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`3 B-digoxigcnin, S-keto-digoxjgenin, and their glucuronkb
`and sulfate conjugates, are polar in nature and are postn-
`lated to be formed via hydrolysis. oxidation. and conjuga-
`tion. The metabolism of digoxin is not dependent upon til
`cytochrome P450 system, and digoxin is not known to in
`duce or inhibit the cytochrome P450 system.
`Excretion:
`Elimination of dlgoxin follows first-order Ei—
`netics (that is, the quantity of digoxin eliminated at any
`time is proportional to the total body content). Following in—
`travenous administration to healthy volunteers. 50% to 70%
`of a digoxin dose is excreted unchanged in the urine. Renal
`excretion of digoxin is proportional to glornerular filtratim
`rate and is largely independent of urine flow. In healthy vol~
`unteers with normal renal function, dlgoxin has a half-bi
`of 1.5 to 2.0 days. The half-life in anuric patients is pro-
`longed to 3.5 to 5 days. Digoxin is not efl'ecfively removed
`from the body by dialysis, exchange transfusion, or during
`cardiopulmonary bypass because most of the drug is bound
`to tissue and does not circulate in the blood.
`Special Populations: Race difi'erences in digoxin pharm—
`cckinetics have 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. pharmacolcinetic difl’erences due to
`race are not expected.
`The clearance of digoxin can be primarily correlated with
`renal function as indicated by creatinine clearance. The
`Cockcroft and Gault formula for estimation of creation:
`clearance includes age, body weight, and gender. A table
`that provides the usual daily maintenance dose requireL
`ments of LANOXIN Tablets based on creatinine clearance
`
`TRATION section.
`(per 70 kg) is presentedin the DOSAGE AND ADMINIS-
`Plasma digmtin concentration profilesin patients with acute
`hepatitis generally fell Within the range of profiles in 2
`group of healthy subjects.
`Pharmecodynamic and Cinical Effects: The times to onset
`of pharmacologic effect and to peak effect of preparations 1"
`LANOXIN are shown in Table 2:
`[See table 2 at botmm of next page]
`Hemodrnamlc Effects: Digoxin produces hemodynamic
`improvement in patients with heart failure. Short- and
`long-term therapy with the drug increases cardiac output
`and lowers pulmonary artery pressure, pulmonary capillary
`wedge pressure, and systemic vascular resistance. These
`hemodynamic edects are accompanied by an increase in the
`lefi: ventricular ejection fraction and a decrease in and-
`systolic and nddiastolic dimensions.
`Chronic HmFaflure:
`Tho 12—week. double-blind. place
`bo—ccntrolled studies enrolled 178 (RADlANCE trial} and as
`(PROVED trial] patients with NYHA class II or III heart
`failure previously treated with digoxin, a diuretic, and an
`ACE inhibitor ERADIANCE only) and randomized them to
`placebo or treatment with LANOXIN. Both trials demon—
`strated 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 hospitaliza-
`tions and emergency care and the need for concomitant
`heart failure therapy. The larger study also showed treat-
`ment-related benefits in NYHA class and patients' global asA
`sessnient. 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. placebocontrallcd
`mortality study of 6301 patients with heart failure and led
`ventricular ejection fraction $0.45. At randomization,'6?'!
`were NYHAclass I or II, 'Fl‘lh had heart failure ofischemic
`etiology, 44% had been receiving digoxin. and most were re-
`ceiving concomitant ACE inhibitor (94%) and diuretic (82%).
`Patients were randomized to placebo or LANOXIN, the dose
`of which was adjusted for the patient's age. sex. lean body
`weight, and serum creatinine (see DOSAGE AND ADMIN-
`ISTRATION}, and followed for up to 53 months (median 37
`months). The median daily dose prescribed was 0.25'n1g.
`Overall all-cause mortality was 35% With no difference be—
`tween groups (95% confidence limits for relative risk of 0.91
`to 13?). [MCKIN was associated with a 25% reduction in
`the number of hospitalizations for heart. failure, a 28% re-
`duction'1n the risk _ofs patient having at least one hospital-
`ization for heart failure. and a 6.5% reduction'in total hos—
`pitalizations (for any cause)
`Use of LANOIUN was associated with a trend to increase
`time to all-cause death or hospitalization. The trend was ev-
`ident 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 sta-
`tistically significant. much of the apparent banefit derived
`from efiects on mortality and hospitalization attributed to
`heart failure.
`"
`[See table 3 at bottom of next page}
`In situations where there is'no statistically significant ben—
`efit of treatment evident from a trial’s primary endpoint, re—
`sults pertaining to a secondary endpoint should be inter
`preted cautiously.
`In patients with chronic atrial
`Chronic Atrial Fibrillation:
`fibrillation, digoxin slows rapid ventricular response rate in
`a linear dose-response fashion from 0.25 to 0.75 inglday. Di—
`goxin should not be used for the treatment of multifocal
`ntri al Lo r‘l‘lvr‘n "tin
`
`
`
`
`
` LANOXIN Tablets
`
`IANOXIN Elixir Pediatric
`MNOXICAPSG
`LANOKLN lnjactioan
`
`'
`
`Equivalent Doses (mcgl*
`Among Dosage Forms
`
`Lanoxin Injection Pediatric—Cont.
`
`DigitaliZing and daily maintenance doses for each age group
`are given in Table 5 and should provide therapeutic efiect
`with minimum risk of toxicity in most patients with heart
`failure and normal sinus rhythm. These recommendations
`assume the presence of normal renal function.
`The loading dose should be administered in several por-
`tions, with roughly half the total given as the first dose. Ad-
`ditional fractions ofthis planned natal dose may be given at
`4— to 8—hour intervals. with careful assessment of clinlcal
`response before each additional dose. If the patient's clin—
`ical response necessitates a change from the calculated
`loading dose of dlgoxin. then calculation of the maintenance
`dose should be based upon the amount actually given.
`[See table 5 at top of previous page]
`In children with renal disease. digoxin dosing must be care-
`fully titrated based on clinical response.
`Gradual Digitallzatlon With A Maintenance Dose: More
`gradual digitalization can also be accomplished by begin-
`ning an appropriate maintenance dose. The range of per-
`c-tages provided in Table 5 can be used in calculating this
`dose for patients with normal renal function.
`It cannot be overamphaslzad that these pediatric dosage
`’idollnes are based upon average patient response and
`abstential individual variation can be expected. Accord-
`m. ultimate dosage selection must be based upon clinl-
`ell mount of the patient.
`Atrial Fibrillation: Peak digoxin body stores larger than
`the 8 to 12 mcgl'kg required for meat patients with heart
`fililure and normal sinus rhythm have been used for control
`of ventricular rate in patients with atrial fibrillation. Doses
`of digoxin used for the treatment of chronic atrial fibrilla-
`tion should he titrated to the minimum dose that achieves
`the desired ventricular rate control without causing unde-
`n'rahle side efi'ccts. Data are not available to establish the
`appropriate resting or exercise target rates that should be
`achieved.
`Dosage Adiustment When Chanfllng Preparations: The
`difierences in bioavailabllity between injectable LANOXIN
`or LANOXICAPS and LANOXIN Elixir Pediatric or
`IANOXJN Tablets must he considered when changing pa-
`deem from one dosage form to another.
`Doses of 100 mcg (0.1 mg} and 200 mcg (0. 2 mg) of
`LANDKICAPB are approximately equivalent to 125 mcg -
`20.125 mg} and 250 mcg (0.25 mg) doses of LANOXIN Tab—
`lets and Elixir Pediatric, respectively [see Table 1 in CLIN-
`ICAL PHARMACOLOGY: Pharmacokinetics).
`now SUPPLIED
`[ARDEN {digoxinl lnjection Pediatric. 100 mcg (0.1 mg} in
`1 ml; In: of 10 ampuls (NBC 0173—0262-3101
`”I" It 25"; lTl’Fl: excursions permitted to 15’ to 30°C
`H" to 86°Fl [m USP Controlled Room Temperature] and
`m from light.
`Manufactured by Catalytica Pharmaceuticals. Inc.
`Greenville. NC 27834
`in Glaxo Wellcome Inc.
`_
`Research Triangle Park, NC 2T709
`comm 1996, 1998. Glaxo Wellcome Inc. All rights re
`med.
`December lQQflI'erfiZB
`
`Shown in Product Identification Guide, page 3'14
`
`LANOXINE
`Uri-non: ' in l
`ligaxinl
`Tillers USP
`13 mg {0.125 mnl Scored I.D. Imprint YaB (yellow)
`30 M lo.25 my] Scored ID Imprint XSA (white)
`
`.
`
`I}
`
`WON
`
`LANOXIN is supplied as l25—mcg {0.125-mg) or 250-n1cg
`(0.25-mg} tablets for oral administration. Each tablet con-
`tains the labeled amount of digoxin USP and the following
`inactive ingredients: corn and potato starches, lactose, and
`magnesium stearate. In addition, the dyes used in the 125-
`mcg {0.125-mgl tablets are 1)ch Yellow No. 10 and FD&C
`Yellow No. 6.
`CLINICAL PHARMACOLOGY
`Mechanism of Action: Digoxin inhibits sodium—potassium
`ATPase, an enzyme that regulates the quantity of sodium
`and potassium inside cells. Inhibition of the enzyme leads to
`an increase in the intracellular concentration of sodium and
`thus [by stimulation of sodium-calcium exchange) an in-
`crease in the intracellular concentration of calcium. The
`beneficial efl‘ects ofdigoxin result from direct actions on car-
`diac muscle, as well as indirect actions on the cardiovascu-
`lar system mediated by effects on the autonomic nervous
`system. The autonomic effects include: (1) a vagomimetic ac-
`tion, which is responsible for the efl'ects of digmrin on the
`sinoatrial and atrioventricular LAV} nodes; and (2} barore—
`oeptor sensitization, which results in increased afi'etent in-
`hibitory activity and reduced activity of the sympathetic
`nervous system and renln—angiotensin system for any given
`increment in mean arterial pressure. The pharmacologic
`consequences of these direct and indirect efiects are? (1) an
`increase in the force and velocity of myocardial systolic con—
`traction {positive inotropic action); (2} a decrease in the de-
`gree of activation of the sympathetic nervous system and
`- renln—angiotensin system (neurobonnonal deactivating ef-
`fact); and {3) slowing of the heart rate and decreased con-
`duction velocity through the AV node {vagomimetic efl'cct}.
`The effects of digoxin in heart failure are mediated by its
`positive inotropic and neurohormonal deactivating efl'ects,
`whereas the efiects of the drug in atrial arrhythmias are re‘
`lated to its vagomimetic actions. In high doses, digoxin in-
`creases sympathetic outflow frcm the central nervous sys-
`tem (CNS). This increase in sympathetic activity may be an
`important factor in digitalis tmdcity.
`rharmacokineticsc Absorption: Following oral adminis-
`tration, peak serum concentrations of digoxin occur at I to 3
`hours. Absorption of digoxjn from LANOXIN Tablets has
`been demonstrated to be 60% to 80% complete compared to
`an identical intravenous dose of digoxln (absolute bioavail-
`ability} or LANOXICAPS® (relative bioavailabilityl. When
`LANOXIN Tablets are taken after meals, the rate ofabsorp-
`tion 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
`shown1n Table].
`equivalent doses for oral preparations of InkNOXIN are
`[See table 1 below}
`In some patients, orally administered digoxin is converted
`to inactive reduction products leg, dihydmdigofin) by co-
`lonic bacteria in the gut. Data suggest that one in ten pa-
`tients treated with digoxfm tablets will degrade 40% or more
`of the ingested dost-2.133 a result, certain antibiotics may in-
`crease 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. The magnitude of
`rise in serum dignxin concentration relates to the extent of
`bacterial inactivation, and may he as much as two-fold in
`some cases.
`.
`_
`Distribution:
`Following drug administration. a 6— to
`8—hour tissue distribution phase is observed. This is fol-
`lowed by a much more gradual decline in the serum comcem
`tration of the drug, which is dependent on the elimination of
`digoxin from the body. The peak height and slope of the
`early portion (absorptionfdlstribution phases) of the serum
`concentration—time curve are dependent upon the route of
`administration and the absorption characteristics of the for—
`mulation. Clinical evidence indicates that the early high
`serum concentrations do not reflect the concentration of di-
`goxin at its site of action, but. that with chronic use, the
`steady-state post-distribution serum concentrations are in
`IANDXIN (digoxin)is one of the cardiac (or digitalis) glyco-
`equilibrium with tissue concentrations and correlate with
`sides, a closely related group of drugs having in common
`specific effects on the myocardium. These drugs are foundin
`pharmacologic efl‘ects. In individual patients, these post—
`distribution serum concentrations may be useful in evaluat-
`a number ofplanbs Digoxinis extracted fi‘om the leaves of
`ing therapeutic and toxic efi‘ects (see DOSAGE AND AD—
`Malia Innate. The term “digitalis” is used to designate
`MINISTRATION: Serum Digoicin Concentrations}.
`the whole group ofglycosides. The glycosides are composed
`d' two portions: a sugar and a card-ofide (hence “glyco-
`Digoxin is concentrated in tissues and therefore has a large
`fies'}.
`apparent volume of distribution. Digoxin crosses both the
`Digoxin is described” chemically as (SB,EB.IZB)-3-[(O-2,6-
`blood~hrain barrier and the placenta. At delivery. the serum
`dideoxy-B-D-ribo-hexopyranosyl-(l—b4)-0-2,6-dideoxy-|3-D-
`digoxin concentration in the newborn is similar to the
`serum concentration in the mother, Approximately 25% of
`ribo—hexopyranosyl-l1—»4)—2,6dideoxy-B-D-ribo-hexopyra—
`will)!“-12,l4-dfliydmxy-card-20i22l-enolide Its molecu-
`digoxin in the plasma is bound to promin. Serum digoxin
`concentrations are not significantly altered by large
`lsr formula is Cal-13‘0“, and its molecular weight is
`733.95.
`changes in fat tissue weight, so that its distribution space
`Iigoxin exists as odorless white crystals that melt with de- I
`correlates best with lean (i.e., ideal) body weight, not. total
`body weight.
`.
`composition above 230°C. The drug is'practically insoluble
`Metabolism: Only a small percentage (16%) of a close of
`in water and in ether; slightly soluble in diluted (50%) alco-
`djgoxin is metabolized. The end metabolites, which include
`hol and in chloroform; and freely soluble in pyridine.
` Table 1: Comparisons ot the firstemic Availahlllty and Equivalent Doses for Oral Preparations of LANDXIN
`Absolute
`
`Biosvailability
`62.5
`
`
`
`400
`
`
`*For example. 125--mcg LANOXIN Tablets equivalent to 125——mcg LANOXIN Elixir Pediatric equivalent to 1.00meg
`IANOXICAPS equivalent to 100--mcg LANGKIN lnjectiona'IV.
`
`

`

`INDICATIONS AND USAGE
`Heart Failure: LANOXIN is indicated for the treatment of
`mild to moderate heart failure. LANOKIN increases left
`ventricular ejection fraction and improves heart failure
`symptoms as evidenced by exercise capacity and heart fail~
`ure-relaoed hospitalizations and emergency care. while hav-
`ing no effect on mortality. Where possible, LANOXIN should
`be used with a diuretic and an angiotensinmnverting en—
`zyme inhibitor, but an optimal order for starting these three
`drugs cannot be specified.
`Atrial Fibrillation: LANOXIN is indicated for the control of
`ventricular response rate in patients with chronic atrial fi-
`brillation.
`CONTRAINDICATIONS
`Digitalis glycosides are contraindicated in patients with
`ventricular fibrillation or in patients with a known hyper-
`sensitivity to digoxin. A hypersensitivity reaction to other
`digitalis preparations usually constitutes a contraindication
`to digoxin.
`WARNINGS
`Sinus Node Disease and AV Block: Because digmdn slows
`sinoatrial and AV conduction, the drug commonly prolongs
`the PR interval. The drug may cause severe sinus bradycar—
`die or sinoatrial block in patients with pie—existing sinus
`node disease and may cause advanced or complete heart
`block in patients with pre-existing incomplete AV block. In
`such patients consideration should be given to the insertion
`of a pacemaker before treatment with digoxin.
`Accessory AV Pathway Molfl-Parlrineon-Wllite Syndromel:
`After intravenous digoxin there-133'. some patients with par-
`oxysmal atrial fibrillation or flutter-and a coexisting acces-
`sory AV pathway have developed increased antegrade con—
`duction across the accessory pathway bypassing the AV
`node, leading to a very rapid ventricular response or ven-
`tricular fibrillation. Unless conduction clown the accessory
`pathway has been blocked (either pharmacologically or by
`surgery}, diguodn should not be used in such patients. The
`treatment of paroxysmal supraventricular tachycardia in
`such patients is usually directcurrent cardioversion.
`Use in Patients wIth Preserved Left Ventricular Systolic
`Function: Patients with certain disorders involving heart
`failure associated with preserved left ventricular ejection
`fraction may be particularly susceptible to toxicity of the
`drug. Such disorders include restrictive cardicmyopathy.
`constrictive pericarditis, amyloid heart disease, and acute
`cor pulmonale. Patients with idiopathic hypertrophic sub-
`aortic stenosis may have worsening of the outflow obstruc-
`tion due to the inotropic effects of digoxin.
`
`will last longer in such patients than in patients with nor-
`mal renal function.
`In patients
`Use in Patients with Electrolyte Disorders:
`with hypokalemia or hypomagnesemia, tocdcity may occur
`despite serum digoxin concentrations below 2.0 nglmL, be—
`cause potassium or magnesium depletion sensitizes the
`myocardium to digoxin. Therefore, it is desirable to main—
`tain normal serum potassium and magnesium concentra-
`tions in patients being treated with digoxin. 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, corticoster—
`oids, antacids, dialysis, and mechanical suction of gastroin—
`testinal secretions
`Hypercalcsmia from any cause predisposes the patient to
`digitalis torddty. Calcium, particularly when administered
`rapidly by the intravenous route, may produce serious 31‘-
`rhythmias in digitalized patients. 0n the other hand, hypo-
`calcemia can nullify the efi'ecta of digoxin in humans; thus.
`digoxin may be ineffective until serum calcium is restored to
`normal. These interactions are related to the fact that'di-
`gox‘in affects contractility and excitability of the heart in a
`manner similar to that ofcalcium.
`Use in Thyroid Disorders and Hypermetobolio States: Hy-
`pothyroidism may reduce the requirements for digoxln.
`Heart failure andfor atrial arrhythmias resulting from by-
`permetabolic or hyperdynamic states le.g., hyperthyroi~
`dism, hypoxia, or arteriovenous shunt] are best treated by
`addressing the underlying condition. Atrial arrhythmias as-
`sociated with hypermetabulic states are particularly resis—
`tant to digoxin treatment. Care must be taken to avoid tox-
`icity if digoxin is used,
`Use in Patients with Acute Myocardial Infarction: Digoxin
`should be used with caution in patients with acute myocan
`dial infarction. The use of isotropic drugs in some patients
`in this setting may result in undesirable increases in myo-
`cardial oxygen demand and ischemia.
`It may be desirable
`Use During Electrical Cardiovmlon:
`to reduce the dose of digoxin for 1 to 2 days prior to electri-
`ca] cardioversion of atrial fibrillation to avoid the induction
`of ventricular arrhythmias, but physicians must consider
`the consequences of increasing the ventricular response if
`digoxin is withdrawn. If digitalis toxicity is suspected, elec-
`tive cardioversion should be delayed. If it is not prudent to
`delay cardioversion, the lowest possible energy level should
`be selected to avoid provoking ventricular arrhythmias.
`Laboratory 'I'eat Monitoring: Patients receiving digoxin
`should have their serum electrolytes and renal function
`(serum creatinine concentrations) assessed periodically; the
`frequency of assessments will depend on the clinical setting.
`_
`PRECAUTIONS
`For discussion of serum djgoxin concentrations, see DOS-
`Use in Patients with Impaired Renal Function: Digoxin is
`AGE AND ADMINISTRATION section.
`primarily excreted by the kidneys; therefore. patients with
`Drug Interactions: Potassium-depleting diuretics are a
`impaired renal function require smaller than usual mainte-
`major contributing factor to digitalis toxicity Calcium, par-
`nance doses of digoxin (see DOSAGE AND ADMINISTRA-
`TION]. Because of the prolonged elimination half-life, a
`ticularly if administered rapidly by the intravenous route,
`longer period of time is required to achieve an initial or new
`may produce serious arrhythmias in digitalized patients.
`steady—state serum concentration in patients with renal im—
`Quinidine, veropomil, omiodmne, propofenone, indomelh-
`coin, itmconazolc, olpmzolum, and spimrwlacfone raise the
`pairment than in patients with normal renal function. lfap-
`propriate care is not taken m reduce the dose of digoxin,
`serum digoxin concentration due to a reduction in clearance
`such patients are at high risk for toxicity, and toxic edects
`andfar in volume of distribution of the drug. with the impli-
`
`
`
`
`Table '2: Times to Onset of Pharmacolbgio Effect and to Peak Effect of Preparations of LANOXW
` Product Time to Onset of Eliot-t“ Time to Peak Effect“
`
`
`LANOXIN Tablets
`0.5 — 2 hours
`2 — 6 hours
`
`2 — 6 hours
`0.5 — 2 hours
`LANOXICAPS
`2 ~ 6 hours
`0.5 ~« 2 hours
`LANOXIN Elixir Pediatric
`
`LANOXIN Injectionl'lV 1 - 4 hours 5 - 30 minutes'l
`
`
`" Demented for ventricular response rate in atrial fibrillation, inotropic effects and electrocardiographic changes.
`t Depending upon rate of infusion.
`
`Table 3: Subgroup Analyses of Mortality and Hospitellzatlon
`During the First Two Years Following Randomization
` Risk ofAll-Cause Mortality or
`Risk of ELF-Related Mortality or
`
`HF-Related Hospitalization*
`
`All-Cause Hospitalization"
`
`
`Relative risk‘i
`Placebo
`LANOXIN
` Placebo 'LANOXLN Relative risk‘l“
`
`
`
`
`0.69
`0.94-
`
`
`
` (0.88—1.00) '
`(0.63n01i'6l
`
`
`
`0.96
`0.70
`
`
`NYHA I f 11
`(0.89-1.04)
`(0.62-0.80)
`
`'
`0.99
`0.14
`
`
`(0.91—1.07)
`BF 0.25—0.45
`(0.66-0.84)
`
` 0.93 0.71
`
`(0.91 - 1.06]
`(0.63-0.81]I
`CTR 50.55
`
`
`
`
`0.33
`0.65
`
`NYHA III 1’ IV
`(0.30-0.97)
`(0.57-0.1‘5)
`
`0.34
`0.61
`(0.76—0.93)
`(0.53-0.71)
`
`035
`0.65
`(0. 77—0.94}
`CTR >0.55
`{0.57—0.75}
`
`
` 0.72
`
`(0.53-0.99)
`BF >045;
`
`“ Number of patients with an event during the first 2 years per 1000 randomized patients.
`Relative risk {95% oonfidenceintorvel).
`t DIGAnciflarySbudy
`
`
`EF 43.25
`
`cation that digitalis intoxication may result Emhmmycin
`and clorithromycin (and possibly other mcmft'de antibiot-
`ics} and tetracycline may increase digmo'n absorption in pa-
`tients who inactivate digoxin by bacterial metabolism in the
`lower intestine, so that digitalis intoidcation may result (see
`CLINICAL PHARMACOLOGY: Absorption}. Pmponrheline
`and diphenmylote, by decreasing gut motility, may moi-ease
`digoxin absorption. Antacids, kaolin-pectin, sulfosuluzlne,
`neomycin, ckolestyrumine, certain anticancer drugs, and
`metoclopromide may interfere with intestinal digoxin ab-
`sorption, resulting in unexpectedly low serum concentra
`tions. Rriflzmpin may decrease serum digoxln concentration,
`especially in patients with renal dysfunction. by increasing
`the non-renal clearance of digoxin. There have been incon-
`sistent reports regarding the efiecfs of other drugs leg, qui-
`nine. penicillamiflel on serum digoxin concentration. Thy-
`mid administration to a digitaliced, hypothyroid patient
`may increase the dose requirement of digoxzin. Concomitant
`use of digoxin and sympathomimefics'increases the risk of
`cardiac arrhythmias. Succinylcholme may cause a sudden
`extrusion of potassium from muscle cells, and may thereby
`cause arrhythmias in digitalized patients. Although beta-
`adrenergic blockers or calcium channel blockers and digoxin
`may be useful in combination to control atrial fibrillation.
`their additive efi‘ec'te 011 AV node conduction can result in
`advanced or complete heart block.
`Due to the considerable variability of these interactions, the
`dosage of digoxin should be individualized when patients re
`ceive these medications concurrently. Flatbed-more, caution
`should be exercised when combining digoidn with any drug
`that may cause a significant deterioration in renal function,
`since a decline in glomerular filtration or tubular secretion
`may impair the excretionofdigoxin.
`DmgfLehoretory Test Interactions: The use oftherapeutic
`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 electro-
`physiologic effects reflect an expected effect of the drug and
`are not indicative of toxicity.
`Carcinogeneals. Mutagenesis. Impairment of Ferllllty:
`There have been no long-term studies performed in animals
`to evaluate carcinogenic potential, nor have studies been
`conducted to assess the mutagenic potential of dlgoxm or its
`potential to affect fertility.
`Pregnancy. Teratogenfc Effecfe:_ Pregnancy Category C.
`Animal 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 preg-
`nant woman only if clearly needed.
`Nursing Mothers: Studies have shown that digoxin conv
`centrations in the mother’s serum and milk are similar.
`However, the estimated exposure of a nursing infant to di-
`goxin 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 nurs-
`ing woman.
`Pediatrlc Use: Newborn infants display considerable vari-
`ability in their tolerance to digoxin. Premature and imma-
`ture infants are particularly sensitive to the effects of di-
`goxin, and the dosage of the drug must not only be reduced
`but must be individualized according to their degree of ma-
`turity. 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 expe-
`rience has not identified differences in response or adverse
`effects between the elderly and younger patients. However,
`this drug is known to be substantially excreted by the kid-
`ney, and the risk of toxic mentions 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 fimction, and it may be useful to
`monitor renal function (see DOSAGE AND ADMINISTRA—
`TION).
`ADVERSE REACTIONS
`In general, the adverse reactions of digoxin are dose-depen—
`dent and occur at doses higher than those needed to achieve
`a therapeutic effect. Hence, adverse reactions are less com-
`mon when digoxin 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 dignxin. the dosage of the drug should al—
`ways be selected carefully and adiusted as the clinical con—
`dition of the patient warrants. In the past, when high doses
`of digorxm were used and little attention was paid to clinical
`status or concurrent medications, adverse reactions to di—
`goxin were more frequent and severe. Cardiac adverse reac-
`
`COanued on next page
`
`
`This product inlennetlon le based on labeling in effect on J—
`10, 1999. For further Information. contact via (not mad. phone.
`or web site Marisol Information: Glaxo ll‘i‘ollcon‘ic Inc. P0 I-
`13398. Research Triangle Park, NC 27709. Health-can
`Professionals [Medical lnfoflnetlonl: soo-ssa-ooas PM
`ICustomer Response Center}: BBS-TALKZGW {14884325626}
`
`Glaxo Welcome Corner-tell“: Site: www.9lexowallcomecom
`
`
`
`
`

`

`Lanoxln Tablets—Cont.
`
`.
`
`
`
`time accounted for about one-half, gastrointestinal disturb-
`ances for about one-fourth. and CNS and other toxicity for
`about one-fourth of these adverse reactions. However. avail-
`able evidence suggests that the incidence and severity of di-
`ym'n toxicity has decreased substantially in recent years.
`In recent controlled clinical trials, in patients with predom-
`inantly mild to moderate heart failure, the incidence ofad—
`verse experiences was comparable in patients taking di-
`guxzin and in those taking placebo. In a large mortality trial,
`the incidence of hospitalization for suspected digmiin toxic-
`ity was 2% in patients taking LANOXIN compared to 0.9%
`in patie