Digitek

DIGITEK (digoxin) 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 is extracted from the leaves of Digitalis lanata. 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 is described chemically as (3 β, 5 β, 12 β)-3-[(O-2, 6-dideoxy-β-D-ribo-hexopyranosyl-(1→4)-O-2,6-dideoxy-β-D-ribo-hexopyranosyl- (1→4)-2,6-dideoxy-β-D-ribo-hexopyranosyl)oxy]-12,14-dihydroxy-card-20(22)-enolide. Its molecular formula is C41H64O14, its molecular weight is 780.94, and the structural formula shown:

Digoxin 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.

DIGITEK (digoxin tablets) is 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 USP and the following inactive ingredients: corn starch, croscarmellose sodium, microcrystalline cellulose, pregelatinized starch, lactose monohydrate and anhydrous lactose, silicon dioxide and stearic acid. In addition, the 125-mcg (0.125-mg) tablet contains D&C Yellow No. 10 Aluminum Lake.

Digoxin is a prescription medication used to treat mild to moderate heart failure and abnormal heart rhythms (atrial fibrillation). Digoxin belongs to a group of drugs called cardiac glycosides, which help control heart rate and strengthens the heart’s pump.

This medication comes in tablet and solution forms and is taken once or twice a day, with or without food. This medication also comes in injection form and is injected by a healthcare professional when needed.

Common side effects of digoxin include headache, nausea, and vomiting. Digoxin can also cause blurred vision or dizziness. Do not drive or operate heavy machinery until you know how this medication will affect you.

Take this medication exactly as prescribed by your doctor. Follow the directions on your prescription label carefully.

The dose your doctor recommends may be based on the following:

• the condition being treated
• other medical conditions you have
• other medications you are taking
• how you respond to this medication
• your weight
• your height
• your age
• your gender

Oral Solution:

• The recommended loading dose range is 10 to 60 mcg/kg.
• The recommended maintenance dose range is 2.3 to 9.4 mcg/kg/dose (each dose taken twice daily).

Injectable:

• The recommended loading dose range is 8 to 35 mcg/kg (IV injection)
• The recommended maintenance dose range for those 10 years of age or older is 2.4 to 3.6 mcg/kg/day. The dose may also be determined according to your renal function plus your lean body weight.

Digox (digoxin tablet):

• The recommended dose range for adults is 125 to 500 mcg once daily. In these studies, the digoxin dose has been generally titrated according to the patient’s age, lean body weight, and kidney function. Therapy is generally started at a dose of 250 mcg once daily in those under age 70 with good kidney function, at a dose of 125 mcg (0.125 mg) once daily in those over age 70 or with impaired kidney function, and at a dose of 62.5 mcg (0.0625 mg) in those with considerable kidney impairment. Doses may be increased every 2 weeks according to clinical response.

This section provides information on the proper use of a number of products that contain digoxin. It may not be specific to Digitek. Please read with care.

To keep your heart working properly, take this medicine exactly as directed even though you may feel well. Do not take more of it than your doctor ordered and do not miss any doses. Take the medicine at the same time each day. This medicine works best when there is a constant amount in the blood.

When you are taking this medicine, it is very important that you get the exact amount of medicine that you need. The dose of digoxin will be different for different patients. Your doctor will determine the proper dose of digoxin for you. Follow your doctor's orders or the directions on the label.

Measure the oral solution correctly using the marked measuring dropper that comes with the package or an oral syringe. Do not use teaspoons and tablespoons that are used for serving and eating food. They do not measure exact amounts.

Dosing

The dose of this medicine will be different for different patients. Follow your doctor's orders or the directions on the label. The following information includes only the average doses of this medicine. If your dose is different, do not change it unless your doctor tells you to do so.

The amount of medicine that you take depends on the strength of the medicine. Also, the number of doses you take each day, the time allowed between doses, and the length of time you take the medicine depend on the medical problem for which you are using the medicine.

• For heart failure or atrial fibrillation:
  • For oral dosage form (solution):
    • Adults, teenagers, and children 10 years of age and older—Dose is based on age, body weight, and medical condition and must be determined by your doctor. At first, the dose is usually 10 to 15 micrograms (mcg) per kilogram (kg) of body weight. Your doctor may adjust your dose as needed. However, the maintenance dose is usually 3 to 4.5 mcg per kg of body weight per day.
    • Children 5 to 10 years of age—Dose is based on age, body weight, and medical condition and must be determined by your doctor. At first, the dose is usually 20 to 35 micrograms (mcg) per kilogram (kg) of body weight. Your doctor may adjust your dose as needed. However, the maintenance dose is usually 5.6 to 11.3 mcg per kg of body weight per day.
    • Children 2 to 5 years of age—Dose is based on age, body weight, and medical condition and must be determined by your doctor. At first, the dose is usually 30 to 45 micrograms (mcg) per kilogram (kg) of body weight. Your doctor may adjust your dose as needed. However, the maintenance dose is usually 9.4 to 13.1 mcg per kg of body weight per day.
    • Infants 1 month to 24 months of age—Dose is based on age, body weight, and medical condition and must be determined by your doctor. At first, the dose is usually 35 to 60 micrograms (mcg) per kilogram (kg) of body weight. Your doctor may adjust your dose as needed. However, the maintenance dose is usually 11.3 to 18.8 mcg per kg of body weight per day.
    • Full-term babies—Dose is based on age, body weight, and medical condition and must be determined by your doctor. At first, the dose is usually 25 to 35 micrograms (mcg) per kilogram (kg) of body weight. Your doctor may adjust your dose as needed. However, the maintenance dose is usually 7.5 to 11.3 mcg per kg of body weight per day.
    • Premature babies—Dose is based on age, body weight, and medical condition and must be determined by your doctor. At first, the dose is usually 20 to 30 micrograms (mcg) per kilogram (kg) of body weight. Your doctor may adjust your dose as needed. However, the maintenance dose is usually 4.7 to 7.8 mcg per kg of body weight per day.
  • For oral dosage form (tablets):
    • Adults—Your doctor will give your first few doses intravenously (rapid digitalization) and then, you'll be switched to oral tablets for maintenance therapy. A maintenance dose of 0.125 to 0.5 milligram (mg) once a day will be given depending on your body weight and medical condition.
    • Teenagers and children older than 10 years of age—Dose is based on body weight and must be determined by your doctor.
    • Children younger than 10 years of age—Use and dose must be determined by your doctor.

Missed Dose

If you miss a dose of this medicine, take it as soon as possible. However, if it is almost time for your next dose, skip the missed dose and go back to your regular dosing schedule. Do not double doses.

If you miss a dose of this medicine, and you remember it within 12 hours, take it as soon as you remember. However, if you do not remember until later, skip the missed dose and go back to your regular dosing schedule. If you have any questions about this or if you miss doses for 2 or more days in a row, check with your doctor.

Storage

Store the medicine in a closed container at room temperature, away from heat, moisture, and direct light. Keep from freezing.

Keep out of the reach of children.

Do not keep outdated medicine or medicine no longer needed.

Ask your healthcare professional how you should dispose of any medicine you do not use.

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:

More common

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

Rare

• 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

Incidence not known

• 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:

Less common

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

Incidence not known

• 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.

Digitek® (digoxin tablets, USP) is available containing 125 mcg (0.125 mg) or 250 mcg (0.25 mg) of digoxin, USP.

• The 125 mcg (0.125 mg) tablets are yellow, round, scored, slope-faced tablets debossed with M above the score and 145 below the score on one side of the tablet and blank on the other side. • The 250 mcg (0.25 mg) tablets are white, round, scored, slope-faced tablets debossed with M above the score and 147 below the score on one side of the tablet and blank on the other side.

Digitek® (digoxin tablets) is contraindicated in patients with:

• Ventricular fibrillation [see Warnings and Precautions (5.1)] • Known hypersensitivity to digoxin (reactions seen include unexplained rash, swelling of the mouth, lips or throat or a difficulty in breathing). A hypersensitivity reaction to other digitalis preparations usually constitutes a contraindication to digoxin.

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 sinoatrial (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 digoxin are shown in Table 7.

Table 7. Times to Onset of Pharmacologic Effect and to Peak Effect of Preparations of Digitek® (digoxin tablets)

* Documented for ventricular response rate in atrial fibrillation, inotropic effects and electrocardiographic changes. † Depending upon rate of infusion.
Product	Time to Onset of Effect*	Time to Peak Effect*
Digitek® (digoxin tablets)	0.5 to 2 hours	2 to 6 hours
Digoxin Injection/IV	5 to 30 minutes†	1 to 4 hours

Hemodynamic Effects

Short- and long-term therapy with the drug increases 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.

ECG Changes

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 testing. These electrophysiologic effects are not indicative of toxicity. Digoxin does not significantly reduce heart rate during exercise.

Pharmacokinetics

Note: The following data are from studies performed in adults, unless otherwise stated.

Absorption

Following oral administration, peak serum concentrations of digoxin occur at 1 to 3 hours. Absorption of digoxin from digoxin tablets has been demonstrated to be 60% to 80% complete compared to an identical intravenous dose of digoxin (absolute bioavailability). When digoxin 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 digoxin 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 (7.2)].

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

Distribution

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 (2.1)].

Digoxin is concentrated in tissues and therefore has a large apparent volume of distribution (approximately 475 L to 500 L). 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.

Metabolism

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.

Excretion

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 (8.5)].

Gender

In a study of 184 patients, the clearance of digoxin was 12% lower in female 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, titrate carefully 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.

Digitek® (digoxin tablets, USP) is available containing 125 mcg (0.125 mg) or 250 mcg (0.25 mg) of digoxin, USP.

The 125 mcg (0.125 mg) tablets are yellow, round, scored, slope-faced tablets debossed with M above the score and 145 below the score on one side of the tablet and blank on the other side. They are available as follows:

NDC 0378-6155-01
bottles of 100 tablets

NDC 0378-6155-10
bottles of 1000 tablets

The 250 mcg (0.25 mg) tablets are white, round, scored, slope-faced tablets debossed with M above the score and 147 below the score on one side of the tablet and blank on the other side. They are available as follows:

NDC 0378-6156-01
bottles of 100 tablets

NDC 0378-6156-10
bottles of 1000 tablets

Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.]

Store in a dry place. Protect from light.

Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.

• Advise patients that digoxin is used to treat heart failure and heart arrhythmias. • Instruct patients to take this medication as directed. • Advise patients that many drugs can interact with digoxin. Instruct patients to inform their doctor and pharmacist if they are taking any over the counter medications, including herbal medication, or are started on a new prescription. • Advise patients that blood tests will be necessary to ensure that their digoxin dose is appropriate for them. • Advise patients to contact their doctor or a healthcare professional if they experience nausea, vomiting, persistent diarrhea, confusion, weakness, or visual disturbances (including blurred vision, green-yellow color disturbances, halo effect) as these could be signs that the dose of digoxin may be too high. • Advise parents or caregivers that the symptoms of having too high digoxin doses may be difficult to recognize in infants and pediatric patients. Symptoms such as weight loss, failure to thrive in infants, abdominal pain, and behavioral disturbances may be indications of digoxin toxicity. • Instruct the patient to monitor and record their heart rate and blood pressure daily. • Instruct women of childbearing potential who become or are planning to become pregnant to consult a physician prior to initiation or continuing therapy with digoxin.

The brands listed are trademarks of their respective owners.

Mylan Pharmaceuticals Inc.
Morgantown, WV 26505 U.S.A.

Revised: 12/2016
DIGI:R6