DIGOXINA 2.doc

7/30/2019 DIGOXINA 2.doc

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DIGOXINEvaluaciones de DRUGDEX

OVERVIEW

1) Class

a) This drug is a member of the following class(es):

AntiarrhythmicCardiac GlycosideCardiovascular AgentDigitalis GlycosideInotropic Agent2) Dosing Information

a)Adult

1)Atrial fibrillation

a) loading dose, 0.25 mg IV/ORALLY every 2 hours up to 1.5 mg MAX;maintenance dose, 0.125 to 0.375 mg IV/ORALLY daily (guideline dosing)[60]

b) (tablet) for rapid digitalization, give total loading dose of 10 to 15 mcg/kgORALLY; administer one-half of total loading dose initially, followed by one-fourth of the total loading dose every 4 to 8 hours twice; for daily maintenancedoses or for gradual digitalization, give 3.4 to 5.1 mcg/kg ORALLY once daily;titrate every 2 weeks (manufacturer dosing)[2]

2) Heart failure

a) (IV) for rapid digitalization, give loading dose of 0.4 to 0.6 mg IV; additionaldoses of 0.1 to 0.3 mg IV may be given cautiously at 6- to 8-hour intervals ifnecessary to achieve response (a 70-kg person typically requires 0.6 to 1 mg)

[1]

b) (tablet) for rapid digitalization, give total loading dose of 10 to 15 mcg/kgORALLY; administer one-half of total loading dose initially, followed by one-fourth of the total loading dose every 4 to 8 hours twice; for initial dailymaintenance doses or for gradual digitalization, give 3.4 to 5.1 mcg/kg ORALLYonce daily; titrate every 2 weeks[2]

c) (oral solution) maintenance dose, 3 mcg/kg ORALLY daily, adjust asnecessary

[3]


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b) Pediatric

1) Heart failure

a) (IV) for rapid digitalization, (premature infant) 15 to 25 mcg/kg; (full-term) 20

to 30 mcg/kg; (1 to 24 months) 30 to 50 mcg/kg; (2 to 5 years) 25 to 35 mcg/kg;(5 to 10 years) 15 to 30 mcg/kg; (over 10 years) 8 to 12 mcg/kg; for dailymaintenance doses or for gradual digitalization, give 20% to 30% of digitalizingdose for premature infants or 25% to 35% of digitalizing dose for all otherpediatric patients; give in divided doses for age under 10 years[4]

b) (oral solution) loading dose, first dose: give half the total loading dose;subsequent doses: as clinically indicated, give additional fractions of the totalloading dose at 4- to 8-hour intervals; TOTAL ORAL loading dose: (premature)20 to 30 mcg/kg; (full term) 25 to 35 mcg/kg; (1 to 24 months) 35 to 60 mcg/kg;

(2 to 5 years) 30 to 45 mcg/kg; (5 to 10 years) 20 to 35 mcg/kg; (over 10 years)10 to 15 mcg/kg[5]

c) (oral solution) maintenance dose, ORALLY (premature) 2.3 to 3.9 mcg/kgtwice daily; (full term) 3.8 to 5.6 mcg/kg twice daily; (1 to 24 months) 5.6 to 9.4mcg/kg twice daily; (2 to 5 years) 4.7 to 6.6 mcg/kg twice daily; (5 to 10 years)2.8 to 5.6 mcg/kg twice daily; (over 10 years) 3 to 4.5 mcg/kg once daily[5]

d) (tablet) 5 to 10 years: for rapid digitalization, give total loading dose of 20 to45 mcg/kg ORALLY; administer one-half of total loading dose initially, followedby one-fourth of the total loading dose every 4 to 8 hours twice; for initial dailymaintenance doses or for gradual digitalization, give 3.2 to 6.4 mcg/kg ORALLYtwice daily[2]

e) (tablet) older than 10 years: for rapid digitalization, give total loading dose of10 to 15 mcg/kg ORALLY; administer one-half of total loading dose initially,followed by one-fourth of the total loading dose every 4 to 8 hours twice; forinitial daily maintenance doses or for gradual digitalization, give 3.4 to 5.1

mcg/kg ORALLY once daily; titrate every 2 weeks[2]

3) Contraindications

a) hypersensitivity to digoxin or other digitalis preparations[2][5][4]

b) ventricular fibrillation

[2][5]


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[4]

4) Serious Adverse Effects

a) Cardiac dysrhythmia

b) Thrombocytopenia5) Clinical Applications

a) FDA Approved Indications

1)Atrial fibrillation2) Heart failure

DOSING INFORMATION

Drug Properties

A) Information on specific products and dosage forms can be obtained byreferring to the Tradename List (Product Index)B) Synonyms

DigoxinC) Physicochemical Properties

1) Molecular Weight

a) 780.95[363][5][844]

2) pH

a) 6.8 to 7.2 (injection: buffered with 0.17% dibasic sodium phosphate and0.08% anhydrous citric acid)[844]

3) Solubility

a) Practically insoluble in water and in ether; slightly soluble in diluted alcohol(50%) and in chloroform; freely soluble in pyridine[363][5][844].4) Melting point, above 230 degrees C[363][844]


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Storage and Stability

A) Preparation

1) Intramuscular route

a) Intramuscular administration (IM) is not the preferred route; however, ifdigoxin is administered IM, inject deep into the muscle and follow withmassage[1][4].b) It is recommended that no more than 500 micrograms (mcg) (2 mL) shouldbe injected into a single site for adults and no more than 200 mcg (2 mL)should be injected into a single site for pediatrics[1]

[4].2) Intravenous route

a) May be administered undiluted or diluted with a 4-fold or greater volume ofSterile Water for Injection (SWFI), 0.9% Sodium Chloride for Injection, or 5%Dextrose for Injection (D5W). Using less than a 4-fold volume of diluent couldlead to precipitation of digoxin[1][4].b) It is recommended to use digoxin immediately after diluting[4].c) Do not flush syringe with the parenteral solution after its contents areexpelled into an indwelling vascular catheter[1][4].d) Slow infusion is preferred over bolus administration. The recommendationis to infuse over at least 5 minutes or longer

[1][4].3) Oral route

a) Take maintenance doses after morning meals (and after evening meals ifgiving in divided doses)[111]

B) Injection route

1) Solution


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a) Store at controlled room temperature, 25 degrees C (77 degrees F);excursions permitted from 15 to 30 degrees C (59 to 86 degrees F). Protectfrom light[844].

C) Oral route

1) Solution/Tablet

a) Store at controlled room temperature, 25 degrees C (77 degrees F);excursions permitted from 15 to 30 degrees C (59 to 86 degrees F). Protectfrom light[5]. Protect tablets from moisture[363].

Adult Dosage

Normal DosageIntramuscular route

Atrial fibrillationa) Intramuscular (IM) injection of digoxin can causesevere pain at the injection site, therefore, intravenousadministration is preferred. If IM injection is required,administer deep into the muscle followed by massage.Administer no more than 500 microgram (2 mL) into asingle injection site[1].

Heart failurea) Intramuscular (IM) injection of digoxin can causesevere pain at the injection site; therefore, intravenousadministration is preferred. If IM injection is required,administer deep into the muscle followed by massage.Administer no more than 500 micrograms (2 mL) into asingle injection site

[1].Intravenous route

Atrial fibrillationa) The American College of Cardiology/American HeartAssociation/European Society of Cardiology guidelinesrecommended digoxin loading dose for the managementof atrial fibrillation was 0.25 mg intravenously every 2hours up to 1.5 mg. The recommended dailymaintenance dose was 0.125 to 0.375 mg intravenouslyor orally

[65]


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.b) Peak digoxin body stores larger than the 8 to 12mcg/kg (eg, heart failure, normal sinus rhythm) havebeen used for control of ventricular rate in patients withatrial fibrillation. Doses of digoxin used for the treatment

of chronic atrial fibrillation should be titrated to theminimum dose that provides the desired ventricular ratecontrol without causing untoward side effects[1].c) The maintenance dose should be based on thepercentage of peak body stores lost each day throughelimination. Daily excretion rates can be calculated fromcreatinine clearance (CrCl) using the following formula[42][1]

.

Maintenance dose = loading dose (ie, peak body stores)x % daily loss/100, where: % daily loss = 14 + creatinineclearance (CrCl) in milliliters/minute (mL/min)/5

Usual daily maintenance dose requirements inmicrograms of digoxin injection for estimated peak bodystores of 10 microgram/kg

[1]:

Daily maintenance doses rounded to the nearest 25-microgram (mcg) increment

Cor CrCl(mL/min/70kg)**

Lean Body Weight (kg (lb)) andDaily Dose (mcg)

DaystoReachSS*

50

kg(110lb)

60

kg(132lb)

70

kg(154lb)

80

kg(176lb)

90

kg(198lb)

100

kg(220lb)

0 75 75 100 100 125 150 22

10 75 100 100 125 150 150 19

20 100 100 125 150 150 175 16

30 100 125 150 150 175 200 14

40 100 125 150 175 200 225 13

50 125 150 175 200 225 250 12


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60 125 150 175 200 225 250 11

70 150 175 200 225 250 275 10

80 150 175 200 250 275 300 9

90 150 200 225 250 300 325 8100 175 200 250 275 300 350 7

KEY: kg = kilograms; lb = pounds; mL = milliliters; min= minute; Cor CrCl = corrected creatinine clearance;mcg = micrograms; * = if no loading doseadministered; ** = corrected creatinine clearance(CrCl) is CrCl corrected to 70 kilogram (kg) body weightor 1.73 m(2) body surface area. For adults, if onlyserum creatinine concentrations (Scr) are available, acorrected CrCl, corrected to 70 kg body weight may be

estimated in men as (140 - Age)/Scr. For women,multiply this result by 0.85. Do not use this equationfor estimating CrCl in pediatric patients.

d) Oral Solution

1) General Dosing Information

a) Recommended doses of digoxin will vary based onpatient age, ideal/lean body weight, renal function, clinical

response, concomitant conditions and concomitantmedications[3].2) Maintenance Dosing

a) The recommended initial digoxin daily oral dose is 3micrograms/kg/day. The dose will tend to producesteady-state post-absorptive level of 1 to 2nanograms/mL in uncompleted patients. although therange around these levels is wide

[3].

Heart failurea) General Dosing Information

1) Recommended doses of digoxin will vary based onpatient age, ideal/lean body weight, renal function, clinicalresponse, concomitant conditions and concomitantmedications[1].


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2) Parenteral administration of digoxin should be usedonly when the need for rapid digitalization is urgent orwhen the drug cannot be taken orally[1].

b) Serum Digoxin Concentrations

1) Serum digoxin concentrations ranging from 0.8 to 2nanograms/milliliter (ng/mL) have corresponded withabout two-thirds of adult patients who were consideredadequately digitalized without signs of toxicity. Isolatedserum concentration measurements are notrecommended for determining dosage adjustments.Sampling should be done just before the next scheduleddose or 6 to 8 hours after the last dose, regardless ofroute of administration. If the patients clinical response

does not correspond to the serum digoxin concentration,reevaluate testing procedure, time of sampling,concomitant medications and conditions, or exercise,which can cause acute decreases in serum digoxinconcentration due to binding of digoxin to skeletal muscle[1].c) Rapid Digitalization, Loading Dose Regimen

1) In adult patients with congestive heart failure andnormal sinus rhythm, rapid digitalization may be achievedwith a loading dose based on projected peak digoxinbody stores of 8 to 12 micrograms/kg[1].2) The loading dose should be administered in divideddoses with approximately one-half of the planned totalloading dose given as the first dose. The remainingdivided doses of the planned total dose may beadministered at 6- to 8-hour intervals, after carefulassessment of clinical response before each subsequent

dose[1].

a)A single initial intravenous (IV) dose of 400 to 600microgram (mcg) of digoxin injection usually produces adetectable effect in 5 to 30 minutes that becomesmaximal in 1 to 4 hours. Additional doses of 100 to 300mcg may be given cautiously at 6- to 8-hour intervals untilclinical evidence of an adequate effect is noted. Theusual dose of digoxin injection is 600 to 1000 mcg for a

70-kg patient required to achieve 8- to 12-mcg/kg peakbody stores


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[1].d) Maintenance Dosing

1) In controlled, clinical trials in patients with heart failure,

maintenance doses of digoxin ranged from 125 to 500micrograms (mcg) once daily based on patient age,ideal/lean body weight and renal function. Treatment wasgenerally titrated at 250 mcg once daily for patients underage 70 years and with good renal function. Doses may beincreased every 2 weeks based on clinical response[43].2) The maintenance dose should be based on thepercentage of peak body stores lost each day throughelimination. Daily excretion rates can be calculated from

creatinine clearance (CrCl) using the following formula[1][42].


Usual daily maintenance dose requirements inmicrograms (mcg) of digoxin injection for estimated peakbody stores of 10 mcg/kg[1]:

Daily maintenance doses rounded to the nearest 25-microgram (mcg) increment

Cor CrCl(mL/min/70

kg)**


DaystoReachSS*

50kg(110lb)

60kg(132lb)

70kg(154lb)

80kg(176lb)

90kg(198lb)

100kg(220lb)

0 75 75 100 100 125 150 22

10 75 100 100 125 150 150 19

20 100 100 125 150 150 175 16

30 100 125 150 150 175 200 14


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40 100 125 150 175 200 225 13

50 125 150 175 200 225 250 12

60 125 150 175 200 225 250 11

70 150 175 200 225 250 275 1080 150 175 200 250 275 300 9

90 150 200 225 250 300 325 8

100 175 200 250 275 300 350 7

KEY: kg = kilograms; lb = pounds; mL = milliliters; min= minute; Cor CrCl = corrected creatinine clearance;mcg = micrograms; * = steady state if no loading doseadministered; ** = corrected creatinine clearance(CrCl) is CrCl corrected to 70 kilogram (kg) body weight

or 1.73 m(2) body surface area. For adults, if onlyserum creatinine concentrations (Scr) are available, acorrected CrCl, corrected to 70 kg body weight may beestimated in men as (140 - Age)/Scr. For women,multiply this result by 0.85. Do not use this equationfor estimating CrCl in pediatric patients.

3) If a change of the calculated loading dose is clinicallywarranted, calculate the maintenance dose based on theactual amount of digoxin administered

[1]

Conversion To Oral Formulation

a) Lanoxicap(R) digoxin capsules have been discontinued bythe manufacturer.b)After rapid digitalization with digoxin injection, whenconverting to oral digoxin formulations, allowances must bemade for differences in bioavailability when calculatingmaintenance dosages with conversion to tablets, capsules, orsolution for maintenance therapy

[2][1]

TABLETS* (60% to 80% Bioavailability)

Equivalent Doses

Tablets Solution Capsule Injection

62.5 mcg 62.5 mcg 50 mcg 50 mcg

125 mcg 125 mcg 100 mcg 100 mcg

250 mcg 250 mcg 200 mcg 200 mcg


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500 mcg 500 mcg 400 mcg 400 mcg

SOLUTION* (70% to 85% Bioavailability)

Equivalent Doses

Solution Tablet Capsule Injection62.5 mcg 62.5 mcg 50 mcg 50 mcg

125 mcg 125 mcg 100 mcg 100 mcg

250 mcg 250 mcg 200 mcg 200 mcg

500 mcg 500 mcg 400 mcg 400 mcg

CAPSULE* (90% to 100% Bioavailability)

Equivalent Doses

Capsule Tablet Solution Injection

50 mcg 62.5 mcg 62.5 mcg 50 mcg

100 mcg 125 mcg 125 mcg 100 mcg

200 mcg 250 mcg 250 mcg 200 mcg

400 mcg 500 mcg 500 mcg 400 mcg

INJECTION* (100% Bioavailability)

Equivalent Doses

Injection Tablet Solution Capsule

50 mcg 62.5 mcg 62.5 mcg 50 mcg

100 mcg 125 mcg 125 mcg 100 mcg

200 mcg 250 mcg 250 mcg 200 mcg

400 mcg 500 mcg 500 mcg 400 mcg

* Lanoxin(R) brand digoxin

Oral route

Atrial fibrillationa) Oral Capsules

1) Important Note

a) Lanoxicap(R) digoxin capsules have beendiscontinued by the manufacturer.b) Due to more complete absorption of digoxin fromcapsules, the recommended oral doses of digoxincapsules are approximately 80% of those for tablets andsolution

[43].


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c) Divided daily dosing is presently recommended forpatients requiring a daily dose of 300 micrograms orgreater, for patients with a previous history of digitalistoxicity, for patients considered likely to become toxic,and patients in whom compliance is not a problem

[43].2) Serum Digoxin Concentrations

a) Serum digoxin concentrations ranging from 0.8 to 2nanograms/mL have corresponded with about two-thirdsof adult patients who were considered adequatelydigitalized without signs of toxicity. Isolated serumconcentration measurements are not recommended fordetermining dosage adjustments. Sampling should bedone just before the next scheduled dose or 6 to 8 hours

after the last dose, regardless of route of administration.If the patients clinical response does not correspond tothe serum digoxin concentration, reevaluate testingprocedure, time of sampling, concomitant medicationsand conditions, or exercise, which can cause acutedecreases in serum digoxin concentration due to bindingof digoxin to skeletal muscle[43].3) Peak digoxin body stores larger than the 8 to 12micrograms/kg (eg, heart failure, normal sinus rhythm)have been used for control of ventricular rate in patientswith atrial fibrillation. Doses of digoxin capsules used forthe treatment of chronic atrial fibrillation should be titratedto the minimum dose that provides the desired ventricularrate control without causing untoward side effects[43].4) The maintenance dose should be based on thepercentage of peak body stores lost each day throughelimination. Daily excretion rates can be calculated from

creatinine clearance (CrCl) using the following formula[42][1].



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Usual daily maintenance dose requirements inmicrograms (mcg) of digoxin capsules for estimated peakbody stores of 10 mcg/kg[43].



DaystoReachSS***

50kg(110lb)

60kg(132lb)

70kg(154lb)

80kg(176lb)

90 kg(198lb)

100kg(220lb)

0 50 100 100 100 150 150 22

10 100 100 100 150 150 150 1920 100 100 150 150 150 200 16

30 100 150 150 150 200 200 14

40 100 150 150 200 200 250 13

50 150 150 200 200 250 250 12

60 150 150 200 200 250 300* 11

70 150 200 200 250 250 300* 10

80 150 200 200 250 300* 300* 9

90 150 200 250 250 300* 350* 8

100 200 200 250 300 300* 350* 7

KEY: kg = kilograms; lb = pounds; mL = milliliters; min= minute; mcg = micrograms; Cor CrCl = creatinineclearance; *** = steady state if no loading doseadministered; ** = corrected creatinine clearance(CrCl) is CrCl corrected to 70 kilogram (kg) body weightor 1.73 m(2) body surface area. For adults, if onlyserum creatinine concentrations (Scr) are available, a

corrected CrCl, corrected to 70 kg body weight may beestimated in men as (140 - Age)/Scr. For women,multiply this result by 0.85. Do not use this equationfor estimating CrCl in pediatric patients. * = Divideddaily dosing is presently recommended for patientsrequiring a daily dose of 300 micrograms or greater,for patients with a previous history of digitalis toxicity,for patients considered likely to become toxic and forpatients in whom compliance is not a problem.

b) Oral Tablets


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1) The American College of Cardiology/American HeartAssociation/European Society of Cardiology guidelinesrecommended digoxin loading dose for the managementof atrial fibrillation was 0.25 mg intravenously every 2hours up to 1.5 mg. The recommended daily

maintenance dose was 0.125 to 0.375 mg intravenouslyor orally[60].2) Recommended doses of digoxin will vary based onpatient age, ideal/lean body weight, renal function, clinicalresponse, concomitant conditions, and concomitantmedications[2].

a) Serum Digoxin Concentrations

1) Serum digoxin levels of less than 0.5 nanograms/mL(ng/mL) have been associated with decreased efficacy,while levels greater than 2 ng/mL have been associatedwith increased toxicity without additional clinical benefit.Isolated serum concentration measurements are notrecommended for determining dosage adjustments.Sampling should be done just before the next scheduleddose or at least 6 hours after the last dose[2].b) Rapid Digitalization, Loading Dose Regimen

1) For rapid digitalization, give a total loading dose of 10to 15 mcg/kg orally, with one-half of the total loading doseadministered initially, followed by one-fourth of the totalloading dose every 4 to 8 hours twice[2].c) Initial Maintenance Dosage or Gradual Digitalization

1) For initial daily maintenance dosage, or for gradualdigitalization, give 3.4 to 5.1 mcg/kg orally once daily.Titrate every 2 weeks based on clinical response, serumdrug levels, and toxicity[2].2)Alternatively, the maintenance dose may be based onthe percentage of peak body stores lost each day throughelimination. Daily excretion rates can be calculated fromcreatinine clearance (CrCl) using the following formula

[2][42]


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.

Maintenance dose = loading dose (ie, peak body stores)x % daily loss/100; where % daily loss = 14 + creatinineclearance (CrCl in mL/min)/5

3) Recommended daily maintenance dosing (in mcg tobe given once daily) based on lean body weight and renalfunction is provided in the following table[2]:

Usual daily maintenance dose requirements inmicrograms (mcg)

Cor CrCl(mL/min/70 kg)**

Lean Body Weight (kg (lb)) and DailyDose (mcg)

DaystoReach SS*

40kg(88lb)

50kg(110lb)

60kg(132lb)

70kg(154lb)

80kg(176lb)

90kg(198lb)

100kg(220lb)

10 62.5 125 125

187.

5

187.

5

187.

5 250 19

20 125 125 125187.5

187.5

250 250 16

30 125 125187.5

187.5

250 250312.5

14

40 125187.5

187.5

250 250312.5

312.5

13

50 125187.5

187.5

250 250312.5

312.5

12

60 125187.5

250 250312.5

312.5

375 11

70187.5

187.5

250 250312.5

375 375 10

80187.5

187.5

250312.5

312.5

375437.5

9

90187.5

250 250312.5

375437.5

437.5

8

100 187.5

250 312.5

312.5

375 437.5

500 7


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KEY: kg = kilograms; lb = pounds; mL = milliliters; min =minute; Cor CrCl = corrected creatinine clearance; mcg =micrograms; * = steady state if no loading doseadministered; ** = corrected creatinine clearance (CrCl)is CrCl corrected to 70 kilogram (kg) body weight or 1.73

m(2) body surface area. For adults, if only serumcreatinine concentrations (Scr) are available, a correctedCrCl, corrected to 70 kg body weight may be estimatedin men as (140 - Age)/Scr. For women, multiply this resultby 0.85. Do not use this equation for estimating CrCl inpediatric patients.

Heart failurea) Oral Tablets


a) Recommended doses of digoxin will vary based onpatient age, ideal/lean body weight, renal function, clinicalresponse, concomitant conditions, and concomitantmedications[2].2) Serum Digoxin Concentrations

a) Serum digoxin levels of less than 0.5 nanograms/mL(ng/mL) have been associated with decreased efficacy,while levels greater than 2 ng/mL have been associatedwith increased toxicity without additional clinical benefit.Isolated serum concentration measurements are notrecommended for determining dosage adjustments.Sampling should be done just before the next scheduleddose or at least 6 hours after the last dose[2].

3) Rapid Digitalization, Loading Dose Regimen

a) For rapid digitalization, give a total loading dose of 10to 15 mcg/kg orally, with one-half of the total loading doseadministered initially, followed by one-fourth of the totalloading dose every 4 to 8 hours twice[2].4) Initial Maintenance Dosage or Gradual Digitalization

a) For initial daily maintenance dosage, or for gradual

digitalization, give 3.4 to 5.1 mcg/kg orally once daily.


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Titrate every 2 weeks based on clinical response, serumdrug levels, and toxicity[2].b)Alternatively, the maintenance dose may be based on

the percentage of peak body stores lost each day throughelimination. Daily excretion rates can be calculated fromcreatinine clearance (CrCl) using the following formula[2][42].

Maintenance dose = loading dose (ie, peak body stores)x % daily loss/100; where % daily loss = 14 + creatinineclearance (CrCl in mL/min)/5

c) The recommended daily maintenance dosing (in mcg,to be given once daily) based on lean body weight andrenal function is provided in the following table[2]:

Usual daily maintenance dose requirements in micrograms (mcg)


Lean Body Weight (kg (lb)) and Daily Dose (m

40 kg(88 lb)

50 kg(110lb)

60 kg(132lb)

70 kg(154lb)

80 kg(176lb)

90 kg(198lb)

1(

10 62.5 125 125 187.5 187.5 187.5 2

20 125 125 125 187.5 187.5 250 2

30 125 125 187.5 187.5 250 250 3

40 125 187.5 187.5 250 250 312.5 3

50 125 187.5 187.5 250 250 312.5 3

60 125 187.5 250 250 312.5 312.5 3

70 187.5 187.5 250 250 312.5 375 3

80 187.5 187.5 250 312.5 312.5 375

90 187.5 250 250 312.5 375 437.5

100 187.5 250 312.5 312.5 375 437.5 5

KEY: kg = kilograms; lb = pounds; mL = milliliters; min = minutecorrected creatinine clearance; mcg = micrograms; * = steady st


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dose administered; ** = corrected creatinine clearance (CrCl) is70 kilogram (kg) body weight or 1.73 m(2) body surface area. Foserum creatinine concentrations (Scr) are available, a correctedto 70 kg body weight may be estimated in men as (140 - Age)/Scmultiply this result by 0.85. Do not use this equation for estimati

pediatric patients.

b) Oral Capsules

1) Important Note

a) Lanoxicap(R) digoxin capsules have beendiscontinued by the manufacturer.b) Due to more complete absorption of digoxin from

capsules, the recommended oral doses of capsules areapproximately 80% of those for tablets and solution[43].c) Divided daily dosing is presently recommended forpatients requiring a daily dose of 300 micrograms (mcg)or greater, for patients with a previous history of digitalistoxicity, for patients considered likely to become toxic,and for patients in whom compliance is not a problem[43].2) General Dosing Information

a) Recommended doses of digoxin will vary based onpatient age, ideal/lean body weight, renal function, clinicalresponse, concomitant conditions and concomitantmedications[43].

1) Serum Digoxin Concentrations

a) Serum digoxin concentrations ranging from 0.8 to 2nanograms/mL (ng/mL) have corresponded with abouttwo-thirds of adult patients who were consideredadequately digitalized without signs of toxicity. Isolatedserum concentration measurements are notrecommended for determining dosage adjustments.Sampling should be done just before the next scheduleddose or 6 to 8 hours after the last dose, regardless ofroute of administration. If the patients clinical responsedoes not correspond to the serum digoxin concentration,

reevaluate testing procedure, time of sampling,concomitant medications and conditions, or exercise,


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which can cause acute decreases in serum digoxinconcentration due to binding of digoxin to skeletal muscle[43].3) Rapid Digitalization, Loading Dose Regimen

a) In adult patients with congestive heart failure andnormal sinus rhythm, rapid digitalization may be achievedwith a loading dose based on projected peak digoxinbody stores of 8 to 12 micrograms per kilogram (mcg/kg)[43].b) The loading dose should be administered in divideddoses with approximately one-half of the planned totalloading dose given as the first dose. The remainingdivided doses of the planned total dose may be

administered at 6- to 8-hour (hr) intervals, after carefulassessment of clinical response before each subsequentdose[43].

1)A single initial dose of 400 to 600 micrograms (mcg) ofdigoxin capsules usually produces a detectable effect in0.5 to 2 hours that becomes maximal in 2 to 6 hours (hr).Additional doses of 100 to 300 mcg may be givencautiously at 6- to 8-hr intervals until clinical evidence ofan adequate effect is noted. The usual dose of digoxincapsules is 600 to 1000 mcg for a 70-kg patient requiredto achieve 8 to 12 mcg/kg peak body stores[43].4) Maintenance Dosing

a) Divided daily dosing is presently recommended forpatients requiring a daily dose of 300 micrograms orgreater, for patients with a previous history of digitalis

toxicity, for patients considered likely to become toxic andfor patients in whom compliance is not a problem[43].b) The maintenance dose should be based on thepercentage of peak body stores lost each day throughelimination. Daily excretion rates can be calculated fromcreatinine clearance (CrCl) using the following formula[1][42].


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Usual daily maintenance dose requirements inmicrograms (mcg) of digoxin capsules for estimated peakbody stores of 10 mcg/kg[43].



DaystoReachSS***

50kg(110lb)

60kg(132lb)

70kg(154lb)

80kg(176lb)

90 kg(198lb)

100kg(220lb)

0 50 100 100 100 150 150 22

10 100 100 100 150 150 150 19

20 100 100 150 150 150 200 16

30 100 150 150 150 200 200 14

40 100 150 150 200 200 250 13

50 150 150 200 200 250 250 12

60 150 150 200 200 250 300* 11

70 150 200 200 250 250 300* 10

80 150 200 200 250 300* 300* 9

90 150 200 250 250 300* 350* 8

100 200 200 250 300 300* 350* 7

KEY: kg = kilograms; lb = pounds; mL = milliliters; min

= minute; mcg = micrograms; Cor CrCl = creatinineclearance; *** = steady state if no loading doseadministered; ** = corrected creatinine clearance(CrCl) is CrCl corrected to 70 kilogram (kg) body weightor 1.73 m(2) body surface area. For adults, if onlyserum creatinine concentrations (Scr) are available, acorrected CrCl, corrected to 70 kg body weight may beestimated in men as (140 - Age)/Scr. For women,multiply this result by 0.85. Do not use this equationfor estimating CrCl in pediatric patients. * = Divideddaily dosing is presently recommended for patientsrequiring a daily dose of 300 micrograms or greater,


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for patients with a previous history of digitalis toxicity,for patients considered likely to become toxic and forpatients in whom compliance is not a problem.

c) If a change of the calculated loading dose is clinicallywarranted, calculate the maintenance dose based on theactual amount of digoxin administered[43].c) Oral Solution


a) Recommended doses of digoxin will vary based onpatient age, ideal/lean body weight, renal function, clinical

response, concomitant conditions and concomitantmedications[3].2) Maintenance Dosing

a) The recommended initial digoxin daily oral dose is 3micrograms/kg/day. The dose will tend to producesteady-state post-absorptive level of 1 to 2nanograms/mL in uncompleted patients. although therange around these levels is wide[3].

Ideal Body Weight Calculations

1) Most clinicians use ideal body weight instead of lean body weight inestimating the loading dose of digoxin since the calculation is easier.Digoxin is similarly distributed into ideal body weight in obese patientsand normal subjects; there is no apparent distribution of digoxin intoexcess body weight over ideal body weight[86]

.2) Ideal body weight may be estimated using the following formulas[87]:

(females) ideal body weight = 48.67 kilograms + 1.65 kilograms perinch over 5 feet

(males) ideal body weight = 51.65 kilograms + 1.85 kilograms per inch

over 5 feet


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3) In adults, if only serum creatinine levels (Scr) are available, acorrected creatinine clearance (CrCl) (corrected to 70 kg body weight)

may be estimated[1].

Males: creatinine clearance (CrCl) = (140 - Age)/serum creatinine (Scr)

Females: creatinine clearance (CrCl) = ((140 - Age)/serum creatinine(Scr)) x 0.85

4) In obese subjects, digoxin loading and maintenance should becalculated on the basis of ideal body weight[86].5) The maintenance dose should be based on the percentage of peakbody stores lost each day through elimination. Daily excretion ratescan be calculated from creatinine clearance (CrCl) using the followingformula[42]

[1].

Maintenance dose = loading dose (ie, peak body stores) x % dailyloss/100, where: % daily loss = 14 + creatinine clearance (CrCl) inmilliliters/minute (mL/min/5)

Conversion To Oral Dosage Forms

1) Lanoxicap(R) digoxin capsules have been discontinued by themanufacturer.2) Typically intravenous digoxin is used to achieve rapid digitalizationwith conversion to an oral dosage form for maintenance therapy.However, when switching a patient from intravenous to oral digoxin,allowances must be made for differences in bioavailability[2][1]:



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Equivalent Doses

Tablets Solution Capsule Injection

62.5 mcg 62.5 mcg 50 mcg 50 mcg

125 mcg 125 mcg 100 mcg 100 mcg250 mcg 250 mcg 200 mcg 200 mcg

500 mcg 500 mcg 400 mcg 400 mcg


Equivalent Doses

Solution Tablet Capsule Injection

62.5 mcg 62.5 mcg 50 mcg 50 mcg

125 mcg 125 mcg 100 mcg 100 mcg

250 mcg 250 mcg 200 mcg 200 mcg

500 mcg 500 mcg 400 mcg 400 mcg


Equivalent Doses


50 mcg 62.5 mcg 62.5 mcg 50 mcg

100 mcg 125 mcg 125 mcg 100 mcg

200 mcg 250 mcg 250 mcg 200 mcg

400 mcg 500 mcg 500 mcg 400 mcg

INJECTION* (100% Bioavailability)

Equivalent Doses


50 mcg 62.5 mcg 62.5 mcg 50 mcg

100 mcg 125 mcg 125 mcg 100 mcg

200 mcg 250 mcg 250 mcg 200 mcg400 mcg 500 mcg 500 mcg 400 mcg


Conversion To Digitoxin

1) Digitoxin has the same pharmacologic actions as digoxin, however,its pharmacokinetic profile does differ. Patients can be converted fromdigitoxin (half-life, 7 days) to digoxin (half-life, 48 hours) or vice versa.To change drug therapy from maintenance doses of digoxin 0.25 mgdaily to digitoxin (assuming a therapeutic digoxin serum concentration


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initially, normal renal function and a loading dose of 0.8 mg ofdigitoxin), the digoxin is stopped abruptly and followed 24 hours laterwith digitoxin 0.4 mg. This same dose is repeated the next day. On thethird day, digitoxin 0.2 mg is administered with subsequent daily dosesof 0.1 mg of digitoxin for maintenance therapy. Patients should be

monitored for further dosage adjustments. To convert frommaintenance digitoxin to digoxin, the digitoxin is stopped for 3 dayswith the anticipated maintenance dose of digoxin being started on day4[88].Withdrawal Schedule

1) One study reported that in most patients in sinus rhythm withcompensated congestive heart failure and ischemic heart disease,digoxin can be withdrawn safely when diuretic and vasodilator

treatment is maximized. Only 2 of 24 patients in the studydemonstrated an increase in heart failure when digoxin wasdiscontinued[89]. Another study indicated that 108 of 134 patients (81%) did not requiredigoxin maintenance therapy[90].

Dosage in Renal FailureA) Renal Failure

1) Doses of digoxin should be adjusted in patients with renalimpairment because of their higher risk for digoxin toxicity[2][43][1].2) The dosage of digoxin must be reduced in renal insufficiency(Marcus, 1966). The most reliable indicator of digoxin excretion iscreatinine clearance[68]

.3) The volume of distribution (Vd) of digoxin can decrease by as muchas 50% in patients with renal failure[93][94]. However, it is not clear whether or not dosage should be reducedcorresponding to the reduced Vd, as tissue uptake (includingmyocardial uptake) of digoxin is reduced in renal failure[95]. The pharmacologic and clinical effects of this reduced uptake are notclear, but increased digitalis tolerance has been reported in uremic

patients[96]


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. Some investigators prefer digitoxin over digoxin in renal failurepatients, since digitoxin pharmacokinetics are not as affected byimpaired renal function[97][98]

[94][99].4) Patients with normal renal function will excrete 35% to 40% ofdigoxin body stores daily, in contrast to 14% daily elimination of totalbody stores in anephric patients[42][94].B) Loading Dose, Renal Failure

1) Loading doses of 0.5 to 1.25 mg or 0.4 to 0.75 mg/45 kg bodyweight) can be given to patients with normal or impaired renal function[94].Since even a small degree of renal failure will decrease the volume ofdistribution (Vd) of digoxin, adjustments in loading dose should bemade. The Vd may be roughly estimated using a linear equation[100]

Vd = 4.5 +(0.028 x CrCl) (creatinine clearance)

The loading dose may then be estimated with the formula, Dose = Cp(desired serum level) x Vd

2) One study compared 2 groups of renal patients receiving digoxinloading doses of 0.625 mg and 1.25 mg given over 48 hours.Maintenance doses of 0.125 mg were given to both groups. Initialplasma levels reflected the difference in loading doses; however, after120 hours of maintenance therapy, plasma levels of the 2 groups werecomparable[101]. Large loading doses (1.25 mg) may account for arrhythmias seen inearly therapy. For patients with creatinine clearance less than 20mL/min, a loading dose of 0.625 mg and maintenance with 0.125 mg isrecommended.C) Maintenance Dose, Renal Failure

1) Recommended daily maintenance dosing (in mcg, to be given oncedaily) based on lean body weight and renal function is provided in thefollowing table[2]

:


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DaystoReach SS*

40kg(88lb)

50kg(110lb)

60kg(132lb)

70kg(154lb)

80kg(176lb)

90kg(198lb)

100kg(220lb)

10 62.5 125 125187.5

187.5

187.5

250 19

20 125 125 125187.5

187.5

250 250 16

30 125 125187.5

187.5

250 250312.5

14

40 125187.5

187.5

250 250312.5

312.5

13

50 125187.5

187.5

250 250312.5

312.5

12

60 125187.5

250 250312.5

312.5

375 11

70187.5

187.5

250 250312.5

375 375 10

80 187.5

187.5

250 312.5

312.5

375 437.5

9

90187.5

250 250312.5

375437.5

437.5

8

100187.5

250312.5

312.5

375437.5

500 7

KEY: kg = kilograms; lb = pounds; mL = milliliters; min =minute; Cor CrCl = corrected creatinine clearance; mcg =micrograms; * = steady state if no loading dose

administered; ** = corrected creatinine clearance (CrCl)is CrCl corrected to 70 kilogram (kg) body weight or 1.73m(2) body surface area. For adults, if only serumcreatinine concentrations (Scr) are available, a correctedCrCl, corrected to 70 kg body weight may be estimatedin men as (140 - Age)/Scr. For women, multiply this resultby 0.85. Do not use this equation for estimating CrCl inpediatric patients.

2) In patients with renal impairment, a dose of 125 micrograms (mcg)(0.125 mg) once daily and at a dose of 62.5 mcg (0.0625 mg) in


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patients with marked renal impairment are recommended. Doses maybe increased every 2 weeks according to clinical response.[1].3) Maintenance doses should replace daily digoxin loss as based upon

daily excretion rates[42].Daily excretion rates can be calculated from creatinine clearance(CrCl) or serum creatinine levels[42][102]:

Maintenance dose = Peak body stores (ie, loading dose) x % dailyloss/100

Where: % daily loss = 14 + CrCl milliliters/minute (mL/min)/5

If only serum creatinine levels are available, creatinine clearance(corrected to 70 kg body weight) may be estimated

Males: creatinine clearance (CrCl) = (140-age)/serum creatinine (Scr)

Females: creatinine clearance (CrCl) = ((140-age)/serum creatinine(Scr)) x 0.85

a) If patients are switched from intravenous to oral dosing, thebioavailability of the dosage forms must be considered[1].4) Digitalization may be achieved gradually with administration of amaintenance dose. This dose is based on lean body weight andcreatinine clearance. Steady-state levels should be reached within 1 to3 weeks depending on renal function[1].5) One of two methods of dosage adjustment in patients with renalfailure have been recommended[103]:

a) The dosing interval may be increased as follows: every 24 hours inpatients with mild renal failure (glomerular filtration rate (GFR) greaterthan 50 mL/minute), every 36 hours in moderate renal failure (GFR 10to 50 mL/minute), and every 48 hours in severe renal failure (GFR lessthan 10 mL/minute).b) The dose may be reduced as follows: glomerular filtration rate

(GFR) 10 to 50 mL/minute, 25% to 75% of the usual dose; GFR less


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than 10 mL/minute, 10% to 25% of the usual dose given at the normaldosage interval.6)A review of the pharmacokinetics of digoxin and other cardiacglycosides in patients with renal insufficiency has been provided[104]

.Dosage in Hepatic Insufficiency

A) No specific dosage adjustment is necessary in patients with hepaticinsufficiency[105]. However, severe impairment of digoxin elimination was reported in 2patients with combined hepatic and renal disease; the effects ofnonrenal excretion mechanisms in reducing elimination were apparent.The presence of hepatic disease superimposed on renal insufficiencymay alter the predicted elimination kinetics that are based upon renalfunction alone

[106].

Dosage in Geriatric PatientsA) Because the geriatric population is more inclined to have impairedrenal function, dosing should be based on renal function[2][1][43].B) Elderly patients appear to have compromised digoxin tolerance andexcretion, thus requiring downward dosing adjustment . This appearsto be related to reduction in lean body mass and reduction in renalclearance[107].C) Digitalizing doses should be calculated based on lean body massand maintenance doses should be calculated using actual creatinineclearance[108].

Dosage Adjustment During Dialysis

A)A patient on dialysis is expected to be receiving a digoxin dosebased on severe renal failure (ie, glomerular filtration rate less than 10mL/minute). Since cardiac glycosides are highly tissue bound,additional doses following dialysis do not appear to be necessary[103][109][110].B) Potassium removal with resultant hypokalemia which predisposes todigitalis toxicity is a significant consideration in the patient on dialysiswho is receiving digoxin. Many centers use a modest (2 to 3 mEq/L)

concentration of potassium in the dialysate for such patients, andreport less difficulty in dialyzing digitalized patients.


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Dosage in Other Disease StatesA) Obesity or Edema (Oral Tablets)

1) Dose reductions are necessary when lean weight is an abnormallysmall fraction of total body mass because of obesity or edema

[2].

Pediatric Dosage

Normal DosageIntramuscular route

Atrial fibrillationa) Intramuscular (IM) injection of digoxin can causesevere pain at the injection site, therefore, intravenousadministration is the preferred route. If IM injection is

required, administer deep into the muscle followed bymassage. Administer no more than 200 microgram (2mL) into a single injection site[4].See Drug Consult reference:TREATMENT OF PEDIATRIC SUPRAVENTRICULARTACHYCARDIAS

Heart failurea) Intramuscular (IM) injection of digoxin can causesevere pain at the injection site; therefore, intravenousadministration is the preferred route. If IM injection isrequired, administer deep into the muscle followed bymassage. Administer no more than 200 micrograms (2mL) into a single injection site[4].

Intravenous routeAtrial fibrillation

a) Peak digoxin body stores larger than the 8 to 12

mcg/kg (heart failure, normal sinus rhythm) have beenused for control of ventricular rate in patients with atrialfibrillation. Doses of digoxin tablets used for the treatmentof chronic atrial fibrillation should be titrated to theminimum dose that achieves the desired ventricular ratecontrol without causing undesirable side effects[4].

Usual maintenance doses of digoxin injection inpediatrics and children with normal renal function based

on lean body weight[4]


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AgeIV DigitalizingDose (mcg/kg)

Daily IV MaintenanceDose (mcg/kg)*

Premature

Infant

15 to 2520% to 30% of IV

digitalizing doseFull-TermInfant

20 to 30

25% to 35% of IVdigitalizing dose**

1 to 24months

30 to 50

2 to 5 years 25 to 35


Over 10years

8 to 12

KEY: mcg = microgram; kg = kilogram; * = intravenousdigitalizing doses are 80% of oral digitalizing doses; **= projected or actual digitalizing dose providing clinicalresponse; IV = intravenous.

b) Divided daily dosing is recommended for childrenunder 10 years of age[4].

c) Intravenous (IV) digitalizing doses are 80% of oraldigitalizing dose[4].See Drug Consult reference:TREATMENT OF PEDIATRIC SUPRAVENTRICULARTACHYCARDIAS

Heart failurea) General Dosing Information

1) Recommended doses of digoxin will vary based onpatient age, ideal/lean body weight, renal function, clinicalresponse, concomitant conditions and concomitantmedications[4].2) Parenteral administration of digoxin should be usedonly when the need for rapid digitalization is urgent orwhen the drug cannot be taken orally[4].

b) Rapid Digitalization, Loading Dose Regimen


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1) In infants and children, rapid digitalization may beachieved with administration of a loading dose based onprojected peak digoxin body stores. Peak digoxin bodystores of 8 to 12 microgram/kg should provide digitaliseffect with minimum risk of toxicity in most patients

assuming normal renal function[4].2) The loading dose should be administered in divideddoses with approximately one-half of the planned totalloading dose given as the first dose. The remainingdivided doses of the planned total dose may beadministered at 6- to 8-hour intervals, after carefulassessment of clinical response before each subsequentdose[4]

.3)After rapid digitalization is achieved, conversion to oralformulation can be used for maintenance treatment.Anticipate bioavailability changes upon conversion to oralformulations[4]:



PrematureInfant

15 to 25 20% to 30% of IVdigitalizing dose

Full-TermInfant

20 to 30

25% to 35% of IVdigitalizing dose**

1 to 24months

30 to 50



Over 10years

8 to 12


4) Maximum total intravenous (IV) digitalizing dose inpediatric patients (17 years and younger) should not

exceed 1 mg (Anon, 1993).


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c) Gradual Digitalization

1) Gradual digitalization may be accomplished startingwith an appropriate maintenance dose. Anticipatesignificant variations in dosages among patients and

proceed based on clinical assessment[4].d) Maintenance Dosing

1) Usual maintenance doses of digoxin injection in infantsand children with normal renal function, based on leanbody weight[4]:



PrematureInfant

15 to 2520% to 30% of IVdigitalizing dose

Full-TermInfant

20 to 30

25% to 35% of IV

digitalizing dose**

1 to 24months

30 to 50

2 to 5 years 25 to 355 to 10 years 15 to 30

Over 10years

8 to 12


2) Divided daily dosing is recommended for childrenunder 10 years of age[4].3) Intravenous (IV) digitalizing doses are 80% of oraldigitalizing dose[4].4) If a change of the calculated loading dose is clinicallywarranted, calculate the maintenance dose based on the

actual amount of digoxin administered[4]


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.Oral route

Atrial fibrillationa) Oral Solution


a) Recommended doses of digoxin will vary based onpatient age, ideal/lean body weight, renal function, clinicalresponse, concomitant conditions and concomitantmedications[6].2) Rapid Digitalization, Loading Dose Regimen

a) Loading dose (rapid digitalization) is generally used

only in urgent situations (eg, treating arrhythmias or acutecongestive heart failure). The total digitalizing dose isusually given over 16 to 24 hours as 3 divided dosesevery 6 to 8 hours[44][6].

Age Loading Dose

Premature

infant 20 mcg/kg

Full-term up to2 mo

30 mcg/kg

2 mo to 2 yr 40 to 50 mcg/kg

2 yr to 10 yr 30 to 40 mcg/kg

Greater than 10yr

0.75 to 1.5 mg total loadingdose (adult dose)

KEY: mcg/kg = micrograms/kilograms; mg =

milligrams; mo = months; yr = years

b) Oral doses should be 25% greater than IV doses[44].3) Gradual Digitalization

a)A slower digitalization can be accomplished byinitiating an appropriate maintenance dose

[44].


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4) Maintenance Dosing

a) Daily maintenance doses are given twice daily inchildren 10 years of age and younger and once daily inchildren older than 10 years

[44][6].

Age Daily Maintenance Dose

Premature infant 5 mcg/kg

Full-term up to 2mo

8 to 10 mcg/kg

2 mo to 2 yr 10 to 12 mcg/kg

2 yr to 10 yr 8 to 10 mcg/kg

Greater than 10yr

0.125 to 0.5 mg/kg (adultdose)

KEY: mcg/kg = micrograms/kilograms; mg =milligrams; mo = months; yr = years

b) Maintenance doses are approximately 25% ofdigitalizing doses

[44].See Drug Consult reference:TREATMENT OF PEDIATRIC SUPRAVENTRICULARTACHYCARDIAS

Heart failurea) Oral Solution


a) Recommended doses of digoxin will vary based onpatient age, ideal/lean body weight, renal function, clinicalresponse, concomitant conditions and concomitantmedications[5].2) Loading Dose Regimen

a) The recommended pediatric loading dose of digoxinoral solution is to give HALF of the total loading dose as a

first dose. Subsequent doses, as clinically indicated, give


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additional fractions of the total loading dose at 4 to 8 hourintervals[5]:

Age Total oral loadingdose

premature 20 to 30 mcg/kg

full-term 25 to 35 mcg/kg

1 to 24months

35 to 60 mcg/kg

2 to 5 years 30 to 45 mcg/kg

5 to 10 years 20 to 35 mcg/kg

over 10years

10 to 15 mcg/kg

b) Oral doses should be 25% greater than IV doses[44].3) Gradual Digitalization

a)A slower digitalization can be accomplished by

initiating an appropriate maintenance dose[5][44]. Steady state will be reached after approximately 5 daysin patients with normal renal function[5].4) Maintenance Dosing

a) Digoxin serum levels less than 0.5 nanograms/mL hasbeen associated with diminished efficacy. Levels above 2nanograms/mL are associated with increased toxicitywithout increased benefit. Sampling of digoxin levelsshould be done just prior to the next scheduled dose[5].b) The recommended maintenance dose or digoxin oralsolution in pediatric patients[5]:

Age Maintenance Dose, Oral


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premature2.3 to 3.9 mcg/kg twicedaily

full-term3.8 to 5.6 mcg/kg twicedaily

1 to 24 months 5.6 to 9.4 mcg/kg twicedaily

2 to 5 years4.7 to 6.6 mcg/kg twicedaily

5 to 10 years2.8 to 5.6 mcg/kg twicedaily

over 10 years 3 to 4.5 mcg/kg once daily

c) Divided doses are recommended in patients less than10 years of age[5].d) Maintenance doses are approximately 25% ofdigitalizing doses[44].b) Oral Tablets


a) Recommended doses of digoxin will vary based onpatient age, ideal/lean body weight, renal function, clinicalresponse, concomitant conditions, and concomitantmedications[2].b) Divided daily dosing is recommended for childrenunder 10 years of age[2]

.2) Rapid Digitalization, Loading Dose Regimen

a) For rapid digitalization in children 5 to 10 years of age,give a total loading dose of 20 to 45 mcg/kg orally, withone-half of the total loading dose administered initially,followed by one-fourth of the total loading dose every 4 to8 hours twice[2].b) For rapid digitalization in children older than 10 years,

give a total loading dose of 10 to 15 mcg/kg orally, withone-half of the total loading dose administered initially,


37/317

followed by one-fourth of the total loading dose every 4 to8 hours twice[2].3) Initial Maintenance Dosage or Gradual Digitalization

a) For initial daily maintenance doses or for gradualdigitalization in children 5 to 10 years, give 3.2 to 6.4mcg/kg orally twice daily[2].b) For initial daily maintenance doses or for gradualdigitalization in children older than 10 years, give 3.4 to5.1 mcg/kg orally once daily; titrate every 2 weeks basedon clinical response, serum drug concentrations, andtoxicity

[2].c) Recommended daily maintenance dosing (in mcg, tobe given twice daily) for pediatric patients 5 to 10 yearsbased on lean body weight and renal function is providedin the following table[2]:

Cor CrCl

(mL/min/70kg)**

Lean Body Weight (kg (lb)) and

Daily Dose (mcg)

Days to

ReachSS*

20 kg(44lb)

30 kg(66lb)

40 kg(88 lb)

50 kg(110lb)

60 kg(132lb)

10 62.5 62.5 125 125 19

20 62.5 62.5 125 125 125 16

30 62.5 62.5 125 125 187.5 14

40 62.5 62.5 125 187.5 187.5 13

50 62.5 125 125 187.5 187.5 12

60 62.5 125 125 187.5 250 11

70 62.5 125 187.5 187.5 250 10

80 62.5 125 187.5 187.5 250 9

90 62.5 125 187.5 250 250 8

100 62.5 125 187.5 250 312.5 7

KEY: kg = kilograms; lb = pounds; mL = milliliters; min

= minute; Cor CrCl = corrected creatinine clearance;mcg = micrograms; * = steady state if no loading dose


38/317

administered; ** = corrected creatinine clearance(CrCl) is CrCl corrected to 70 kilogram (kg) body weightor 1.73 m(2) body surface area. For pediatrics, themodified Schwartz equation corrected to 1.73 m(2)body surface area may be used.

d) Recommended daily maintenance dosing (in mcg, tobe given once daily) for pediatric patients older than 10years based on lean body weight and renal function isprovided in the following table[2]:



DaystoReach SS*

40kg(88lb)

50kg(110lb)

60kg(132lb)

70kg(154lb)

80kg(176lb)

90kg(198lb)

100kg(220lb)

10 62.5 125 125187.5

187.5

187.5

250 19

20 125 125 125 187.5

187.5

250 250 16

30 125 125187.5

187.5

250 250312.5

14

40 125187.5

187.5

250 250312.5

312.5

13

50 125187.5

187.5

250 250312.5

312.5

12

60 125187.5 250 250

312.5

312.5 375 11

70187.5

187.5

250 250312.5

375 375 10

80187.5

187.5

250312.5

312.5

375437.5

9

90187.5

250 250312.5

375437.5

437.5

8

100187.

5

250312.

5

312.

5

375437.

5

500 7

KEY: kg = kilograms; lb = pounds; mL = milliliters; min =


39/317

minute; Cor CrCl = corrected creatinine clearance; mcg =micrograms; * = steady state if no loading doseadministered; ** = corrected creatinine clearance (CrCl)is CrCl corrected to 70 kilogram (kg) body weight or 1.73m(2) body surface area. For pediatrics, the modified

Schwartz equation corrected to 1.73 m(2) body surfacearea may be used.

Atrial flutterSee Drug Consult reference:TREATMENT OF PEDIATRIC SUPRAVENTRICULARTACHYCARDIAS

Ectopic atrial tachycardia

See Drug Consult reference:TREATMENT OF PEDIATRIC SUPRAVENTRICULARTACHYCARDIAS

His Bundle (junctional ectopic) tachycardiaSee Drug Consult reference:TREATMENT OF PEDIATRIC SUPRAVENTRICULARTACHYCARDIAS

Re-entrant atrial tachycardiaSee Drug Consult reference:TREATMENT OF PEDIATRIC SUPRAVENTRICULARTACHYCARDIAS

Wolff-Parkinson-White syndromeSee Drug Consult reference:TREATMENT OF PEDIATRIC SUPRAVENTRICULARTACHYCARDIAS

General Dosing Information

1) Injection contains propylene glycol 40% and alcohol 10%[4].2) Digoxin injection can be administered undiluted or diluted with a 4-fold or greater volume. It is important if diluting the digoxin to use theappropriate volume to avoid precipitation and to use the dilutedsolution immediately[4].3) Unless oral dosing is precluded, intravenous dosing provides littleclinical benefit since full onset of action from this route will not be

apparent for up to 6 hours. Intramuscular injections may be given butare seldom justified and are extremely painful. Digitalization with


40/317

loading dose regimens are usually only necessary in the managementof arrhythmias or acute congestive failure. Non-acute conditions arebest managed using the gradual digitalization/maintenance doseapproach. Serum levels should be monitored weekly until stabilized,with samples drawn immediately prior to a dose, but at least 6 to 8

hours after the previous dose. Therapeutic range is 0.8 to 2 nanogramper milliliter, but with great individual variation possible for theexpression of both clinical benefit or toxicity[4][91].Conversion To Oral Dosage Forms

1) Lanoxicap(R) digoxin capsules have been discontinued by themanufacturer.2) Typically intravenous digoxin is used to achieve rapid digitalization

with conversion to an oral dosage form for maintenance therapy.However, when switching a patient from intravenous to oral digoxin,allowances must be made for differences in bioavailability[2][1]:


Equivalent Doses

Tablets Solution Capsule Injection62.5 mcg 62.5 mcg 50 mcg 50 mcg

125 mcg 125 mcg 100 mcg 100 mcg

250 mcg 250 mcg 200 mcg 200 mcg

500 mcg 500 mcg 400 mcg 400 mcg


Equivalent Doses

Solution Tablet Capsule Injection

62.5 mcg 62.5 mcg 50 mcg 50 mcg

125 mcg 125 mcg 100 mcg 100 mcg

250 mcg 250 mcg 200 mcg 200 mcg

500 mcg 500 mcg 400 mcg 400 mcg


Equivalent Doses


50 mcg 62.5 mcg 62.5 mcg 50 mcg


41/317

100 mcg 125 mcg 125 mcg 100 mcg

200 mcg 250 mcg 250 mcg 200 mcg

400 mcg 500 mcg 500 mcg 400 mcg

INJECTION* (100% Bioavailability)Equivalent Doses


50 mcg 62.5 mcg 62.5 mcg 50 mcg

100 mcg 125 mcg 125 mcg 100 mcg

200 mcg 250 mcg 250 mcg 200 mcg

400 mcg 500 mcg 500 mcg 400 mcg


Drug Resistance

1) One study reported that the observed resistance to digoxin in infantsand in children is not related to bacterial inactivation by gut flora.Excretion of large amounts of cardioinactive digoxin metabolites wasnot observed in patients younger than 9 years of age. Therefore, thecapacity to inactivate digoxin in vivo develops gradually. In this study,children were colonized with intestinal bacteria that were capable of

metabolizing the drug as early as the second week of life, with theadult frequency of colonization being achieved by 2 years of age andthe adult pattern of metabolism being achieved at adolescence. Othermechanisms appear to be responsible for the increased digoxindosage requirements in infants and children[92].

Dosage in Renal FailureA) Renal Failure

1) Because renal clearance is decreased in the newborn and

pronounced in premature infants, dosage adjustments arerecommended[4][3].2) The dosage of digoxin must be reduced in renal insufficiency(Marcus, 1966). The most reliable indicator of digoxin excretion iscreatinine clearance[68].3) The volume of distribution (Vd) of digoxin can decrease by as muchas 50% in patients with renal failure[93]


42/317

[94]. However, it is not clear whether or not dosage should be reducedcorresponding to the reduced Vd, as tissue uptake (includingmyocardial uptake) of digoxin is reduced in renal failure[95]

. The pharmacologic and clinical effects of this reduced uptake are notclear, but increased digitalis tolerance has been reported in uremicpatients[96]. Some investigators prefer digitoxin over digoxin in renal failurepatients, since digitoxin pharmacokinetics are not as affected byimpaired renal function[97][98][94][99]

.4) Patients with normal renal function will excrete 35% to 40% ofdigoxin body stores daily, in contrast to 14% daily elimination of totalbody stores in anephric patients[42][94].B) Maintenance Dose, Renal Failure

1) Recommended daily maintenance dosing (in mcg, to be given twicedaily) for pediatric patients 5 to 10 years based on lean body weightand renal function is provided in the following table[2]:



Days toReachSS*

20 kg(44lb)

30 kg(66lb)

40 kg(88 lb)

50 kg(110lb)

60 kg(132lb)

10 62.5 62.5 125 125 19

20 62.5 62.5 125 125 125 16

30 62.5 62.5 125 125 187.5 14

40 62.5 62.5 125 187.5 187.5 13

50 62.5 125 125 187.5 187.5 12

60 62.5 125 125 187.5 250 11

70 62.5 125 187.5 187.5 250 10

80 62.5 125 187.5 187.5 250 9


43/317

90 62.5 125 187.5 250 250 8

100 62.5 125 187.5 250 312.5 7

KEY: kg = kilograms; lb = pounds; mL = milliliters; min= minute; Cor CrCl = corrected creatinine clearance;

mcg = micrograms; * = steady state if no loading doseadministered; ** = corrected creatinine clearance(CrCl) is CrCl corrected to 70 kilogram (kg) body weightor 1.73 m(2) body surface area. For pediatrics, themodified Schwartz equation corrected to 1.73 m(2)body surface area may be used.

2) Recommended daily maintenance dosing (in mcg to be given oncedaily) for children older than 10 years based on lean body weight and

renal function is provided in the following table[2]:



DaystoReach SS*

40kg

(88lb)

50kg

(110lb)

60kg

(132lb)

70kg

(154lb)

80kg

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90kg

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100kg

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5 5 5 5

100187.5

250312.5

312.5

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500 7

KEY: kg = kilograms; lb = pounds; mL = milliliters; min =

minute; Cor CrCl = corrected creatinine clearance; mcg =micrograms; * = steady state if no loading doseadministered; ** = corrected creatinine clearance (CrCl)is CrCl corrected to 70 kilogram (kg) body weight or 1.73m(2) body surface area. For pediatrics, the modifiedSchwartz equation corrected to 1.73 m(2) body surfacearea may be used.

3) Maintenance doses should replace daily digoxin loss as based upon

daily excretion rates[42].Daily excretion rates can be calculated from creatinine clearance(CrCl) or serum creatinine levels[42][102]:Maintenance dose = Peak body stores (ie, Loading dose) x % dailyloss/100Where: % daily loss = 14 + creatinine clearance (CrCl) milliliters/minute(mL/min)/5

a) If patients are switched from intravenous to oral dosing, thebioavailability of the dosage forms must be considered[1].4) Digitalization may be achieved gradually with administration of amaintenance dose. This dose is based on lean body weight andcreatinine clearance. Steady-state levels should be reached within 1 to3 weeks depending on renal function

[1].5) One of two methods of dosage adjustment in patients with renalfailure have been recommended[103]:

a) The dosing interval may be increased as follows: every 24 hours inpatients with mild renal failure (glomerular filtration rate (GFR) greaterthan 50 mL/minute), every 36 hours in moderate renal failure (GFR 10to 50 mL/minute), and every 48 hours in severe renal failure (GFR less

than 10 mL/minute).


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b) The dose may be reduced as follows: glomerular filtration rate(GFR) 10 to 50 mL/minute, 25% to 75% of the usual dose; GFR lessthan 10 mL/minute, 10% to 25% of the usual dose given at the normaldosage interval.

Dosage in Hepatic Insufficiency

A) No specific dosage adjustment is necessary in patients with hepaticinsufficiency[105]. However, severe impairment of digoxin elimination was reported in 2patients with combined hepatic and renal disease; the effects ofnonrenal excretion mechanisms in reducing elimination were apparent.The presence of hepatic disease superimposed on renal insufficiencymay alter the predicted elimination kinetics that are based upon renalfunction alone[106].

Dosage Adjustment During DialysisA) No specific dosage adjustment necessary during dialysis[109][103]since cardiac glycosides are highly tissue bound[110].B) Potassium removal with resultant hypokalemia which predisposes todigitalis toxicity is a significant consideration in the patient on dialysiswho is receiving digoxin. Many centers use a modest (2 to 3 mEq/L)concentration of potassium in the dialysate for such patients, andreport less difficulty in dialyzing digitalized patients.

Dosage in Other Disease StatesA) Obesity or Edema (Oral Tablets)

1) Dose reductions are necessary when lean weight is an abnormallysmall fraction of total body mass because of obesity or edema[2].

PHARMACOKINETICS

Onset and Duration

A) Onset

1) Initial Response

a) ORAL, tablet, capsule, or elixir: 30 minutes to 2 hours[776][777].

b) INTRAVENOUS: 5 to 30 minutes[778]


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[777].c) INTRAMUSCULAR: 30 minutes to 2 hours[778].

2) Peak Response

a) ORAL, tablet, capsule, or elixir: within 2 to 6 hours[776][777].b) INTRAVENOUS: 1.5 to 4 hours[778][779].c) INTRAMUSCULAR: 2 to 6 hours

[778].

Drug Concentration Levels

A) Therapeutic Drug Concentration

1) The therapeutic serum levels range from 0.8 to 2 ng/mL[776][780].

a)A post hoc analysis based on data from the Digitalis Investigation Group(DIG) trial suggested that serum digoxin concentrations (SDC) in the range of0.5 to 0.8 ng/mL may be associated with reduced all-cause mortality andhospitalization compared with SDCs of 0.9 ng/mL and above for men withheart failure (left ventricular ejection fraction below 46%). Data were stratifiedaccording to 3 digoxin serum levels: 0.5 to 0.8 ng/mL (n=572), 0.9 to 1.1ng/mL (n=322); or 1.2 ng/mL and above (n=277). Subjects were followed formean 37 months. Rates of all cause mortality were 29.9%, 38.8%, and 48.0%for the groups according to serum levels, 0.5 to 0.8, 0.9 to 1.1, and 1.2 ng/mL

and over, respectively (p=0.006 for trend). The patients with the highestdigoxin concentrations (1.2 ng/mL and above) had 11.8% and 11.5% moreall-cause deaths and cardiovascular deaths, respectively, than the placebogroup[781].b) Drug levels should be drawn during the post-absorptive, post-distributivephase of drug elimination, ie, during the 8 to 24 hour interval following theprevious dose[782].

c) Plasma levels are significantly lower and urinary excretion levels aresignificantly higher in patients that are hyperthyroid


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[783].d) There are no controlled clinical trials which have established a therapeuticdigoxin serum level for the management of neonatal supraventriculartachycardia.

e) Studies in pregnant women[784][785]and in adults with renal impairment[786]who were not receiving digoxin have demonstrated false positive digoxinvalues on most assays.f) The serum of neonates not receiving digoxin contains a digoxin-likeimmunoreactive substance (DLIS) which confounds measurement oftherapeutic serum levels in neonates who receive digoxin. Studies alsodemonstrate lot-to-lot variability with immunoassay kits and day-to-day

variation in DLIS levels appear to preclude serum measurement prior toadministration of digoxin to obtain a base-line level. It has been speculatedthat DLIS may be coming from the fetal adrenal cortex since involution of thefetal adrenal cortex appears to coincide with peak levels of DLIS and there issome similarity between the structure of digoxin and adrenal corticosteroids[787][788][789][790][791].g)According to 1 study, there is no correlation between hair and blooddigoxin concentrations. However, determination of digoxin in hair is a rapidand inexpensive method to screen for the presence or absence of digoxin[792].

ADME

AbsorptionA) Bioavailability

1) ORAL, tablets: 60% to 80%[776].

a)Absorption from tablets is reported to be 60% to 80%, as comparedto 70% to 85% with the pediatric elixir and by the intramuscular route.Although some gastric absorption is reported, the major site ofabsorption is the small intestine[793][794]


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. Impaired absorption has been reported due to mucosal abnormalities,gastrointestinal irradiation, alteration in gastrointestinal motility andneomycin[795].

b) Tablets and elixir are approximately 80% as bioavailable as thecapsule (90% to 100%) and IV (100%) formulations[776]. Bioavailability problems have been documented with oraladministration of products from various manufacturers[777][779]. Bioavailability is not dependent on dose[796].2) INTRAMUSCULAR: incomplete and erratic absorption

[797].B) Effects of Food

1) Reduces absorption[776].

a)Administration with meals reduces the rate of absorption, but thetotal amount absorbed is usually unchanged. However, oraladministration with meals high in bran fiber may reduce the extent ofabsorption[776].

DistributionA) Distribution Sites

1) Protein Binding

a) 20% to 25%[776]

.2) OTHER DISTRIBUTION SITES

a) TISSUES, good[800]

1) Highest levels occur in heart muscle, kidneys, and liver[801]. Digoxin also distributes to red blood cells[800]

.


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B) Distribution Kinetics

1) Volume of Distribution

a) large 4 to 7 L/kg

[776][802][803].

1) Vd is proportional to lean body mass, with muscular individualshaving a larger Vd than obese individuals based on body weight[776][803].2) Vd is increased in hyperthyroid patients but is reduced in the

presence of hypothyroidism and impaired renal function[804][805]. Vd can decrease by as much as 50% in patients with renal failure[806]. A significantly smaller Vd at steady state in severe renal failure(creatinine clearance less than 10 mL/min) was confirmed usingfluorescence polarization immunoassay[807].3) In the ELDERLY, the volume of distribution may be reduced, whichcould increase serum concentrations[802].

MetabolismA) Metabolism Sites and Kinetics

1) LIVER, 16%[776].

a) There does not appear to be any significant difference betweendigoxin capsules and tablets with respect to the drug's metabolism inthe elderly[808].b) The metabolism of digoxin is not dependent upon the cytochrome P-450 system. Digoxin is not known to induce or inhibit the cytochromeP-450 system[776].B) Metabolites

1) Digoxigenin bisdigitoxoside, (active)


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[809].2) Digoxigenin monodigitoxoside, (active)[809].

ExcretionA) Kidney

1) Renal Excretion (%)

a) 57% to 80%[809][810][811].2) Excretion of unchanged drug is by glomerular filtration without

significant reabsorption by the renal tubule. Single IV dose studiesreport 57% to 80% of the administered dose is excreted in urine within6 to 12 hours[809][810][811]. Approximately 30% to 35% of total body stores of digoxin areexcreted unchanged in the urine daily[806].3)Although digoxin renal clearance correlates with creatinineclearance and somewhat with increasing urinary output, diuresis doesnot appear to significantly increase digoxin excretion[793].4) Urinary excretion was similar whether administered by rapid IV bolusover 3 to 5 minutes, or the same dose by constant IV infusion over 1hour[812].5) Urinary excretion of digoxin increases and fecal excretion decreases

in elderly subjects with hypochlorhydria (HC). In 1 study involving 10elderly subjects, urinary excretion of digoxin increased from 37% of thedose in normochlorhydric (NC) subjects to 46% in HC subjects,whereas fecal excretion decreased from 29% in NC subjects to 14% inHC subjects. The altered route of excretion in subjects with HC may bethe result of decreased hydrolysis of digoxin by stomach acid andincreased intestinal metabolism[813].B) Other

1) OTHER EXCRETION


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a) BILE, 6% to 8%[820][821].

1) Biliary excretion with enterohepatic recycling is reported to beapproximately 6% to 8%[820][821]. However, another study indicates that enterohepatic cycling may begreater with 30% of an IV dose reaching the GI tract in 24 hours[822]. Approximately 14% to 28% is eliminated by non-renal routes[809][823].

b) FECES, 3% to 5%[806][793].

1) Only 3% to 5% of total body stores are excreted in the stool daily[806][793]. Approximately 14% to 28% is eliminated by non-renal routes[809][823].2) Fecal excretion of digoxin decreases and urinary excretionincreases in elderly subjects with hypochlorhydria (HC). In 1 studyinvolving 10 elderly subjects, urinary excretion of digoxin increasedfrom 37% of the dose in normochlorhydric (NC) subjects to 46% in HCsubjects, whereas fecal excretion decreased from 29% in NC subjectsto 14% in HC subjects. The altered route of excretion in subjects withHC may be the result of decreased hydrolysis of digoxin by stomachacid and increased intestinal metabolism[813]

.Elimination Half-lifeA) Parent Compound

1) ELIMINATION HALF-LIFE

a) 1.3 to 2.2 days[810][824][825].

1)Average half-life is 1.5 to 1.8 days in normal patients


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[810][824][825].2) Half-life is unaffected by thyroid function

[804].

Extracorporeal EliminationA) Hemodialysis

1) Dialyzable: No[814][815]

a) Very little digoxin is removed from the body in renal failure patients

during dialysis. Mean clearances of 10 to 26 mL/min have beenreported[814][815].b)A major concern of dialysis in digitalized patients is the possible shiftof potassium levels. To avoid cardiac arrhythmias it is recommendedthat the dialysate potassium be 3 mEq/L[816].B) Peritoneal

1) Dialyzable: No[799][798]

a) Digoxin is not removed by hemodialysis[799][798].

b) Small amounts of digoxin are removed by peritoneal dialysis[806]. This is true with either intermittent peritoneal dialysis or continuousambulatory peritoneal dialysis[817].c)A major concern of dialysis in digitalized patients is the possible shiftof potassium levels. To avoid cardiac arrhythmias it is recommendedthat the dialysate potassium be 3 mEq/L[816].

C) Hemoperfusion


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1) Dialyzable: Yes[818]

a) In the first case report of direct hemoperfusion, a beta-2-

microglobulin absorption column connected to the arterial end of ahemodialysis unit reduced serum digoxin levels from 6.0 to 2.31nanograms per milliliter over 4 hours. A second session 3 days laterfurther reduced serum digoxin levels from 3.59 to 1.70 ng/mL. Withhemodialysis alone prior to the use of the B-2-MG column, a 4-hoursession reduced serum digoxin from 6.38 to 5.30 ng/mL[818].D) Hemofiltration

1) Dialyzable: Yes

[819]

CAUTIONS

Adverse Reactions

Cardiovascular EffectsCardiac dysrhythmia

1) Summary

a) Many types of arrhythmia can be seen with digitalis toxicity.The most common arrhythmias seen with digitalis toxicity areunifocal or multifocal ventricular premature complexes andnonparoxysmal atrioventricular (AV) junctional tachycardia.Bigeminal and trigeminal rhythms are also characteristic ofdigoxin toxicity. Digitalis-induced arrhythmias should be treatedby discontinuing digoxin therapy, determining potassium levels,and administering potassium chloride and antiarrhythmics asnecessary. In children and infants, arrhythmias are a morereliable indication of toxicity

[112].2) In 2 parallel, double-blind, placebo-controlled withdrawal trialsof patients stable on digoxin and also taking diuretics with orwithout ACE inhibitors, palpitations, ventricular extrasystole,tachycardia, and cardiac arrest were reported in less than 2% ofpatients taking digoxin (n=123) compared with 3% of patientstaking placebo[112].3) High doses of digoxin may cause first-degree, second-

degree, or third-degree heart block (including asystole);ventricular tachycardia; ventricular fibrillation; atrioventricular


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(AV) dissociation; accelerated junctional (nodal) rhythm; atrialtachycardia with block; and/or unifocal or multiform ventricularpremature contractions (especially bigeminy or trigeminy).Excessive slowing of the pulse is a potential clinical sign ofdigoxin toxicity

[112].4) Therapeutic doses of digoxin may cause heart block inpatients with preexisting sinoatrial or atrioventricular (AV)conduction disorders; heart block can be avoided by adjustingthe dose of digoxin. Additionally, digitalis-induced AV block mayproceed to complete heart block[112].5) In children and infants, gastrointestinal (nausea, vomiting,diarrhea) and CNS symptoms are rare as initial signs of toxicity,

but arrhythmias are a more reliable indication of toxicity.Although any type of arrhythmia is possible, the most commonlyreported are conduction disturbances or supraventriculartachyarrhythmias such as atrial tachycardia with or without blockand junctional (nodal) tachycardia. Ventricular arrhythmias areless common. Sinus bradycardia may also be seen, particularlyin infants, even in the absence of first-degree heart block. Anyalteration in cardiac conduction that develops in a child takingdigoxin should be assumed to be caused by digoxin until furtherevaluation proves otherwise[112].6) Exercise-induced ventricular tachycardia and a wide QRScomplex were reported in a patient 2 weeks after therapy withdigoxin (0.25 mg/day) had been instituted[116].7) Cardiac arrhythmias with acute exposure may be morepronounced than with chronic exposure. However, patients ondigoxin therapy in the absence of toxicity were no moresensitive than controls to induced cardiac arrhythmias by

electrical cardioversion[117].

Electrocardiogram abnormal1) Summary

a) ECG changes associated with digoxin use appear to affectatrioventricular conduction primarily. ECG changes aremanifested as T-wave depression or inversion, ST-segmentdepression or elevation, and prolonged PR interval. Toxicitymay mimic almost any arrhythmia

[118][119]


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; however, PR prolongation and ST-segment depression shouldnot by themselves be considered digoxin toxicity[112]. A prospective, randomized, placebo-controlled study alsoreported results that indicated IV administration of digoxin

produces marked changes on ECG in patients with recent-onsetatrial fibrillation[120].2) Results of a prospective, randomized, placebo-controlledstudy indicate that IV administration of digoxin produces markedchanges on ECG in patients with recent-onset atrial fibrillation(maximum 7 days duration). In this study, patients (n=167; meanage 66.7 years, range 21 to 89 years) received either IV placeboor digoxin (mean total dose 0.012 mg/kg; 0.92 mg). Comparedwith placebo, digoxin caused a significant prolongation of the

RR intervals (p less than 0.0001), a marginal increase in QRSwidth, and a significant decrease in ST-segment, T-waveamplitude, and QTc interval (p=0.009, p=0.002, and p=0.01,respectively). Digoxin produced these changes within 2 hoursafter the first dose and were more pronounced after 16 hours.There was no statistically significant correlation between digoxinserum concentration and changes in ECG or heart rate[120].3) Digitalis causes characteristic ECG changes within 2 to 4hours after a large dose. Changes first appear in the T waveand ST segment, which may occur alone or together. The Twave becomes diminished in amplitude, isoelectric, or inverted.The ST segment usually becomes depressed when the QRScomplex is upward, or may be elevated when the QRSdeflection is downward. The PR interval becomes prolonged(rarely greater than 0.25 second unless underlying conductiondisease exists) sometime after the T wave and ST segmentECG changes occur. Digitalis accelerates ventricularrepolarization causing the QT interval to shorten. In addition tothese changes, digitalis may simulate almost every possible

ECG tracing associated with heart disease, with the exception ofQRS widening[118].4) Toxic doses of digitalis may mimic almost any arrhythmia.Digitalis toxicity may include the following manifestations on theECG : SA (sinoatrial) block, sinus arrest, AV (atrioventricular)block, atrial tachycardia with block, atrial fibrillation with high-grade AV block, nonparoxysmal AV junctional tachycardia,complex ventricular premature beats, and ventriculartachycardia

[118][119]


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.Dermatologic Effects

Rash1) In 2 parallel, double-blind, placebo-controlled, withdrawaltrials, patients on stable doses of digoxin and concomitant

diuretics with or without ACE inhibitors were randomized todigoxin (n=123) or placebo (n=125). Rash was reported by 2patients treated with digoxin compared with 1 patient treatedwith placebo. Maculopapular rash has rarely been observed[112].2)Although rare, cases of erythematous, raised, pruritic rash,maculopapular rash, and Stevens-Johnson syndrome havebeen reported in patients receiving digitalis compounds[146][147]

.Endocrine/Metabolic Effects

Breast cancer1) In a population-based, prospective case-control study ofpostmenopausal Danish women (age 55 years and older),digoxin treatment was associated with a higher breast tumorincidence rate. Registries identified 5565 cases of incidentinvasive breast carcinoma diagnosed in postmenopausalwomen and 55,650 matched population controls. During thestudy period, there were 324 breast cancer cases (5.6%) and2546 controls (4.6%) identified with a history of digoxin use asthe sole cardiac glycoside. There was a higher incidence ofbreast cancer among digoxin users compared with nonusers inboth unadjusted and adjusted analyses (adjusted odds ratio(OR), 1.3; 95% confidence interval (CI), 1.14 to 1.48). Thebreast cancer OR was higher as duration of digoxin exposureincreased (adjusted OR, 1.39; 95% CI, 1.1 to 1.74 for 7 to 18years of digoxin use). An association between digoxin andincident breast cancer was still observed when the digoxin-exposed women were compared with an alternative referencegroup of unexposed women with cardiovascular medical

histories (adjusted OR, 1.42; 95% CI, 1.14 to 1.77). The resultswere robust with adjustment for age, confounding by indication,medical detection bias, and concurrent drug therapy withanticoagulants, NSAIDs, aspirin, and hormone replacementtherapy[126].

Gynecomastia1) Unilateral and bilateral gynecomastia have been reportedoccasionally after chronic therapy[112]

. These effects are usually reversible on drug discontinuation.Androstenedione, the immediate precursor of most naturally


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occurring estrogens, has the samecyclopentanoperhydrophenanthrene (steroid) chemical nucleusas digitalis glycosides. While the addition of different chemicalside chains significantly alters the effects of various substanceswith this nucleus, these structural similarities may be sufficient

to provide an explanation for the occurrence of certain digitalis-associated effects which appear estrogenic in nature[102][133][134][135][136][137][138].

Hypokalemia

1) Incidence: 9%[127][128][129][130][131]

2) Hypokalemia and/or hypomagnesemia predisposes patientsand facilitates the development of digitalis toxicity.Hypomagnesemia has been reported in 19% of patientsreceiving digitalis while only 9% have been shown to behypokalemic, suggesting that hypomagnesemia may more oftencontribute to the development of digitalis toxicity thanhypokalemia. Serum electrolyte levels, particularly potassiumand magnesium levels, should be routinely monitored in patientsreceiving digitalis glycosides[127][128][129][130][131]

.Hypomagnesemia1) Incidence: 19%[127][128][129][130][131]

2) Hypokalemia and/or hypomagnesemia predisposes patientsand facilitates the development of digitalis toxicity.

Hypomagnesemia has been reported in 19% of patientsreceiving digitalis while only 9% have been shown to be

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