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Lanoxin (Digoxin) - Drug Interactions, Contraindications, Overdosage, etc

 
 



DRUG INTERACTIONS

Digoxin has a narrow therapeutic index, increased monitoring of serum digoxin concentrations and for potential signs and symptoms of clinical toxicity is necessary when initiating, adjusting, or discontinuing drugs that may interact with digoxin. Prescribers should consult the prescribing information of any drug which is co-prescribed with digoxin for potential drug interaction information.

P-Glycoprotein (PGP) Inducers/Inhibitors

Digoxin is a substrate of P-glycoprotein. Drugs that induce or inhibit P-glycoprotein in intestine or kidney have the potential to alter digoxin pharmacokinetics.

Pharmacokinetic Drug Interactions

NA – Not available/reported

Digoxin concentrations increased greater than 50%

   Digoxin Serum   
Concentration Increase

   Digoxin AUC   
Increase

Recommendations

Amiodarone

70%

NA

Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing dose by approximately 30-50% or by modifying the dosing frequency and continue monitoring.

Captopril

58%

39%

Clarithromycin

NA

70%

Dronedarone

NA

150%

Gentamicin

129-212%

NA

Erythromycin

100%

NA

Itraconazole

80%

NA

Nitrendipine

57%

15%

Propafenone

NA

60-270%

Quinidine

100%

NA

Ranolazine

50%

NA

Ritonavir

NA

86%

Tetracycline

100%

NA

Verapamil

50-75%

NA

Digoxin concentrations increased less than 50%

Atorvastatin

22%

15%

Measure serum digoxin concentrations before initiating concomitant drugs. Reduce digoxin concentrations by decreasing the dose by approximately 15-30% or by modifying the dosing frequency and continue monitoring.

Carvedilol

16%

14%

Diltiazem

20%

NA

Indomethacin

40%

NA

Nefazodone

27%

15%

Nifedipine

45%

NA

Propantheline

24%

24%

Quinine

NA

33%

Saquinavir

27%

49%

Spironolactone     

25%

NA

Telmisartan

20-49%

NA

Tolvaptan

30%

NA

Trimethoprim

22-28%

NA

Digoxin concentrations increased, but magnitude is unclear

Alprazolam, azithromycin, cyclosporine, diclofenac,
diphenoxylate, epoprostenol, esomeprazole, ibuprofen,
ketoconazole, lansoprazole, metformin, omeprazole,
rabeprazole,

Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and reduce digoxin dose as necessary.

Digoxin concentrations decreased

Acarbose, activated charcoal, albuterol, antacids, certain
cancer chemotherapy or radiation therapy, cholestyramine,
colestipol, extenatide, kaolin-pectin, meals high in bran,
metoclopramide, miglitol, neomycin, penicillamine,
phenytoin, rifampin, St. John’s Wort, sucralfate,
sulfasalazine

Measure serum digoxin concentrations before initiating concomitant drugs. Continue monitoring and increase digoxin dose by approximately 20-40% as necessary.

No significant Digoxin exposure changes

Please refer to section 12 for a complete list of drugs which     
were studied but reported no significant changes on digoxin exposure.

No additional actions are required.     

Potentially Significant Pharmacodynamic Drug Interactions

Because of considerable variability of pharmacodynamic interactions, the dosage of digoxin should be individualized when patients receive these medications concurrently.

Drugs that Affect Renal Function

A decline in GFR or tubular secretion, as from ACE inhibitors, angiotensin receptor blockers, nonsteroidal anti-inflammatory drugs [NSAIDS], COX-2 inhibitors may impair the excretion of digoxin.

Antiarrthymics

Dofetilide

Concomitant administration with digoxin was associated with a higher rate of torsades de pointes

Sotalol

Proarrhythmic events were more common in patients receiving sotalol and digoxin than on either alone; it is not clear whether this represents an interaction or is related to the presence of CHF, a known risk factor for proarrhythmia, in patients receiving digoxin.

Dronedarone

Sudden death was more common in patients receiving digoxin with dronedarone than on either alone; it is not clear whether this represents an interaction or is related to the presence of advanced heart disease, a known risk factor for sudden death in patients receiving digoxin.

Parathyroid Hormone Analog

Teriparatide

Sporadic case reports have suggested that hypercalcemia may predispose patients to digitalis toxicity. Teriparatide transiently increases serum calcium.

Thyroid supplement

Thyroid

Treatment of hypothyroidism in patients taking digoxin may increase the dose requirements of digoxin.

Sympathomimetics

Epinephrine
Norepinephrine     
Dopamine

Can increase the risk of cardiac arrhythmias

Neuromuscular Blocking Agents     

Succinylcholine

May cause sudden extrusion of potassium from muscle cells causing arrhythmias in patients taking digoxin.

Supplements

Calcium

If administered rapidly by intravenous route, can produce serious arrhythmias in digitalized patients.

Beta-adrenergic blockers and calcium channel blockers

Additive effects on AV node conduction can result in bradycardia and advanced or complete heart block.

Drug/Laboratory Test Interactions

Endogenous substances of unknown composition (digoxin-like immunoreactive substances, [DLIS]) can interfere with standard radioimmunoassays for digoxin. The interference most often causes results to be falsely positive or falsely elevated, but sometimes it causes results to be falsely reduced. Some assays are more subject to these failings than others. Several LC/MS/MS methods are available that may provide less susceptibility to DLIS interference. DLIS are present in up to half of all neonates and in varying percentages of pregnant women, patients with hypertrophic cardiomyopathy, patients with renal or hepatic dysfunction, and other patients who are volume-expanded for any reason. The measured levels of DLIS (as digoxin equivalents) are usually low (0.2-0.4 ng/mL), but sometimes they reach levels that would be considered therapeutic or even toxic.

In some assays, spironolactone, canrenone, and potassium canrenoate may be falsely detected as digoxin, at levels up to 0.5 ng/mL. Some traditional Chinese and Ayurvedic medicine substances like Chan Su, Siberian Ginseng, Asian Ginseng, Ashwagandha or Dashen, can cause similar interference.

Spironolactone and DLIS are much more extensively protein-bound than digoxin. As a result, assays of free digoxin levels in protein-free ultrafiltrate (which tend to be about 25% less than total levels, consistent with the usual extent of protein binding) are less affected by spironolactone or DLIS. It should be noted that ultrafiltration does not solve all interference problems with alternative medicines. The use of an LC/MS/MS method may be the better option according to the good results it provides, especially in terms of specificity and limit of quantization.

OVERDOSAGE

Signs and Symptoms in Adults and Children

The signs and symptoms of toxicity are generally similar to those described in the Adverse Reactions (6.1) but may be more frequent and can be more severe. Signs and symptoms of digoxin toxicity become more frequent with levels above 2 ng/mL. However, in deciding whether a patient’s symptoms are due to digoxin, the clinical state together with serum electrolyte levels and thyroid function are important factors [see Dosage and Administration (2)].

Adults: The most common signs and symptoms of digoxin toxicity are nausea, vomiting, anorexia, and fatigue that occur in 30-70% of patients who are overdosed. Extremely high serum concentrations produce hyperkalemia especially in patients with impaired renal function. Almost every type of cardiac arrhythmia has been associated with digoxin overdose and multiple rhythm disturbances in the same patient are common. Peak cardiac effects occur 3-6 hours following ingestion and may persist for 24 hours or longer. Arrhythmias that are considered more characteristic of digoxin toxicity are new-onset Mobitz type 1 A-V block, accelerated junctional rhythms, non-paroxysmal atrial tachycardia with A-V block, and bi-directional ventricular tachycardia. Cardiac arrest from asystole or ventricular fibrillation is usually fatal.

Digoxin toxicity is related to serum concentration. As digoxin serum levels increase above 1.2 ng/mL, there is a potential for increase in adverse reactions. Furthermore, lower potassium levels increases the risk for adverse reactions. In adults with heart disease, clinical observations suggest that an overdose of digoxin of 10-15 mg results in death of half of patients. A dose above 25 mg ingested by an adult without heart disease appeared to be uniformly fatal if no Digoxin Immune Fab (DIGIBIND®, DIGIFAB®) was administered.

Among the extra-cardiac manifestations, gastrointestinal symptoms (e.g., nausea, vomiting, anorexia) are very common (up to 80% incidence) and precede cardiac manifestations in approximately half of the patients in most literature reports. Neurologic manifestations (e.g., dizziness, various CNS disturbances), fatigue, and malaise are very common. Visual manifestations may also occur with aberration in color vision (predominance of yellow green) the most frequent. Neurological and visual symptoms may persist after other signs of toxicity have resolved. In chronic toxicity, non-specific extra-cardiac symptoms, such as malaise and weakness, may predominate.

Children: In pediatric patients, signs and symptoms of toxicity can occur during or shortly after the dose of digoxin. Frequent non-cardiac effects are similar to those observed in adults although nausea and vomiting are not seen frequently in infants and small pediatric patients. Other reported manifestations of overdose are weight loss in older age groups, failure to thrive in infants, abdominal pain caused by mesenteric artery ischemia, drowsiness, and behavioral disturbances including psychotic episodes. Arrhythmias and combinations of arrhythmias that occur in adult patients can also occur in pediatric patients although sinus tachycardia, supraventricular tachycardia, and rapid atrial fibrillation are seen less frequently in pediatric patients. Pediatric patients are more likely to develop A-V conduction disturbances, or sinus bradycardia. Any arrhythmia in a child treated with digoxin should be considered related to digoxin until otherwise ruled out. In pediatric patients aged 1-3 years without heart disease, clinical observations suggest that an overdose of digoxin of 6-10 mg would result in death of half of the patients. In the same population, a dose above 10 mg resulted in death if no Digoxin Immune Fab were administered.

Treatment

Chronic Overdose

If there is suspicion of toxicity, discontinue LANOXIN and place the patient on a cardiac monitor. Correct factors such as electrolyte abnormalities, thyroid dysfunction, and concomitant medications [see Dosage and Administration ]. Correct hypokalemia by administering potassium so that serum potassium is maintained between 4.0 and 5.5 mmol/L. Potassium is usually administered orally, but when correction of the arrhythmia is urgent and serum potassium concentration is low, potassium may be administered by the intravenous route. Monitor electrocardiogram for any evidence of potassium toxicity (e.g., peaking of T waves) and to observe the effect on the arrhythmia. Avoid potassium salts in patients with bradycardia or heart block. Symptomatic arrhythmias may be treated with Digoxin Immune Fab.

Acute Overdose

Patients who have intentionally or accidently ingested massive doses of digoxin should receive activated charcoal orally or by nasogastric tube regardless of the time since ingestion since digoxin recirculates to the intestine by enterohepatic circulation. In addition to cardiac monitoring, temporarily discontinue LANOXIN until the adverse reaction resolves. Correct factors that may be contributing to the adverse reactions [see Warnings and Precautions (5)]. In particular, correct hypokalemia and hypomagnesemia. Digoxin is not effectively removed from the body by dialysis because of its large extravascular volume of distribution. Life threatening arrhythmias (ventricular tachycardia, ventricular fibrillation, high degree A-V block, bradyarrhythma, sinus arrest) or hyperkalemia requires administration of Digoxin Immune Fab. Digoxin Immune Fab has been shown to be 80-90% effective in reversing signs and symptoms of digoxin toxicity. Bradycardia and heart block caused by digoxin are parasympathetically mediated and respond to atropine. A temporary cardiac pacemaker may also be used. Ventricular arrhythmias may respond to lidocaine or phenytoin. When a large amount of digoxin has been ingested, especially in patients with impaired renal function, hyperkalemia may be present due to release of potassium from skeletal muscle. In this case, treatment with Digoxin Immune Fab is indicated; an initial treatment with glucose and insulin may be needed if the hyperkalemia is life-threatening. Once the adverse reaction has resolved, therapy with LANOXIN may be reinstituted following a careful reassessment of dose.

CONTRAINDICATIONS

LANOXIN is contraindicated in patients with:

  • •Ventricular fibrillation [see Warnings and Precautions]
  • •Known hypersensitivity to digoxin (reactions seen include unexplained rash, swelling of the mouth, lips or throat or a difficulty in breathing). A hypersensitivity reaction to other digitalis preparations usually constitutes a contraindication to digoxin.

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