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`PHYSICIANS’
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`BIOCON PHARMA LTD (IPR2020-01263) Ex. 1022, p. 001
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`(0.25-mg) tablets for oral administration. Each tablet con-
`and sulfate conjugates, are polar in nature and are poste-
`tains the labeled amount of digoxin USP and the following
`lated to be formed via hydrolysis, oxidation, and conjuge-
`Digitalizing and daily maintenance doses for each age group
`inactive ingredients: corn and potato starches, lactose, and
`tion. The metabolism of digoxin is not dependent upon the
`are given in Table 5 and should provide therapeutic effect
`magnesium stearate. In addition, the dyes used in the 125-
`eytochrome P-450 system, and digoxin is not known to im-
`with minimum risk of toxicity in most patients with heart
`meg (0.125-mg) tablets are D&C Yellow No. 10 and FD&C
`Yellow No. 6.
`duce or inhibit the cytochrome P-450 system.
`failure and normal sinus rhythm. These recommendations
`Excretion:
`Elimination of digoxin followsfirst-order ki-
`assume the presence of normal renal function.
`CLINICAL PHARMACOLOGY
`The loading dose should be administered in several por-
`netics (that is, the quantity of digoxin eliminated at any
`Mechanism of Action: Digoxin inhibits sodium-potassium
`tions, with roughly half the total given asthefirst dose. Ad-
`timeis proportional to the total body content). Following in-
`ATPase, an enzyme that regulates the quantity of sodium
`ditionalfractions of this planned total dose may be given at
`travenous administration to healthy volunteers, 50% to 70%
`and potassium inside cells, Inhibition of the enzyme leads to
`+ to 8-hour intervals, with careful assessment ofclinical
`an increase in the intracellular concentration of sodium and
`of a digoxin dose is excreted unchangedin the urine. Rena!
`response before each additional dose. If the patient's clin-
`thus (by stimulation of sodium-calcium exchange) an in-
`excretion of digoxin is proportional to glomerular filtration
`crease in the intracellular concentration of calcium. The
`teal response necessitates a change from the calculated
`rate and is largely independent of urine flow. In healthy vol-
`beneficial effects of digoxin result from direct actions on car-
`loading doseof digoxin, then calculation of the maintenance
`unteers with normal renal function, digoxin has a half-life
`diac muscle, as well as indirect actions on the cardiovascu-
`dose should be based upon the amount actually given.
`of 1.5 to 2.0 days. The half-life in anuric patients is pro-
`lar system mediated by effects on the autonomic nervous
`(See table 5 at top of previous page]
`longed to 3.5 to 5 days. Digoxin is not effectively removed
`system. The autonomic effects include: (1) a vagomimetic ac-
`In children with renal disease, digoxin dosing must be care-
`from the body by dialysis, exchange transfusion, or during
`tion, which is responsible for the effects of digoxin on the
`fully titrated based on clinical response.
`cardiopulmonary bypass because most of the drug is bound
`sinoatrial and atrioventricular (AV) nodes; and (2) barore-
`Gradual Digitalization With A Maintenance Dose: More
`to tissue and does not circulate in the blood.
`ceptor sensitization, which results in increased afferent in-
`gradual digitalization can also be accomplished by begin-
`Special Populations: Race differences in digoxin pharme-
`hibitory activity and reduced activity of the sympathetic
`ning an appropriate maintenance dose. The range of per-
`cokinetics have not been formally studied. Because digoxin
`nervous system and renin-angiotensin system for any given
`centages provided in Table 5 can be used in calculating this
`is primarily eliminated as unchanged drug via the kidney
`dose for patients with normal renal function.
`inerement in mean arterial pressure. The pharmacologic
`ft cannot be overemphasized that these pediatric dosage
`and because there are no important differences in creatinine
`consequences ofthese direct and indirect effects are: (1) an
`clearance among races, pharmacokinetic differences due te
`increase in the force and velocity of myocardial systolic con-
`guidelines are based upon average patient response and
`traction (positive inotropic action); (2) a decrease in the de-
`substantial individual variation can be expected. Accord-
`race are not expected.
`gree of activation of the sympathetic nervous system and
`ingly, ultimate dosage selection must be based upon clini-
`The clearance of digoxin can be primarily correlated with
`cal assessmentof the patient.
`-renin-angiotensin system (neurohormonal deactivating ef-
`renal function as indicated by creatinine clearance. The
`fect); and (3) slowing of the heart rate and decreased con-
`Atrial Fibrillation: Peak digoxin body stores larger than
`Cockcroft and Gault formula for estimation of creatinine
`duction velocity through the AV node (vagomimetic effect).
`the 8 to 12 meg/kg required for most patients with heart
`clearance includes age, body weight, and gender. A table
`The effects of digoxin in heart failure are mediated by its
`failure and normalsinus rhythm have been used for control
`that provides the usual daily maintenance dose require
`of ventricular rate in patients with atrial fibrillation. Doses
`positive inotropic and neurohormonal deactivating effects,
`ments of LANOXIN Tablets based on creatinine clearance
`of digoxin used for the treatment of chronic atrial fibrilla-
`whereas the effects of the drug in atrial arrhythmias are re-
`tion should be titrated to the minimum dose that achieves
`(per 70 kg) is presented in = DOSAGE AND ADMINIS-
`lated to its vagomimetic actions. In high doses, digoxin in-
`TRATIONsection.
`creases sympathetic outflow from the central nervous sys-
`the desired ventricular rate control without causing unde-
`Plasma digoxin concentration profiles iin patients with acute
`sirable side effects. Data are not available to establish the
`tem (CNS). This increase in sympathetic activity may be an
`hepatitis generally fell within the range of profiles in =
`important factor in digitalis toxicity.
`appropriate resting or exercise target rates that should be
`achieved.
`group of healthy subjects.
`Pharmacokinetics: Absorption: Following oral adminis-
`Pharmacodynamic andClinical Effects: The times to onset
`Dosage Adjustment When Changing Preparations: The
`tration, peak serum concentrations of digoxin occur at 1 to 3
`hours. Absorption of digoxin from LANOXIN Tablets has
`@ifferences in bioavailability between injectable LANOXIN
`of pharmacologic effect and to peak effect of preparations of
`or LANOXICAPS and LANOXIN Elixir Pediatric or
`LANOXIN are shown in Table 2:
`been demonstrated to be 60% to 80% complete compared to
`an identical intravenous dose of digoxin (absolute bioavail-
`LANOXIN Tablets must be considered when changing pa-
`[Seetable 2 at bottom of next page]
`Gents from one dosage form to another.
`ability) or LANOXICAPS® (relative bioavailability). When
`Hemodynamic Effects: Digoxin produces hemodynamic
`LANOXINTablets are taken after meals, the rate of absorp-
`Doses of 100 meg (0.1 mg) and 200 mcg (0.2 mg) of
`improvement in patients with heart failure. Short- and
`tion is slowed, -but the total amount of digoxin absorbed is
`LANOXICAPS are approximately equivalent to-125 meg--
`long-term therapy with the drug increases cardiac output
`(0.125 mg) and 250 meg (0.25 mg) doses of LANOXIN Tab-
`usually unchanged, When taken with meals high in bran
`and lowers pulmonary artery pressure, pulmonary capillary
`lets and Elixir Pediatric, respectively (see Table 1 in CLIN-
`fiber, however, the amount absorbed from an oral dose may
`wedge pressure, and systemic vascular resistance. These
`ICAL PHARMACOLOGY: Pharmacokinetics).
`be reduced. Comparisons of the systemic availability and
`hemodynamic effects are accompanied by an increase in the
`BOW SUPPLIED
`equivalent doses. for oral preparabions of LANOXIN are
`left ventricular ejection fraction and a decrease in end-
`shown in Table 1
`.
`(See table 1 below
`systolic and end-diastolic dimensions.
`LANOXIN (digoxin) Injection Pediatric, 100 meg (0.1 mg) in
`1 mL; box of 10 ampuls (NDC 0173-0262-10).
`Chronic Heart Failure:©Two 12-week, double-blind, place-
`In somepatients, orally administered digoxin is converted
`Store at 25°C (77°F); excursions permitted to 15° to 30°C
`bo-controlled studies enrolled 178 (RADIANCEtrial) and 88
`to inactive reduction products (e.g., dihydrodigoxin) by co-
`(69° to 86°F) [see USP Controlled Room Temperature] and
`(PROVEDtrial) patients with NYHA class II or III heart
`lonic bacteria in the gut. Data suggest that one in ten pa-
`protect from light.
`tients treated with digoxin tablets will degrade 40% or more
`failure previously treated with digoxin, a diuretic, and an
`Manufactured by Catalytica Pharmaceuticals, Inc.
`ACE inhibitor (RADIANCE only) and randomized them to
`of the ingested dose. As a result, certain antibiotics may in-
`Greenville, NC 27834
`placebo or treatment with LANOXIN. Both trials demon-
`crease the absorption of digoxin in such patients. Although
`for Glaxo Wellcome Inc.
`inactivation of these bacteria by antibiotics is rapid, the
`strated better preservation of exercise capacity in patients
`Research Triangle Park, NC 27709
`serum digoxin concentration will rise at a rate consistent
`randomized to LANOXIN. Continued treatment with
`CCop¥right 1996, 1998, Glaxo Wellcome Inc. All rights re-
`with the elimination half-life of digoxin. The magnitude of
`served.
`LANOXIN reduced therisk of developing worsening heart
`rise in serum digoxin concentration relates to the extent of
`December 1998/RL-623
`failure, as evidenced by heart failure-related hospitaliza-
`bacterial inactivation, and may be as much as two-fold in
`tions and emergency care and the need for concomitant
`some cases.
`;
`f
`Shown in Product Identification Guide, page 314
`heart failure therapy. The larger study also showed treat-
`Distribution;—Following drug administration, a 6- to
`ment-related benefits in NYHA class and patients’ global as-
`8-hour tissue distribution phase is observed. This is fol-
`sessment. In the smaller trial, these trended in favor of a
`lowed by a much more gradualdecline in the serum concen-
`treatment benefit.
`tration of the drug, which is dependent on the elimination of
`The Digitalis Investigation Group (DIG) main trial was a
`digoxin from the body. The peak height and slope of the
`early portion (absorption/distribution phases) of the serum
`multicenter, randomized, double-blind, placebo-controlled
`mortality study of 6801 patients with heart failure andleft
`concentration-time curve are dependent upon the route of
`administration and the absorption characteristics of the for-
`ventricular ejection fraction =0.45. At randomization, 67%
`were NYHA classI or II, 71% had heart failure of ischemic
`mulation. Clinical evidence indicates that the early high
`serum concentrations do not reflect the concentration of di-
`etiology, 44% had been receiving digoxin, and most were re-
`goxin at its site of action, but that with chronic use, the
`ceiving concomitant ACE inhibitor (94%) and diuretic (824).
`steady-state post-distribution serum concentrations are in
`LANOXIN (digoxin)is one ofthe cardiac (or digitalis) glyco-
`Patients were randomized to placebo or LANOXIN,the dose
`equilibrium with tissue concentrations and correlate with
`sides, a closely related group of drugs having in common
`of which was adjusted for the patient's age, sex, lean body
`Specific effects on the myocardium. These drugs are found in
`pharmacologic effects. In individual patients, these post-
`weight, and serum creatinine (see DOSAGE AND ADMIN-
`distribution serum concentrations may be useful in evaluat-
`2 sumberof plants. Digoxin is extracted from the leavesof
`ISTRATION), and followed for up to 58 months (median 37
`ing therapeutic and toxic effects (see DOSAGE AND AD-
`Digitalis lanata. The term “digitalis” is used to designate
`months). The median daily dose prescribed was 0.25 mg.
`MINISTRATION:Serum Digoxin Concentrations).
`the whole groupofglycosides. The glycosides are composed
`Overall all-cause mortality was 35% with nodifference be-
`ef two portions: a sugar and a cardenolide (hence “glyco-
`Digoxin is concentratedin tissues and therefore has a large
`sides”).
`tween groups (95% confidencelimits for relative risk of 0.91
`apparent volume of distribution. Digoxin crosses both the
`to 1.07). LANOXIN was associated with a 25% reduction in
`Digoxin is described’ chemically as (36,58,126)-3-[(O-2,6-
`blood-brain barrier and theplacenta. At delivery, the serum
`the number of hospitalizations for heart failure, a 28% re-
`dideoxy-f-D-ribo-hexopyranosyl-(1—-4)-O0-2,6-dideoxy-B-D-
`digoxin concentration in the newbornis similar to the
`duction in the risk of a patient having at least one hospital-
`serum concentration in the mother, Approximately 25% of
`ribo-hexopyranosyl-(1+4)-2,6-dideoxy-B-D-ribo-hexopyra-
`nosyloxy]-12,14-dihydroxy-card-2((22)-enolide. Its molecu-
`ization for heart failure, and a 6.5% reduction in total hos-
`| digoxin in the plasma is bound to protein. Serum digoxin
`pitalizations (for any cause).
`concentrations are not significantly altered by large
`ler formula is C,,;Hg4O,,, and its molecular weight is
`780.95.
`Use of LANOXIN was associated with a trend to increase
`changes in fat tissue weight, so that its distribution space
`time to all-cause death or hospitalization. The trend was ev-
`Digoxin exists as odorless white crystals that melt with de-
`correlates best with lean (i.e., ideal) body weight, not total
`ident in subgroups of patients with mild heart failure as
`body weight.
`t
`composition above 230°C. The drug is practically insoluble
`well as more severe disease, as shown in Table 3. Although
`Metabolism: Only a small percentage (16%) of a dose of
`im water and in ether; slightly soluble in diluted (50%) alco-
`the effect on all-cause death or hospitalization was not sta-
`digoxin is metabolized. The end metabolites, which include
`bel and in chloroform; and fréely soluble in pyridine,
`tistically significant, much of the apparent benefit derived
`from effects on mortality and hospitalization attributed to
` Table 1: Comparisons of the Systemic Availability and Equivalent Doses for Oral Preparations of LANOXIN
`heart failure.
`©
`Absolute
`
`[See table 3 at bottom of next page]
`Equivalent Doses (meg)*
`Among Dosage Forms
`Bioavailability
`_
`In situations where there isno statistically significant ben-
`efit of treatmentevident fromatrial’s primary endpoint, re-
`62.5
`
`sults pertaining to a secondary endpoint should beinter-
`LANOXIN Elixir Pediatric
`preted cautiously.
`
`LANOXICAPS®
`In patients with chronic atrial
`
`Chronic Atrial Fibrillation:
`400
`LANOXIN Injection/IV
`fibrillation, digoxin slows rapid ventricular response rate in
`
`
`a linear dose-responsefashion from 0.25 to 0.75 mg/day. Di-
`goxin should not be used for the treatment of multifocal
`*For example, 125-meg LANOXIN Tablets equivalent to 125-mcg LANOXINElixir Pediatric equivalent to L00-meg
`atrial tachurardia
`LANOXICAPS equivalent. to 100-mceg LANOXIN Injection/TV.
`
` 3 Q-digoxigenin, 3-keto-digoxigenin, and their glucuronide
`
` LANOXIN is supplied as 125-mcg (0.125-mg) or 250-meg
`
`aS
`
`
`
`Lanoxin Injection Pediatric—Cont.
`
`LANOXIN®
`Ua-néx ' in J
`(digoxin)
`Tablets, USP
`125 meg (0.125 mg) Scored I.D. Imprint ¥3B (yellow)
`250 meg (0.25 mg) Scored |.D. Imprint X3A (white)
`
`4
`
`DESCRIPTION
`
` LANOXINTablets
`
`

`

`such patients are at high risk for toxicity, and toxic effects will last longer in such patients than in patients with nor-
`
`cation that digitalis intoxication may result. Erythromycin
`and clarithromycin (and possibly other macrolide antibiot-
`ies) and tetracycline may increase digoxin absorption in pa-
`tients who inactivate digoxin by bacterial metabolism in the
`lower intestine, so that digitalis intoxication may result (see
`CLINICAL PHARMACOLOGY: Absorption). Propantheline
`and diphenoxylate, by decreasing gut motility, may increase
`digoxin absorption. Antacids, kaolin-pectin, sulfasalazine,
`neomycin, cholestyramine, certain anticancer drugs, and
`metoclopramide may interfere with intestinal digoxin ab-
`sorption, resulting in unexpectedly low serum concentra-
`tions. Rifampin may decrease serum digoxin concentration,
`especially in patients with renal dysfunction, by incréasing
`the non-renal clearance of digoxin. There have been incon-
`sistent reports regarding the effects of other drugs[e.g., qui-
`nine, penicillamine] on serum digoxin concentration. Thy-
`roid administration to a digitalized, hypothyroid patient
`may increase the dose requirementof digoxin, Concomitant
`use of digoxin and sympathomimetics increases the risk of
`cardiac arrhythmias. Succinylcholine may cause a sudden
`extrusion of potassium from musclecells, and may thereby
`cause arrhythmias in digitalized patients. Although beta-
`adrenergic blockers or calcium channelblockers and digoxin
`may be useful in combination to control atrial fibrillation,
`their additive effects on AV node conduction can result in
`advanced or complete heart block.
`Dueto the considerable variability of these interactions, the
`dosage of digoxin should be individualized when patients re-
`ceive these medications concurrently. Furthermore, caution
`should be exercised when combining digoxin with any drug
`that may cause a significant deterioration in renal function,
`since a decline in glomerular filtration or tubular secretion
`may impair the excretion of digoxin.
`Drug/Laboratory Test Interactions: 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 electro-
`physiologic effects reflect an expected effect of the drug and
`are not indicative of toxicity.
`Carcinogenesis, Mutagenesis, Impairment of Fertility:
`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 digoxin orits
`potential to affect fertility.
`Pregnancy: Teratogenic Effects: 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 womanor can affect
`reproductive capacity. Digoxin should be given to a preg-
`nant woman only if clearly needed.
`Nursing Mothers: Studies have shown that digoxin con-
`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.
`Pediatric 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 reactions 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
`Table 3; Subgroup Analyses of Mortality and Hospitalization
`should be based on renal function, and it may be useful to
`During the First Two Years Following Randomization
`monitor renal function (see DOSAGE AND ADMINISTRA-
`TION).
` Risk of All-Cause Mortality or
`
`HF-Related Hospitalization*
`Risk of HF-Related Mortality or
`ADVERSE REACTIONS
`
`All-Cause Hospitalization*
`
`
`In general, the adverse reactions of digoxin are dose-depen-
` Placebo
` Relative risk
`
`
`Placebo|LANOXIN dent and occur at doses higher than those needed to achieve
`| LANOXIN|Relative risk?’
`a therapeutic effect. Hence, adverse reactions are less com-
`0.69
`
`All patients
`mon when digoxin is used within the recommended dose
`
`
`(0.63-0.76)
`(EF =0.45)
`range or therapeutic serum concentration range and when
`
`
`
`there is careful attention to concurrent medications and
`0.96
`
`conditions.
` NYHAI/ IL (0.89-1.04) (0.62-0.80)
`
`
`Because some patients may be particularly susceptible to
`
`:
`0.99
`0.74
`side effects with digoxin, the dosage of the drug should al-
`
`(0.91-1.07)
`EF 0.25-0.45
`(0.66-0.84)
`ways be selected carefully and adjusted as the clinical con-
`
`
` 0.98 0.71
`dition of the patient warrants. In the past, when high doses
`(0.91-1.06)
`(0.63-0.81)
`CTR =0.55
`of digoxin were used and little attention was paid to clinics!
`
`
`
`status or concurrent medications, adverse reactions te =
`
`goxin were more frequent and severe. Cardiac adverse Tes
`(0.57-0.75)
`NYHA III/IV
`
`0.61
`(0.76-0:93)
`(0.53-0.71)
`
`0.85
`0.65
`(0.77-0.94)
`CTR >0.55
`(0.57-0.75)
`
`
` 0.72
`
`(0.53-0.99)
`EF >0.45;
`
`* Number of patients with an event during the first 2 years per 1000 raadopained patients.
`+ Relative risk (95% confidenceaptarzel)
`;
`+ DIG Ancillary Study.
`
`
`mal renal function.
`In patients
`Use in Patients with Electrolyte Disorders:
`with hypokalemia or hypomagnesemia, toxicity may occur
`despite serum digoxin concentrations below 2.0 ng/mL, 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.
`Hypercalcemia from any cause predisposes the patient to
`digitalis toxicity. Calcium, particularly when administered
`rapidly by the intravenous route, may produce serious ar-
`rhythmias in digitalized patients, On the other hand, hypo-
`calcemia can nullify the effects of digoxin in humans; thus,
`digoxin may beineffective until serum calcium is restored to
`normal. These interactions are related to the fact that di-
`goxin affects contractility and excitability of the heart in a
`mannersimilar to that of calcium,
`Use in Thyroid Disorders and Hypermetabolic States: Hy-
`pothyroidism may reduce the requirements for digoxin.
`Heart failure and/or atrial arrhythmias resulting from hy-
`permetabolic or hyperdynamic states (e.g., hyperthyroi-
`dism, hypoxia, or arteriovenous shunt) are best treated by
`addressing the underlying condition. Atrial arrhythmias as-
`sociated with hypermetabolic states are particularly resis-
`tant to digoxin treatment. Care must be taken to avoid tox-
`icity if digoxin is used.
`Usein Patients with Acute Myocardial Infarction:. Digoxin
`should be used with caution in patients with acute myocar-
`dial infarction. The use of inotropic 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 Cardioversion:
`to reduce the dose of digoxin for 1 to 2 daysprior to electri-
`eal 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 prudentto
`delay cardioversion, the lowest possible energy level should
`be selected to avoid provoking ventricular arrhythmias,
`Laboratory Test 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.
`For discussion of serum digoxin concentrations, see DOS-
`AGE AND ADMINISTRATIONsection.
`Drug Interactions: Potassium-depleting diuretics are a
`major contributing factor to digitalis toxicity. Calcium, par-
`ticularly if admiriistered rapidly by the intravenous route,
`may produce serious arrhythmias in digitalized patients.
`Quinidine, verapamil, amiodarone, propafenone, indometh-
`acin, itraconazole, alprazolam, and spironolactone raise the
`serum digoxin concentration due to a reduction in clearance
`and/orin volumeof distribution of the drug, with the impli-
`
`
`
`Continued on next page
`
`
`This product information is based on labeling in effect on June
`10, 1999. For further information, contact via direct mail, phom=.
`or web site Medical Information: Glaxo Wellcome Inc., PO Box
`13398, Research Triangle Park, NC 27709. Healthcare
`Professionals (Medical Information): 800-334-0089 Patients
`(Customer Response Center): 888-TALK2GW (1-888-825-5243)
`Glaxo Wellcome Corporate Web Site: www.glaxowellcome.com
`
`INDICATIONS AND USAGE
`Heart Failure: LANOXINis indicated for the treatment of
`mild to moderate heart failure. LANOXIN increasesleft
`ventricular ejection fraction and improves heart failure
`symptoms as evidenced by exercise capacity and heart fail-
`ure-related hospitalizations and emergency care, while hav-
`ing no effect on mortality. Where possible, LANOXIN should
`be used with a diuretic and an angiotensin-converting en-
`zyme inhibitor, but an optimal order for starting these three
`drugs cannot be specified.
`Atrial Fibrillation; LANOXINis 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 digoxin slows
`sinoatrial and AV conduction, the drug commonly prolongs
`the PR interval. The drug may cause severe sinus bradycar-
`dia or sinoatrial block in patients with pre-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 (Wolff-Parkinson-White Syndrome):
`After intravenous digoxin therapy, some patients with par-
`oxysmalatrial 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 down the accessory
`pathway has been blocked (either pharmacologically or by
`surgery), digoxin should not be used in such patients. The
`treatment of paroxysmal supraventricular tachycardia in
`such patients is usually direct-current 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 cardiomyopathy,
`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.
`
`;
`PRECAUTIONS
`Use in Patients with Impaired Renal Function: Digoxin is
`primarily excreted by the kidneys; therefore, patients with
`impaired renal function require smaller than usual mainte-
`nance doses of digoxin (see DOSAGE AND ADMINISTRA-
`TION). Because of the prolonged elimination half-life, a
`longer period of time is required to achieve an initial or new
`steady-state serum concentration in patients with renal im-
`pairment than in patients with normal renal function. If ap-
`propriate care is not taken to reduce the dose of digoxin,
`
`Table 2: Times to Onset of Pharmacologic Effect and to Peak Effect of Preparations of LANOXIN
` Product Time to Onset of Effect* Time to Peak Effect*
`
`
`LANOXIN Tablets
`0.5 — 2 hours
`2 -6-hours
`LANOXIN Elixir Pediatric
`0.5 - 2 hours
`2-6 hours
`LANOXICAPS
`0.5 - 2 hours
`2-6 hours
`
`5 - 30 minutestLANOXIN Injection/IV 1-4 hours
`
`* Documented for ventricular response rate in atrialfibrillation, inotropic effects and electrocardiographic changes,
`> Depending upon rate of infusion.
`
`
`EF <0.25
`
`

`

`sumed to be caused by digoxin, until further evaluation
`proves otherwise.
`OVERDOSAGE |
`Treatment of Adverse Reactions Produced by Overdosage:
`Digoxin should be temporarily discontinued until the ad-
`verse reaction resolves. Every effort should also be made to
`correct factors that may contribute to the adverse reaction
`(such as electrolyte disturbances or concurrent medica-
`tions). Once the adverse reaction has resolved, therapy with
`digoxin may be reinstituted, following a careful reassess-
`ment of dose.
`;
`Withdrawal of digoxin may be all that is required to treat
`the adverse reaction. However, when the primary manifes-
`tation of digoxin overdosage is a cardiac arrhythmia, addi-
`tional therapy may be needed