P&T News: February 1997

A Practical Approach to Digoxin Serum Level Sample Monitoring

Timothy G. Burke, Pharm.D. and Douglas E. Morgan, M.S.
Peer Review Status: Internally Peer Reviewed by John W. McBride, M.D., Division of Cardiovascular Diseases, Department of Internal Medicine

Digoxin has a narrow therapeutic index and medication-related toxicity is reported in as many as 5 to 23% of digoxin recipients.4 This narrow margin between toxic and non-toxic serum digoxin concentrations, coupled with substantial variability among patients, has led to the routine use of serum digoxin concentration to guide therapy.

While the monitoring of serum digoxin concentrations may be a valuable tool, inappropriate use of assay results remains an important concern.5 Inappropriate use may adversely affect patient care decisions and add cost to patient therapy. Inappropriate serum digoxin concentration monitoring often stems from a failure to interpret basic pharmacokinetic properties of the cardiac glycoside within the specific clinical setting.

This review will focus on the pharmacokinetics of digoxin and the role of digoxin serum assays in patient care, including common problems in the serum sampling process. The results of a recent Drug Use Evaluation of the use of inpatient digoxin serum assays at UIHC are discussed. Recommendations are presented that may help to reduce inappropriate use of serum digoxin assay results. Guidelines for digoxin dosing and dosage adjustments based on the results of serum assays are beyond the scope of this review, but are reviewed in detail elsewhere.6-9 Clinical pharmacy staff are available to provide patient-focused advice regarding digoxin therapy or interpretation of digoxin serum assay results.

Pharmacokinetic Properties of Digoxin
(Table 1) and concomitant medications. Medications that can affect absorption include kaolin-pectin suspensions, cholestyramine, and aluminum- containing antacids (Table 2). These drugs physically bind digoxin and should be administered at least two hours after the digoxin to prevent the interaction.' In a number of patients (possibly as high as 10%), erythromycin and tetracycline may increase the bioavailability of digoxin by preventing its metabolism by bacteria (Eubacterium lentum) located in the gastrointestinal tract.

Digoxin has a large volume of distribution and alterations in distribution can have an impact on both serum levels and therapeutic effects. Dosing of digoxin should be based on ideal body weight as digoxin has little affinity for adipose tissue. Digoxin loading doses based on actual body weight in obese individuals can result in higher than expected serum levels and greater than expected pharmacologic effects. Certain disease states and medications (Tables 2 and 3) can have an effect on digoxin's volume of distribution and this must be taken into account when assessing digoxin assay results. Digoxin distribution follows a two-compartment model and this must be considered when interpreting serum levels. Serum levels drawn before distribution is complete will be falsely elevated. To be meaningful, digoxin serum levels should be obtained AT LEAST C to 8 hours after an intravenous dose and AT LEAST 8 to 12 hours after an oral dose.

Since digoxin is primarily excreted by the kidneys, renal disease can substantially alter the half-life and serum levels of digoxin (Table l). Other patient conditions that can alter the renal elimination of digoxin include pregnancy and congestive heart failure (Table 3). Drugs which alter the renal and nonrenal clearance of digoxin are discussed in Table 2. In most patients only small amounts of digoxin are metabolized, but this can vary substantially between patients. It is known that anuric patients eliminate approximately 14% of the total body stores of digoxin daily via nonrenal mechanisms.9 A significant amount of digoxin undergoes enterohepatic circulation; this amount may be as high as 30% of the total body stores.6,7,10

Digoxin has a 36-hour half-life in patients with normal renal function. When a drug is first initiated, it takes a total of four half-lives for the drug to reach the steady state serum level (assuming continued dosing of the drug). In the case of digoxin, four half-lives would be 144 hours or 6 days. For this reason drawing digoxin levels 1 to 2 days after the drug is started or a dose change implemented will not be representative of the serum levels from chronic administration.

Table 1. Pharmacokinetic Parameters of Digoxin^a

Oral Absorption	75% (tablets) 85% (elixir) 95% (capsule)
Volume of Distribution: Normal Renal Function Renal Failure	7.3 L/kg (Ideal Body Weight) 4.7 L/kg (Ideal Body Weight)
Nonrenal Eliminatiohn: Renal Elimination: Enterohepatic Circulation: Half Life (Normal Renal Function): Half Life (End Stage Renal Disease):	14% 86% Up to 30% 36 hours 120 hours

^a Adapted from references 3, 6-9

Table 2. Drug-Drug Interactions^a

Drug Affecting Digoxin Serum Concentration	Mechanism of Drug Interaction Effect	Magnitude of Drug Interaction Effect	Recommendation to Minimize Effect
Antacids	Decreases oral absorption	Decrease up to 62%	Administer 2 hrs apart
Kaolin-Pectin	Decreases oral absorption	Decrease up to 20 to 35%	Administer 2 hrs apart
Cholestyramine	Decreases oral absorption	Decrease up to 20 to 35%	Administer 2 hrs apart
Erythromycin	Increases oral absorption	Increase up to 116%	Monitor digoxin levels
Tetracycline	Increases oral absorption	Increase up to 116%	Monitor digoxin levels
Quinidine	Decreases renal elimination, Decreases distribution volume	May double digoxin levels	Decrease digoxin load and maintenance dose by 50%
Verapamil	Decreases renal elimination	May double digoxin levels	Decrease digoxin dose by 50%
Amiodarone	Decreases renal elimination	May double digoxin levels	Decrease digoxin dose by 50%
Potassium salts	Hypokalemia increases digoxin effects Hyperkalemia decreases digoxin effects	Life-threatening complications have been reported	Monitor potassium and digoxin levels

^a Adapted from references 6-8.

Table 3. Disease State Effects on the Pharmacokinetic Parameters of Digoxin^a

Disease	Pharmacokinetic Effect	Recommendation to Minimize Effect
Renal Failure	Decreased elimination Decreased volume of distribution	Decrease maintenance dose Decrease loading dose by 35%
Pregnancy	Increased volume of distribution	Adjust dose as necessary
Hypothyroidism	Decreased volume of distribution	Adjust dose as necessary
Congestive Heart Failure	Decreased volume of distribution	Adjust dose as necessary

^a Adapted from reference 6-8.

Serum Digoxin Assays in Patient Care
The typically defined therapeutic range of serum digoxin concentrations is 1 to 2 ng/ml.8 Digoxin concentrations of 2 to 3 ng/ml are sometimes required for patients with an inadequate ventricular slowing in management of atrial fibrillation.6 Despite a significant overlap between effective and toxic digoxin serum concentrations found in some studies,11 the appropriate measurement of serum digoxin concentrations may reduce the frequency of digoxin toxicity.4,11

Unnecessary serum digoxin assays or inappropriate digoxin serumsampling techniques have been reported for 30 to 73% of serum digoxin assay requests.5,l2 Inappropriate timing and incomplete documentation can contribute to clinically inappropriate patient-care decisions.13 Typical problems in the digoxin serum sampling process are described in Table 4.

Daily digoxin levels in a stable patient will yield little useful information as the daily differences between the levels will not be clinically significant. Therefore, digoxin levels should be drawn at steady state (i.e., at least 3 to 5 days) after new therapy or dose changes. Exceptions to this would be limited to unusual circumstances such as the need to rule out digoxin toxicity in a symptomatic patient or the need to evaluate a digoxin level after a loading dose has been given to hasten the attainment of steady-state.

Table 4. Digoxin Serum Sampling: Problems and Pitfalls

Sampling Problem	Result
Sample drawn before steady-state has been attained	Falsely low assay result. Inappropriate dose increase.
Sample dran too soon after administration of dose	Falsely high assay result. Inappropriate dose reduction.
No clear indication for sampling: Stable patient Disease controlled No toxicity or toxicity risk	No clinical benefit. Wasted resources.
Samples drawhn too frequently	No clinical benefit. Wasted resources.
Incomplete documentation Last dose (dosage form and strength) Date and time of last dose Date and time assay specimen drawn	Cannot interpret assay result. Misinterpreted assay result.

Consensus-based criteria for appropriate indications for digoxin serum assays, coupled with proper digoxin serum sampling procedures, may reduce inappropriate digoxin serum sampling. UIHC guidelines have been developed and approved by Cardiology faculty, and the Drug Use Evaluation and Pharmacy and Therapeutics Subcommittees (Tables 5 and 6).

Table 5. Indications for Digoxin Serum Level Monitoring

• Baseline steady-state serum level for new digoxin therapy (wait at least 3 to 5 days).
• Steady-state level after digoxin maintenance dose change (wait at least 3 to 5 days).
• Rule out digoxin toxicity in symptomatic patients.
• Rule out digoxin accumulation (to reduce toxicity risk) in patients with changing renal function.
• Confirm therapeutic serum level in patients with uncontrolled disease (e.g., elevated heart rate).
  1. Evaluate suspected patient compliance problems
  2. Evaluate the need for maintenance digoxin dose change
  3. Evaluate digoxin level after loading dose to assist in acute management.
• Steady-state level after adding or deleting a second drug known to affect digoxin concentration.
• Digoxin assays do not need to be repeated in patients with stable clinical condition at steady-state.
  1. Weekly qt assays may be helpful for select patients with changing clinical conditions.
  2. Assays do not need to be repeated more often than twice weekly unless one of the above criteria is met.
  3. Daily digoxin assays are unnecessary, waste hospital resources, and inconvenience the patient.

Table 6. Suggested Digoxin Serum Level Sampling Procedures

• Draw digoxin levels at steady state (at least 3 to S days after dose changes or addition of new therapies).
• Exceptions to drawing levels before steady state is reached:
  1. Need to confirm or rule out digoxin toxicity in a symptomatic patient.
  2. Need to evaluate digoxin level after an IV/PO loading dose to help establish acute control of dysrhythmia (at least 6 hrs after IV and 8 hrs after PO loading dose).
• Avoid premature sampling after a digoxin dose. Levels should be drawn no sooner than 6 to 8 hours after an IV dose and 8 to 12 hours after a PO dose.
  1. Before drawing digoxin samples at the above times, confirm the time that the dose was given and document the date and time of both the last dose and sampling time on the A-la Doctor's Order for Therapeutic Drug Assay.
  2. For warranted admission digoxin assays, ask the exact time of last dose (+t- an hour) given at home.
  3. Clarification of last dose time is imperative before a digoxin specimen is drawn.
• Document the time of the last digoxin dose and the assay draw time on the A-la Doctor's Order for Therapeutic Drug Assay form. All digoxin assay requests must be made through this form. Do not use Miscellaneous Form 0-4 or other requisition forms.

The results of serum digoxin serum sampling must be interpreted in the context of patient care. The adage "do not treat the number, treat the patient" holds true for digoxin serum assay results. Digoxin efficacy and toxicity are a result of a complex interplay that includes not only the serum digoxin concentration, but also concurrent electrolyte status (e.g., potassium, calcium), acid-base balance, underlying cardiac disease (e.g., prior myocardial infarction, advanced coronary artery disease), hypoxia (e.g., severe respiratory distress), thyroid status, and concurrent drug therapy.6 These factors should be considered before ordering digoxin serum assays or when interpreting assay results (Table 7). An unexpectedly high or low serum digoxin assay result should be viewed with initial skepticism in a patient with adequate disease control and no signs or symptoms of digoxin toxicity .In patients with toxicity, the assay result, coupled with the expected half-life of the drug, can help to determine how long to withhold digoxin therapy. In poorly controlled patients with digoxin assays drawn at steady state, an increase in dose will lead to a proportional rise in the subsequent steady state digoxin serum concentration 3 to 4 half-lives following the dose change. Poorly controlled disease, despite "therapeutic" digoxin serum concentrations (i.e., digoxin concentrations at the upper end of the normal range for the condition treated), suggests a possible need for additional or alternative drug therapy.

Table 7. Checklist When Ordering and Evaluating Digoxin "Levels"

• Is the patient's disease controlled?
• Does the patient show signs or symptoms of digoxin toxicity?
• Are the patient's electrolytes normal?
  • potassium, calcium, magnesium
• Interacting drugs that decrease oral absorption?
  • kaolin-pectin, cholestyramine, aluminum-containing antacids
• Interacting drugs that decrease volume of distribution or reduce the clearance of digoxin, resulting in a subsequent rise in serum digoxin concentration?
  • amiodarone, quinidine, verapamil
• Have all digoxin doses been administered?
  • check nursing cardex, discuss with nurse for inpatients
  • evaluate outpatient compliance upon admission or at clinic visit
• What was the time (and date) of the last administered dose of digoxin?
  • confirm with patient, family or nurse as appropriate
  • more than 6 to 8 hrs after IV dose, 8 to 12 hrs after PO dose (preferably 12 to 24 hrs after dose)
• How long has the patient been on a stable dose of digoxin?
  • at least 3 days (preferably 5 to 7 days)
  • in ESRD, as long as 10 to 14 days
• Appropriate therapeutic drug assay request form used?
  • use A-la Doctor's Order for Therapeutic Drug Assay

Conclusions and Recommendations
Unnecessary or inappropriate serum digoxin assays may occur in more than 30 % of requested assays. Greater consideration of digoxin pharmacokinetics may reduce common serum sampling problems which include: 1) sampling too soon following a digoxin dose; 2) sampling before a steady-state serum digoxin concentration has been reached; 3) sampling too frequently; and 4) clinically unnecessary sampling.

Consensus-based criteria for appropriate indications for requesting a digoxin serum assay, coupled with specific recommendations for appropriate digoxin serum sampling procedures, may help reduce inappropriate digoxin serum sampling. UIHC guidelines have been developed and approved by Cardiology faculty physicians, the Drug Use Evaluation Subcommittee, and the Pharmacy and Therapeutics Subcommittee (Tables 5 and 6).

References

1. Pharmacy Times 1996; 62(4):27-36.

2. Konstam M, Dracup K, Baker D, et al. Heart Failure: Evaluation and Care of Patients With Left-Ventricular Systolic Dysfunction. Clinical Practice Guideline No. 11. AHCPR Publication No. 94-0612. Rockville, MD: Agency for Health Care Policy and Research, Public Health Service, U.S. Department of Health and Human Services. June 1994;49-66.

3. Burroughs Wellcome Co. Lanoxin tablets package insert.. Research Triangle Park, N.C.: 1995 February.

4. Clin Pharmacol Ther 1974;16:284-7.

5. Ther Drug Monitor 1992;14:155-8.

6. Applied Pharmacokinetic, Principles of Therapeutic Drug Monitoring, 3rd Edition. Vancouver: Applied Therapeutic, Inc.; 1992; 20/1-20/48.

7. Basic Clinical Pharmacokinetic, 3rd Edition. Vancouver: Applied Therapeutic, Inc.;1994;198-235.

8. Therapeutic Drug Monitoring. Norwalk, CT: Appleton ~ Lango; 1995;469-91.

9. American Hospital Formulary Service: Drug Information 96. Bethesda, MD: American Society of Health-System Pharmacists; 1996; 1096-8.

10. Clin Pharmacol Ther 1985;37:367-71.

11. J Clin Invest 1970;49:2377-86.

12. Can J Hosp Pharm 1978;31:97-9.

13. Heart D;s Stroke 1992; 1:117-22.

PHARMACY AND THERAPEUTIC SUBCOMMITTEE ACTIONS

Drugs Added to Stock

CEFEPIME Injection: I g and 2 g Cefepime (Maxipime. - BMS) is a "fourth-generation" cephalosporin similar in spectrum of activity to ceftazidime, with the advantages of better gram-positive coverage and less resistance to beta-lactamase producing strains of bacteria.

NOTE: Cefepime has been designated as a protocol drug. See the January 1997 issue of the P&T News for a detailed review of cefepime and the criteria for use.

FOSPHENYTOIN Injection: 50 mg P.E. per ml Fosphenytoin (Cerebyx. - Parke-Davis) is a pro-drug of phenytoin intended for short term (S 5 days) use in seizure control. To avoid dosing errors, fosphenytoin must be prescribed in phenytoin equivalents (i.e., mg P.E.)

NOTE: Due to the high cost of fosphenytoin and its lack of a clear advantage over phenytoin in many clinical settings, fosphenytoin has been designated a protocol drug. Prescribing is restricted to the following settings/clinical situations:

EMERGENCY THERAPY (therapeutic phenytoin concentrations needed within 20 minutes): Note: Infuse I. V. fosphenytoin at a rate of 100 to 150 mg P.E. /min to avoid delayed onset.

• Emergency transport,(before or during helicopter or ambulance transport).
• Poor venous access (e.g., vein in dorsum of hand, 20 or more than gauge needle or I.V. cannula).
• Prior history of DOCUMENTED phenytoin-related cardiovascular toxicity at an 1. V. phenytoin infusion rate s 25 mg/min or patient with concurrent hypotension or significant cardiovascular compromise.

URGENT THERAPY (therapeutic phenytoin concentrations can be delayed up to 4 hours):

• Venous access is unavailable (I.M. fosphenytoin only).
• A monitored bed is unavailable or not feasible (I.M. fosphenytoin only).
• Prior history of DOCUMENTED phenytoin-related cardiovascular toxicity at an 1. V. phenytoin infusion rate s 25 mg/min (LM. fosphenytoin OR l.V. fosphenytoin infused at a rate of S150 mg P.E./min for patient in monitored bed).

ROUTINE THERAPY (therapeutic phenytoin concentrations can be delayed for over 4 hours):

• P.O./N.G. phenytoin is not feasible AND venous access is unavailable (I.M. fosphenytoin only).
• P.O./N.G. phenytoin is not feasible AND phenytoin dose is greater than 300 mg AND a monitored bed is unavailable or not feasible (L M. fosphenytoin only).
• P.O./N.G. phenytoin is not feasible AND patient has a DOCUMENTED phenytoin-related cardiovascular toxicity at an 1. V. phenytoin infusion rale of s 25 mg/min (I.M. fosphenytoin OR 1. V. fosphenytoin infused at a rate of S150 mg P.E./min for patient in monitored bed).

Additional Actions
CETIRIZINE ORAL LIQUID ( ZYRTEC.) The 1 mg per ml oral liquid was added to stock.

DIAZEPAM EMULSIFIED INJECTION (DIZAC.) The product is now available as a 10 mg per 2 ml ampule. The 3 ml vial has been discontinued by the manufacturer.

NOTE: The coat following each brief monograph is the UIHC acquisition coat.

Drugs Deleted from Stock
AMOXICILLIN/CLAVULANATE The 250 mg tablets, 250 mg chewable tablets, and the 250 mg per 5 ml oral suspension (three-times- per-day dosing products) were deleted from stock; twice daily dosing preparations are available. See the November 1996 issue of the P&T News for the dosage conversion chart.

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