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digitalis glycosides is unwarranted. Moreover, since they may cause potentially fatal arrhythmias or other adverse effects, the use of these drugs in the treatment of obesity is dangerous.

Many of the arrhythmias for which digoxin is advised closely resemble those reflecting digoxin intoxication. If the possibility of digoxin intoxication cannot be excluded, cardiac glycosides should be temporarily withheld if permitted by the clinical situation.

The patient with congestive heart failure may complain of nausea and vomiting. These symptoms may also be indications on digoxin intoxication. A clinical determination of the cause of these symptoms must be attempted before further drug administration. Patients with renal insufficiency require smaller than usual doses of digoxin. See ACTION Section for mechanism.

PRECAUTIONS

Atrial arrhythmias associated with hypermetabolic states are particularly resistant to digoxin treatment. Care must be taken to avoid digoxin toxicity if digoxin is used to help the arrhythmia.

Digoxin is not indicated for the treatment of ventricular tachycardia unless congestive heart failure supervenes after a protracted episode not itself due to digoxin.

Potassium depletion sensitizes the myocardium to digoxin, and toxicity may develop even with the usual dosage. Hypokalemia may also alter the rate of onset and intensity of the positive inotropic effect of digoxin. Therefore, it is desirable to maintain normal serum potassium levels in patients being treated with digoxin.

Potassium wastage may result from diuretic or corticosteriod therapy, hemodialysis, and from suction of gastrointestinal secretions. It may accompany malnutrition, diarrhea, prolonged vomiting, old age, and long-standing congestive heart failure. In general, rapid changes in serum potassium or other electrolytes are to be avoided, and intravenous treatment with potassium should be reserved only for special circumstances as described below (see TREATMENT OF ARRHYTHMIAS PRODUCED BY OVERDOSAGES section).

Patients with acute myocardial infarction, severe pulmonary disease, or far advanced heart failure may be more sensitive to digoxin and more prone to disturbances of rhythm.

Calcium affects contractility and excitability of the heart in a manner similar to that of digoxin. Calcium may produce serious arrhythmias in digitalized patients.

In myxedema the digoxin requirements are less because excretion rate is decreased and blood levels are significantly higher.

In incomplete A-V block, especially in patients subject to Stokes-Adams attacks, ad

vanced or complete heart block may develop if digoxin is given. Heart failure in these patients can usually be controlled by other measures and by increasing the heart rate. Patients with chronic constructive pericarditis may respond unfavorably to digoxin.

Patients with idiopathic hypertrophic subaortic stenosis must be managed extremely carefully. Unless cardiac failure is severe, it is doubtful whether digoxin should be employed.

Renal insufficiency delays the excretion of digoxin, and dosage must be adjusted accordingly in patients with renal disease. NOTE: This applies also to potassium administration should it become necessary.

Electrical conversion of arrhythmias may require reduction of digoxin dosage.

ADVERSE REACTIONS

Gynecomastia, uncommon.
Overdosage or toxic effects.

Gastrointestinal: Anorexia, nausea, vomiting, diarrhea are the most common early symptoms of overdosages in the adult (but rarely conspicuous in infants). Uncontrolled heart failure may also produce such symptoms.

Central nervous system: Visual disturbances (blurred vision, yellow vision), headache, weakness, apathy.

Cardiac disturbances (arrhythmias): Ventricular premature beats are the most common, except in infants and young children. Paroxysmal and nonparoxysmal nodal rhythms, atrioventricular (interference) disassociation and paroxysmal atrial tachycardia (PAT) with block are also common arrhythmias due to digoxin overdosage. Conduction disturbances: Excessive slowing of the pulse is a clinical sign of digoxin overdosage. Atrioventricular block of increasing degree may proceed to complete heart block. Note: The electrocardiogram is fundamental in determining the presence and nature of these cardiac toxic disturbances. Digoxin may also induce other changes (as of the ST segment), but these provide no measure of the degree of digitalization.

TREATMENT OF ARRHYTHMIAS PRODUCED BY

OVERDOSAGES

Digoxin should be discontinued until all signs of toxicity are abolished. Discontinuation may be all that is necessary if toxic manifestations are not severe and appear after the time for peak effect of the drug.

Potassium salts are commonly used. Potassium chloride in divided oral doses totaling 4-6 grams for adults (see PEDIATRIC INFORMATION section for pediatric dosage) may be given provided renal function is adequate.

When correction of the arrhythmia is urgent and the serum potassium level is low or normal, potassium should be administered

intravenously in a solution of 5 percent dextrose in water. A total of 40-100 milliequivalents (30 milliequivalents per 500 milliliters) is given at the rate of 20 milliequivalents per hour unless limited by pain due to local irritation.

Additional amounts may be given if the arrhythmia is uncontrolled and the potassium well tolerated.

Continuous electrocardiographic monitoring should be performed to watch for any evidence of potassium toxicity, e.g., peaking of T waves, and to observe the effect on the arrhythmia so that the infusion may be promptly stopped when the desired effect is achieved.

CAUTION: Potassium should not be used and may be dangerous for severe or complete heart block due to digoxin and not related to any tachycardia.

Other agents that have been approved for the treatment of digoxin intoxication include procainamide, lidocaine, and propranolol.

DOSAGE AND ADMINISTRATION

Oral digoxin is administered slowly or rapidly as required until the desired therapeutic effect is obtained without symptoms of overdosage. The amount can be predicted approximately from the lean body mass of the patient with allowances made for excretion during the time taken to induce digitalization.

Subsequent maintenance dosage is also determined tentatively by the amount necessary to sustain the desired therapeutic effect.

Recommended dosages are practical average figures that may require considerable modification as dictated by individual sensitivity or associated conditions. Diminished renal function is the most important factor requiring modification of recommended or average doses. (See WARNINGS and PRECAUTIONS sections.)

The average amount of digoxin that patients must accumulate to be digitalized with digoxin tablets is 1.0-1.5 milligrams. Digitalization may be accomplished by any of several approaches that vary in dosage and frequency of administration, but reach the same endpoint in terms of total amount accumulated.

In previously undigitalized patients, a single loading dose of 0.5-0.75 milligram orally usually produces a detectable effect in 1-2 hours that becomes maximal in 6-8 hours. Additional doses of 0.25-0.5 milligram may be given cautiously at 6-8 hour intervals to full digitalization.

In previously undigitalized patients, institution of daily maintenance therapy (0.1250.5 milligram, see next paragraph) without a loading dose results in development of a steady-state plateau concentrations in about

7 days in patients with normal renal function.

The average daily oral maintenance dose is 0.125-0.5 milligram, usually 0.25 milligram. In the elderly patient, 0.125-0.25 milligram should be considered the average maintenance dose.

In patients with renal impairment, digoxin excretion is impaired and serum half-life is prolonged (see ACTION section). Digitalizing and maintenance doses are lower than those recommended for patients with normal renal functions. Signs of digoxin toxicity develop sooner in patients with renal impairment, and it takes longer for toxic signs and symptoms to disappear. Because of the prolonged half-life, a longer period of time is required to achieve an initial or new steady-state plateau in patients with renal impairment than in patients with normal renal function.

It cannot be overemphasized that the values given are averages and substantial individual variation can be expected.

(If pediatric dosage is available, the labeling sections above should be expanded to include the following information.)

PEDIATRIC INFORMATION

WARNINGS

Newborn infants display considerable variability in their tolerance to digoxin, depending on their degree of maturity.

Premature and immature infants are particularly sensitive, and dosage must be reduced and digitalization should be even more individualized and cautiously approached than in more mature infants. Impaired renal function must also be carefully taken into consideration.

Congestive heart failure accompanying acute glomerulonephritis requires extreme care in digitalization. A relatively low total dose administered in divided doses and concomitant use of antihypertensive drugs has been recommended. ECG monitoring is essential. Digoxin should be discontinued as soon as possible.

Patients with idiopathic hypertrophic subaortic stenosis must be managed extremely carefully. Unless cardiac failure is severe, it is doubtful whether digoxin should be employed.

Patients with rheumatic carditis, especially when severe, are unusually sensitive to digoxin and prone to disturbances of rhythm. If heart failure develops, digitalization may be initiated with relatively low doses; then it can be cautiously increased until a beneficial effect is obtained. If a therapeutic trial does not result in improvement, the drug should be considered ineffective and be discontinued.

NOTE: Digitalis glycosides are an important cause of accidental poisoning in children.

PRECAUTIONS

Dosage must be carefully titrated and differences in the bioavailability of parenteral preparations, elixirs, and tablets should be taken into account when switching patients from one preparation to another.

Electrocardiographic monitoring may be necessary to avoid intoxication.

Premonitory signs of toxicity in the newborn are undue slowing of the sinus rate, sinoatrial arrest, and prolongation of PR interval.

ADVERSE REACTIONS

Toxic signs differ from the adult in a number of respects. Cardiac arrhythmias are the more reliable and frequent signs of toxicity. Vomiting and diarrhea, neurologic and visual disturbances are rare as initial signs. Premature ventricular systoles are rarely seen; nodal and atrial systoles are more frequent.

Atrial arrhythmias, atrial ectopic rhythms, and paroxysmal atrial tachycardia with A-V block particularly are more common manifestations of toxicity in children. Ventricular arrhythmias are rare.

TREATMENT OF ARRHYTHMIAS PRODUCED BY OVERDOSAGES

(See adult section for other recommendations for the treatment of arrhythmias produced by overdosages and for additional recommendations and cautions regarding the use of potassium.) Potassium preparations may be given orally in divided doses totaling 1-1.5 milliequivalents/kilogram (1 gram K contains 13.4 milliequivalents). When correction of the arrhythmia is urgent, approximately 0.5 milliequivalents/kilogram of potassium per hour may be given, with careful electrocardiographic monitoring, as a solution of 20 milliequivalents or less per 500 milliliters in 5 percent dextrose in water. The total dose should generally not exceed 2 milliequivalents of potassium/kilogram.

DOSAGE AND ADMINISTRATION Digitalization must be individualized. Generally, premature and immature infants are particularly sensitive, requiring reduced dosage that must be determined by careful titration.

Oral Dosage. Beyond the immediate newborn period, children require proportionally greater doses than adults on the basis of body weight or surface area. The recommended oral digitalizing dosages in children with normal renal function are:

Newborn infants (normal), up to 1 month, require 40-60 micrograms/kilogram.

Infants, 1 month to 2 years, require approximately 60-80 micrograms/kilogram. Children 2 years to 10 years, require 40-60 micrograms/kilogram.

Children, over 10 years of age, require adult dosages in proportion to their body weight.

Maintenance therapy is 20-30 percent of the digitalizing dose administered each day. Long term use of digoxin is indicated in almost all infants who have been digitalized for acute congestive heart failure unless the cause is transient. Many favor maintaining digoxin until at least 2 years of age in all infants with paroxysmal atrial tachycardia or in those who show either definite or latent failure.

Many children with severe inoperable congenital defects need digoxin throughout childhood and often for life.

(f) Abbreviated new drug applications shall be submitted to the Food and Drug Administration, Center for Drug Evaluation and Research, Office of Generic Drugs, 5600 Fishers Lane, Rockville, MD 20857.

(g) All samples of digoxin tablets required by paragraph (a)(3) of this section to be submitted to the Food and Drug Administration shall be handled as follows:

(1) The sample shall consist of 6 subsamples of 1000 tablets each collected at random from throughout the manufacturing run. Each of the 6 subsamples shall be identified with the name of the product, the labeled potency, the date of manufacture, the batch number, and the name and address of the manufacturer.

(2) The sample together with the batch production record and results of all tests conducted by or for the manufacturer to determine the product's identity, strength, quality, and purity, content uniformity and dissolution shall be submitted to the Department of Health and Human Services, Public Health Service, FDA National Center for Drug Analysis, 1114 Market St., St. Louis, MO 63101. The outer wrapper shall be identified "SAMPLE-DIGOXIN CERTIFICATION.”

(h) The Food and Drug Administration is aware of data with two in vitro methods, in addition to that described in The United States Pharmacopeia (USP XVIII), developed to measure digoxin tablets dissolution. These two methods, the so-called "paddle-water” and "paddle-acid" methods, are described below and are identical with the exception of the nature of the dissolution medium used in the procedures (i.e., distilled or deionized water

vs. dilute hydrochloric acid (0.6 percent volume/volume)). The dissolution apparatus used in these two methods differs significantly from the apparatus described in the method in the compendium. The Food and Drug Administration is aware that the three methods (i.e., USP, "paddle-water," and "paddle-acid") show significant differences in dissolution in comparative tests on some formulations. Definitive bioavailability data to compare the relative value of each of these methods to predict bioavailability of the few formulations where the methods show significant differences in dissolution rate are not now available. Manufacturers who conduct research utilizing the "paddle-water" and "paddle-acid" methods, particularly in comparison with the method in The United States Pharmacopeia, shall submit any data obtained using these methods to the Food and Drug Administration pursuant to section 505(k) of the act.

(1) Dissolution apparatus.

(NOTE: Throughout this procedure use scrupulously clean glassware, which previously has been rinsed with dilute hydrochloric acid, distilled or deionized water, then with alcohol, and carefully and carefully dried. Take precautions to prevent contamination from airborne, fluorescent particles and from metal and rubber surfaces.) The apparatus consists of a suitable water bath, a 1000 milliliter glass vessel (Kimble Glass No. 26220 or equivalent), a motor, and a polytetrafluoroethylene stirring blade (Sargent S-76637, Size B, 3 inch length; or equivalent) on a glass stirring shaft (Sargent 5-76636, 14.5 inch length; or equivalent). The water bath may be of any convenient size that permits keeping the water temperature uniformly at 37° C. ±0.5° C. throughout the test. The vessel is spherical, and is provided with three ports at the top, one of which is centered. The lower half of the vessel is 65 millimeters in inside radius and the vessel's nominal capacity is 1000 milliliters. The glass stirring shaft from the motor is placed in the center port, and one of the outer ports may be used for insertion of a thermometer. Samples may be removed for analysis through the other port. The motor is fitted with a speed-regulating device that allows the motor speed to be held at 50 rpm +2 rpm. The motor is suspended above the vessel in such a way that it may be raised or lowered to position the stirring blade. The glass stirring shaft is 10 millimeters in diameter and about 37 centimeters in length. It must run true on the motor axis without perceptible wobble. The polytetrafluoroethylene stirring blade is 4 millimeters

thick and forms a section of a circle, whose diameter is 83 millimeters and which is subtended by parallel chords of 42 and 77 millimeters. The blade is positioned horizontally, with the 42-millimeter edge down, 2.5 centimeters 10.2 centimeter above the lowest inner surface of the vessel.

(2) Reagents—(i) Dissolution medium. For "paddle-water," use distilled or deionized water. For "paddle-acid," use dilute hydrochloric acid (0.6 percent volume/volume). Use the same batch of dissolution medium throughout the test.

(ii) Standard solutions. Accurately weigh approximately 25 milligrams of The United States Pharmacopeia Digoxin Reference Standard, dissolve in a minimum amount of 95 percent ethanol in a 500 milliliter volumetric flask and add 95 percent ethanol to volume and mix. Dilute 10.0 milliliters of this first solution to 100.0 milliliters with 95 percent ethanol and mix for the second solution. Just prior to use, individually dilute 1.0, 2.0, 3.0, 4.0, and 5.0 milliliter aliquots of the second solution with dissolution medium to 50.0 milliliters. These solutions are equivalent to 20, 40, 60, 80, and 100 percent of dissolution, respectively, for a 0.25 milligram digoxin tablet.

(iii) Extraction solvent. Prepare a solvent containing 6 volumes of chloroform, analytical reagent grade, with 1 volume of n-propyl alcohol, analytical reagent grade.

(iv) Ascorbic acid-methanol solution. Prepare a solution containing 2 milligrams of ascorbic acid, analytical reagent grade, per 1 milliliter of methanol, absolute, analytical reagent grade.

(v) Hydrochloric acid, concentrated reagent grade.

(vi) Hydrogen peroxide-methanol solution. On the day of use, dilute 2.0 milliliters of recently assayed 30 percent hydrogen peroxide, reagent grade, with methanol, absolute, analytical reagent grade to 100.0 milliliters. Store in a refrigerator. Just prior to use, dilute 2.0 milliliters of this solution with methanol to 100.0 milliliters.

(3) Procedure—(i) Dissolution. Place 500 milliliters of dissolution medium in the vessel, immerse it in the constanttemperature bath set at 37°C.±0.5°C., and allow the dissolution medium to assume the temperature of the bath.

Position the shaft so that there is a distance of 2.5 centimeters ±0.2 centimeter between the midpoint of the bottom of the blade and the bottom of the vessel. With the stirrer operating at a speed of 50 rpm±2 rpm, place 1 tablet into the flask. After 60 minutes, accurately timed, withdraw 25 milliliters, using a glass syringe connected to a glass sampling tube, of solution from a point midway between the stirring shaft and the wall of the vessel, and approximately midway in depth. Filter the solution promptly after withdrawal, using a suitable membrane filter of not greater than 0.8 micron porosity (Millipore AAWP 025 00, or equivalent), mounted in a suitable holder (Millipore Swinnex SX00 025 00, or equivalent), discarding the first 100 milliliters of filtrate. This is the test solution. Repeat the dissolution procedure on 5 additional tablets.

(ii) Extraction. Transfer 10.0 milliliters of each of the six filtrates, 10.0 milliliters of each of the five standard solutions, and 10.0 milliliters of dissolution medium, to provide a blank, in separate 60-milliliter separators. Extract each solution with two 10-milliliter portions of extraction solvent. Combine the extracts of each solution in separate, glass-stoppered, 50-milliliter conical flasks, and evaporate on a steam bath with the aid of a stream of nitrogen to dryness, rinsing the sides of the flasks with extraction solvent. Take care to ensure that all traces of solvent are removed, but avoid prolonged heating. For convenience the residues may be stored in a vacuum desiccator overnight.

(iii)

Measurement of fluorescence. Begin with the standard solutions, and keep all flasks in the same sequence throughout, so that the elapsed time from addition of reagents to reading of fluorescence is the same for each. Carry the test solutions, standard solutions, and the blank through the determination in one group. Add the following three reagents in as rapid a sequence as possible, swirling after each addition, treating 1 flask at a time, in the order named: 1.0 milliliter of ascorbic acid-methanol solution, 3.0 milliliters of concentrated hydrochloric acid, and 1.0 milliliter of hydrogen peroxide-methanol solution. Insert the

stoppers in the flasks, and after 2 hours, measure the fluorescence at about 485 millimicrons, using excitation at about 372 millimicrons. In order to provide a check on the stability of the fluorometer, reread one or more standard solutions. Correct each reading for the blank and plot a standard curve of fluorescence versus precentage dissolution. Determine the percentage dissolution of digoxin in the test solutions by reading from the standard graph.

(iv) Digoxin tablets formulated so that the quantity of digoxin dissolved at one hour, when tested by the method in The United States Pharmacopeia (USP XVIII), is greater than 95 percent of the assayed amount of digoxin and so that the quantity of digoxin dissolved at 15 minutes is greater than 90 percent of the assayed amount of digoxin are new drugs which may be marketed only with an approved full new drug application as provided for in §314.50 of this chapter. The application shall include, but not be limited to, clinical studies establishing significantly greater bioavailability than digoxin tablets meeting compendial requirements and dosage recommendations based on clinical studies establishing the safe and effective use of the bioavailable digoxin product. Marketing of these digoxin products will be allowed only under a proprietary or trade name, established name, and labeling which differs from that used for digoxin tablets that meet all of the requirements in The United States Pharmacopeia (USP XVIII) and that are formulated so that either (a) the quantity of digoxin dissolved at one hour is not more than 95 percent of the assayed amount of digoxin or (b) the quantity of digoxin dissolved at 15 minutes is not more than 90 percent of the assayed amount of digoxin. New drug applications for these digoxin products shall be submitted to the Food and Drug Administration, Center for Drug Evaluation and Research, Office of Drug Evaluation I (HFD-100), 5600 Fishers Lane, Rockville, MD 20857.

[39 FR 11680, Mar. 29, 1974, as amended at 41 FR 43137, Sept. 30, 1976; 41 FR 49482, Nov. 3, 1976; 50 FR 8996, Mar. 6, 1985; 55 FR 11578, Mar. 29, 1990]

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