering blood vessels more sensitive to endogenous or exogenous catecholamines
• increases baroreceptor sensitization, with consequent increased carotid sinus nerve activity and enhanced sympathetic withdrawal for any given increment in mean arterial pressure
• increases (at higher concentrations) sympathetic outflow from the central nervous system (CNS) to both cardiac and peripheral sympathetic nerves
• allows (at higher concentrations) progressive efflux of intracellular potassium, with consequent increase in serum potassium levels.

The cardiologic consequences of these direct and indirect effects are an increase in the force and velocity of myocardial systolic contraction (positive inotropic action), a slowing of the heart rate (negative chronotropic effect), decreased conduction velocity through the AV node, and a decrease in the degree of activation of the sympathetic nervous system and renin-angiotensin system (neurohormonal deactivating effect).

Pharmacodynamics

The times to onset of pharmacologic effect and to peak effect of preparations of LANOXIN are shown in Table 7.

Table 7: Times to Onset of Pharmacologic Effect and to Peak Effect of Preparations of LANOXIN

Short-and long-term therapy with the drug increase cardiac output and lowers pulmonary artery pressure, pulmonary capillary wedge pressure, and systemic vascular resistance in patients with heart failure. These hemodynamic effects are accompanied by an increase in the left ventricular ejection fraction and a decrease in end-systolic and end-diastolic dimensions.

The use of therapeutic doses of LANOXIN may cause prolongation of the PR interval and depression of the ST segment on the electrocardiogram. LANOXIN may produce false positive ST-T changes on the electrocardiogram during exercise testing. These electrophysiologic effects are not indicative of toxicity. LANOXIN does not significantly reduce heart rate during exercise.

Pharmacokinetics

Following oral administration, peak serum concentrations of digoxin occur at 1 to 3 hours. Absorption of digoxin from LANOXIN Tablets has been demonstrated to be 60% to 80% complete compared to an identical intravenous dose of digoxin (absolute bioavailability). When LANOXIN Tablets are taken after meals, the rate of absorption is slowed, but the total amount of digoxin absorbed is usually unchanged. When taken with meals high in bran fiber, however, the amount absorbed from an oral dose may be reduced. Comparisons of the systemic availability and equivalent doses for oral preparations of LANOXIN are shown in Dosage and Administration (2.6).

Digoxin is a substrate for P-glycoprotein. As an efflux protein on the apical membrane of enterocytes, P-glycoprotein may limit the absorption of digoxin.

In some patients, orally administered digoxin is converted to inactive reduction products (e.g., dihydrodigoxin) by colonic bacteria in the gut. Data suggest that 1 in 10 patients treated with digoxin tablets, colonic bacteria will degrade 40% or more of the ingested dose. As a result, certain antibiotics may increase the absorption of digoxin in such patients. Although inactivation of these bacteria by antibiotics is rapid, the serum digoxin concentration will rise at a rate consistent with the elimination half-life of digoxin. Serum digoxin concentration relates to the extent of bacterial inactivation, and may be as much as doubled in some cases [see DRUG INTERACTIONS].

Patients with malabsorption syndromes (e.g., short bowel syndrome, celiac sprue, jejunoileal bypass) may have a reduced ability to absorb orally administered digoxin.

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 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 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 DOSAGE AND ADMINISTRATION].

Digoxin is concentrated in tissues and therefore has a large apparent volume of distribution (approximately 475 to 500L). Digoxin crosses both the blood-brain barrier and the placenta. At delivery, the serum digoxin concentration in the newborn is similar to the serum concentration in the mother. Approximately 25% of digoxin in the plasma is bound to protein. Serum digoxin 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.

Only a small percentage (13%) of a dose of digoxin is metabolized in healthy volunteers. The urinary metabolites, which include dihydrodigoxin, digoxigenin bisdigitoxoside, and their glucuronide and sulfate conjugates, are polar in nature and are postulated to be formed via hydrolysis, oxidation, and conjugation. The metabolism of digoxin is not dependent upon the cytochrome P-450 system, and digoxin is not known to induce or inhibit the cytochrome P-450 system.

Elimination of digoxin follows first-order kinetics (that is, the quantity of digoxin eliminated at any time is proportional to the total body content). Following intravenous administration to healthy volunteers, 50% to 70% of a digoxin dose is excreted unchanged in the urine. Renal excretion of digoxin is proportional to creatinine clearance and is largely independent of urine flow. In healthy volunteers with normal renal function, digoxin has a half-life of 1.5 to 2 days. The half-life in anuric patients is prolonged to 3.5 to 5 days. Digoxin is not effectively removed from the body by dialysis, exchange transfusion, or during cardiopulmonary bypass because most of the drug is bound to extravascular tissues.

Special Populations

Geriatrics: Because of age-related declines in renal function, elderly patients would be expected to eliminate digoxin more slowly than younger subjects. Elderly patients may also exhibit a lower volume of distribution of digoxin due to age-related loss of lean muscle mass. Thus, the dosage of digoxin should be carefully selected and monitored in elderly patients [see Use In Specific Populations].

Gender: In a study of 184 patients, the clearance of digoxin was 12% lower in females than in male patients. This difference is not likely to be clinically important.

Hepatic Impairment: Because only a small percentage (approximately 13%) of a dose of digoxin undergoes metabolism, hepatic impairment would not be expected to significantly alter the pharmacokinetics of digoxin. In a small study, plasma digoxin concentration profiles in patients with acute hepatitis generally fell within the range of profiles in a group of healthy subjects. No dosage adjustments are recommended for patients with hepatic impairment; however, serum digoxin concentrations should be used as appropriate to help guide dosing in these patients.

Renal Impairment: Since the clearance of digoxin correlates with creatinine clearance, patients with renal impairment generally demonstrate prolonged digoxin elimination half-lives and greater exposures to digoxin. Therefore, digoxin must be carefully titrated in these patients based on clinical response, and based on monitoring of serum digoxin concentrations, as appropriate.

Race: The impact of race differences on digoxin pharmacokinetics has not been formally studied. Because digoxin 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.

Drug-drug Interactions

Based on literature reports no significant changes in digoxin exposure were reported when digoxin was co-administered with the following drugs:

alfuzosin, aliskiren, amlodipine, aprepitant, argatroban, aspirin, atorvastatin, benazepril, bisoprolol, black cohosh, bosentan, candesartan, citalopram, clopidogrel, colesevelam, dipyridamole, disopyramide, donepezil, doxazosin, dutasteride, echinacea, enalapril, eprosartan, ertapenem, escitalopram, esmolol, ezetimibe, famciclovir, felodipine, finasteride, flecainide, fluvastatin, fondaparinux, galantamine, gemifloxacin, grapefruit juice, irbesartan, isradipine, ketorlac, levetiracetam, levofloxacin, lisinopril, losartan, lovastatin, meloxicam, mexilitine, midazolam, milk thistle, moexipril, montelukast, moxifloxacin, mycophenolate, nateglinide, nesiritide, nicardipine, nisoldipine, olmesartan, orlistat, pantoprazole, paroxetine,perindopril, pioglitazone, pravastatin, prazosin, procainamide, quinapril, raloxifene, ramipril, repaglinide, rivastigmine, rofecoxib, ropinirole, rosiglitazone, rosuvastatin, sertraline, sevelamer, simvastatin, sirolimus, solifenacin, tamsulosin, tegaserod, terbinafine, tiagabine, ticlopidine, tigecycline, topiramate, torsemide, tramadol, trandolapril, triamterene, trospium, trovafloxacin, valacyclovir, valsartan, varenicline, voriconazole, zaleplon, zolpidem

Clinical Studies

Chronic Heart Failure

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, a diuretic, and an ACE inhibitor (RADIANCE only) and randomized them to placebo or treatment with LANOXIN. Both trials demonstrated better preservation of exercise capacity in patients randomized to LANOXIN. Continued treatment with LANOXIN 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 Digitalis Investigation Group (DIG) main trial was a 37-week, multicenter, randomized, double-blind mortality study comparing digoxin to placebo in 6800 adult 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 a concomitant ACE inhibitor (94%) and diuretics (82%). As in the smaller trials described above, patients who had been receiving open-label digoxin were withdrawn from this treatment before randomization. Randomization to digoxin was again associated with a significant reduction in the incidence of hospitalization, whether scored as number of hospitalizations for heart failure (relative risk 75%), risk of having at least one such hospitalization during the trial (RR 72%), or number of hospitalizations for any cause (RR 94%). On the other hand, randomization to digoxin had no apparent effect on mortality (RR 99%, with confidence limits of 91 to 107%).

Chronic Atrial Fibrillation

Digoxin has also been studied as a means of controlling the ventricular response to chronic atrial fibrillation in adults. Digoxin reduced the resting heart rate, but not the heart rate during exercise.

In 3 different randomized, double-blind trials that included a total of 315 adult patients, digoxin was compared to placebo for the conversion of recent-onset atrial fibrillation to sinus rhythm. Conversion was equally likely, and equally rapid, in the digoxin and placebo groups. In a randomized 120-patient trial comparing digoxin, sotalol, and amiodarone, patients randomized to digoxin had the lowest incidence of conversion to sinus rhythm, and the least satisfactory rate control when conversion did not occur.

In at least one study, digoxin was studied as a means of delaying reversion to atrial fibrillation in adult patients with frequent recurrence of this arrhythmia. This was a randomized, double-blind, 43-patient crossover study. Digoxin increased the mean time between symptomatic recurrent episodes by 54%, but had no effect on the frequency of fibrillatory episodes seen during continuous electrocardiographic monitoring.

Avoid becoming overheated or dehydrated during exercise, in hot weather, or by not drinking enough fluids. Digoxin overdose can occur more easily if you are dehydrated.

Serious side effects have been reported with digoxin. See "Digoxin Precautions" section.

Common side effects of digoxin include:

• Dizziness
• Nausea
• Vomiting
• Vision changes (blurred or yellow)
• Upset stomach
• Loss of appetite
• Rash
• Mental changes (anxiety, depression, hallucination)
• Diarrhea
• Feet or hands swelling
• Weakness

This is not a complete list of digoxin side effects. Ask your doctor or pharmacist for more information.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Tell your doctor if you are pregnant or plan to become pregnant.

The FDA categorizes medications based on safety for use during pregnancy. Five categories - A, B, C, D, and X, are used to classify the possible risks to an unborn baby when a medication is taken during pregnancy.

Digoxin falls into category C. This medication may be given to a pregnant woman if her healthcare provider believes that its benefits to the pregnant woman outweigh any possible risks to her unborn baby.

It is not known if digoxin will harm your unborn baby.

Tell your doctor if you are breastfeeding or plan to breastfeed.

You should not take digoxin if you are breastfeeding. It may be excreted in your breast milk and may harm your nursing child.

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur:

• Dizziness
• fainting
• fast, pounding, or irregular heartbeat or pulse
• slow heartbeat

• Black, tarry stools
• bleeding gums
• blood in the urine or stools
• bloody vomit
• pinpoint red spots on the skin
• rash with flat lesions or small raised lesions on the skin
• severe stomach pain
• unusual bleeding or bruising

• Chest pain or discomfort
• nausea
• shortness of breath
• sweating
• swelling of the feet and lower legs
• troubled breathing
• unusual tiredness or weakness

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Agitation or combativeness
• anxiety
• confusion
• depression
• diarrhea
• expressed fear of impending death
• hallucinations
• rash
• vomiting

• Blurred or loss of vision
• disturbed color perception
• double vision
• halos around lights
• headache
• lack of feeling or emotion
• loss of appetite
• night blindness
• overbright appearance of lights
• swelling of the breasts or breast soreness in both females and males
• tunnel vision
• weakness
• weight loss

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

You should not use Lanoxin if you are allergic to digoxin, or if you have ventricular fibrillation (a heart rhythm disorder of the ventricles, or lower chambers of the heart that allow blood to flow out of the heart).

To make sure Lanoxin is safe for you, tell your doctor if you have:

• a serious heart condition such as "sick sinus syndrome" or "AV block" (unless you have a pacemaker);

• a recent history of heart attack;

• Wolff-Parkinson-White Syndrome (sudden fast heartbeats);

• kidney disease;

• a thyroid disorder;

• an electrolyte imbalance (such as low levels of calcium, potassium, or magnesium in your blood);

• if you are malnourished or have recently been sick with vomiting or diarrhea; or

• if you take a diuretic (water pill), or use steroid medicine.

It is not known whether Lanoxin will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant.

Digoxin can pass into breast milk and may harm a nursing baby. Tell your doctor if you are breast-feeding a baby.