Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2019 Publisher: Accord-UK Ltd (Trading style: Accord), Whiddon Valley, Barnstaple, Devon, EX32 8NS
Patients receiving digoxin should have their serum electrolytes and renal function (serum creatinine concentration) assessed periodically; the frequency of assessments will depend on the clinical setting.
Serum concentrations of digoxin may be expressed in Conventional Units of nanograms/ml or SI Units of nanomol/l. To convert nanograms/ml to nanomol/l, multiply nanograms/ml by 1.28.
The serum concentration of digoxin can be determined by radioimmunoassay.
Blood should be taken six hours or more after the last dose of digoxin.
There are no rigid guidelines as to the range of serum concentrations that are most efficacious. Post hoc analyses of heart failure patients in the Digitalis Investigation Group trial suggest that the optimal trough digoxin serum level may be 0.5 nanogram/ml (0.64 nanomol/l) to 1.0 nanogram/ml (1.28 nanomol/l).
Digoxin toxicity is more commonly associated with serum digoxin concentrations greater than 2 nanogram/ml. However, serum digoxin concentration should be interpreted in the clinical context. Toxicity may occur with lower digoxin serum concentrations. In deciding whether a patient’s symptoms are due to digoxin, the clinical state together with the serum potassium level and thyroid function are important factors (see Section 4.9).
Determination of the serum digoxin concentration may be very helpful in making a decision to treat with further digoxin, but other glycosides and endogenous digoxin-like substances, including metabolites of digoxin, can interfere with the assays that are available and one should always be wary of values which do not seem commensurate with the clinical state of the patient. Observations while temporary withholding digoxin might be more appropriate.
Arrhythmias may be precipitated by digoxin toxicity, some of which can resemble arrhythmias for which the drug could be advised (e.g. atrial tachycardia with varying atrioventricular block requires care as clinically the rhythm resembles atrial fibrillation).
Many beneficial effects of digoxin on arrhythmias result from a degree of atrioventricular conduction blockade. However, when incomplete atrioventricular block already exists the effects of a rapid progression in the block should be anticipated. In complete heart block the idioventricular escape rhythm may be suppressed.
In some cases of sinoatrial disorder (i.e. sick sinus syndrome) digoxin may cause or exacerbate sinus bradycardia or cause sinoatrial block.
The administration of digoxin in the period immediately following myocardial infarction is not contraindicated. However, the use of inotropic drugs in some patients in this setting may result in undesirable increases in myocardial oxygen demand and ischaemia, and some retrospective follow-up studies have suggested digoxin to be associated with an increased risk of death. The possibility of arrhythmias arising in patients who may be hypokalaemic after myocardial infarction and are likely to be haemodynamically unstable must be borne in mind. The limitations imposed thereafter on direct current cardioversion must also be remembered.
Treatment with digoxin should generally be avoided in patients with heart failure associated with cardiac amyloidosis. However, if alternative treatments are not appropriate, digoxin can be used to control the ventricular rate in patients with cardiac amyloidosis and atrial fibrillation.
Digoxin can rarely precipitate vasoconstriction and therefore should be avoided in patients with myocarditis.
Patients with beri-beri heart disease may fail to respond adequately to digoxin if the underlying thiamine deficiency is not treated concomitantly.
Digoxin should not be used in constrictive pericarditis unless it is used to control the ventricular rate in atrial fibrillation or to improve systolic dysfunction.
Digoxin improves exercise tolerance in patients with impaired left ventricular systolic dysfunction and normal sinus rhythm. This may or may not be associated with an improved haemodynamic profile. However, the benefit of digoxin in patients with supraventricular arrhythmias is most evident at rest, less evident with exercise.
In patients receiving diuretics and an ACE inhibitor, or diuretics alone, the withdrawal of digoxin has been shown to result in clinical deterioration.
The use of therapeutic doses of digoxin may cause prolongation of the PR interval and depression of the ST segment on the electrocardiogram.
Digoxin may produce false positive ST-T changes on the electrocardiogram during exercise testing. These electrophysiologic effects reflect an expected effect of the drug and are not indicative of toxicity.
Hypokalaemia sensitises the myocardium to the actions of cardiac glycosides. Digoxin should be used with caution in patients taking drugs that may cause hypokalaemia (see section 4.5). Hypokalaemia may also accompany malnutrition, diarrhoea, vomiting and long standing wasting disease and the dose may be need to be reduced in such patients. Hypomagnesaemia and marked hypercalcaemia also increase myocardial sensitivity to cardiac glycosides.
Administering digoxin to a patient with thyroid disease requires care. Initial and maintenance doses of digoxin should be reduced when thyroid function is subnormal. In hyperthyroidism there is relative digoxin resistance and the dose may have to be increased. During the course of treatment of thyrotoxicosis, dosage should be reduced as the thyrotoxicosis comes under control.
Patients with malabsorption syndrome or gastro-intestinal reconstructions may require larger doses of digoxin.
Direct current cardioversion is the preferred method of treatment for atrial flutter. The risk of provoking dangerous arrhythmias with direct current cardioversion is greatly increased in the presence of digitalis toxicity and is in proportion to the cardioversion energy used.
For elective direct current cardioversion of a patient who is taking digoxin, the drug should be withheld for 24 hours before cardioversion is performed. In emergencies, such as cardiac arrest, when attempting cardioversion the lowest effective energy should be applied. Direct current cardioversion is inappropriate in the treatment of arrhythmias thought to be caused by cardiac glycosides.
The administration of digoxin in the period immediately following myocardial infarction is not contraindicated. However, the possibility of arrhythmias arising in patients who may be hypokalaemic after myocardial infarction and are likely to be cardiologically unstable must be borne in mind. The limitations imposed thereafter on direct current-cardioversion must also be remembered.
Although many patients with chronic congestive cardiac failure benefit from acute administration of digoxin, there are some in which it does not lead to constant, marked or lasting haemodynamic improvement. It is therefore important to evaluate the response of each patient individually when digoxin is continued long-term.
Patients with severe respiratory disease may have increased myocardial sensitivity to digitalis glycosides.
Patients with malabsorption syndrome or gastrointestinal reconstruction may require larger doses of digoxin.
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take digoxin.
These may arise from effects on the renal excretion, tissue binding, plasma protein binding, distribution within the body, gut absorptive capacity and sensitivity to digoxin. Consideration of the possibility of an interaction whenever concomitant therapy is contemplated is the best precaution and a check on serum digoxin level is recommended when any doubt exists.
Digoxin is a substrate of P-glycoprotein. Thus, inhibitors of P-glycoprotein (e.g. clarithromycin, telithromycin, nefazodone, itraconazole, ketoconazole, atazanavir, darunavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, tipranavir) may increase blood concentrations of digoxin by enhancing its absorption and/or by reducing its renal clearance (see Section 5.2). Induction of P-glycoprotein can result in decreases in plasma concentrations of digoxin.
Amiodarone: plasma levels of digoxin are considerably increased by concurrent administration of amiodarone. This is due to a decrease in the renal and non-renal clearance of digoxin, a prolongation of its half life and a possible increase in absorption. Children are especially sensitive. The dose of digoxin should be reduced by a third to a half when it is given concurrently with amiodarone. Disopyramide may modify the cardiovascular effects of digoxin and reduce its volume of distribution. The loading dose of digoxin should be reduced in patients who are also receiving disopyramide.
Flecainide: plasma levels of digoxin are increased by concurrent administration of flecainide. This is likely to be clinically significant only in patients with high plasma levels of digoxin or those with atrioventricular nodal dysfunction.
Moracizine: digoxin and moracizine have additive effects on cardiac conduction.
Propafenone: plasma levels of digoxin are increased by concurrent administration of propafenone. There is considerable interindividual variation in the extent of this interaction but the dose of digoxin should be reduced and patients monitored for signs of digoxin toxicity.
Quinidine: the renal and non-renal excretion of digoxin is reduced by co-administration of digoxin. Excretion in bile and tissue binding of digoxin may also be reduced Significant effects occur as soon as quinidine is given to a patient stabilised on digoxin and plasma levels of digoxin are usually doubled within 5 days. The dose of digoxin should be halved when quinidine is added to therapy and the possibility of an alternative anti-arrhythmic should be examined.
Macrolides, tetracycline: presystemic metabolism of digoxin to inactive metabolites in the gastrointestinal tract occurs in about 10% of patients. Co-administration of macrolide antibiotics (azithromycin, clarithromycin, erythromycin, telithromycin), gentamicin or tetracycline to this sub-group of patients can result in a clinically significant increase in plasma digoxin levels. Neomycin: absorption of digoxin from the gastrointestinal tract is inhibited by neomycin and plasma levels are reduced.
Rifampicin: the metabolism of digoxin may be increased by co-administration with rifampicin. The interaction may be enhanced in patients with renal impairment.
Trimethoprim: the renal excretion of digoxin is decreased by concurrent administration with trimethoprim. The interaction is more significant in elderly patients or those with renal impairment and digoxin plasma levels should be monitored.
Amphotericin: hypokalaemia due to amphotericin administration may potentiate digoxin toxicity. Patients should be monitored and given potassium supplements when necessary. Itraconazole can cause a marked increase in plasma digoxin levels and toxicity may occur if the dose of digoxin is not reduced. Itraconazole may also oppose the positive inotropic effects of digoxin. Quinine, hydroxychloroquine and chloroquine can increase plasma levels of digoxin by decreasing non-renal clearance.
Diltiazem and digoxin co-administration can result in increased digoxin plasma levels and toxicity and patients should be monitored. Nifedipine may increase digoxin plasma levels but there is considerable interindividual variation. Patients taking high doses of digoxin or those with renal impairment are most at risk. Nisoldipine may also increase plasma levels of digoxin but amlodipine, felodipine, isradipine, lercanidipine, nicardipine, nimodipine and nitrendipine do not appear to have significant effects on digoxin plasma levels but it is prudent to monitor the effects of co-administration. Verapamil increases plasma digoxin levels by inhibiting the active tubular secretion and non-renal clearance of digoxin. The dose of digoxin should be reduced and plasma levels monitored. Verapamil may also increase atrioventricular block and tachycardia in patients taking digoxin.
Intravenous administration of calcium salts to patients taking digoxin can result in dangerous cardiac arrhythmias and should be avoided. Vitamin D analogues can also increase digoxin toxicity due to elevations in plasma calcium concentrations.
ACE inhibitors and angiotensin II antagonists may cause hyperkalaemia which can reduce tissue binding of digoxin resulting in higher serum levels. These drugs may also cause a deterioration in renal function resulting in elevated serum levels of digoxin because of impaired renal excretion. Concurrent administration of captopril has been associated with increases in plasma digoxin levels but this may only be clinically significant in patients with impaired renal function or severe congestive heart failure. Telmisartan administration has been associated with increases in plasma digoxin levels and patients receiving both drugs should be monitored. No clinically significant interactions have been noted with other ACE inhibitors or angiotensin II antagonists examined (cilazapril, enalapril, imidapril, lisinopril, moexipril, perindopril, quinapril, ramipril and trandolapril; candesartan, eprosartan, irbesartan, losartan and valsartan)) but it is prudent to monitor the effects of co-administration. There is an increased risk of atrioventricular block and bradycardia when digoxin and beta blockers are taken concomitantly. Nitroprusside and hydralazine increase the renal clearance of digoxin by increasing renal blood flow and tubular secretion and lowering plasma digoxin levels.
St John’s wort: co-administration of digoxin with St John’s wort should be avoided because plasma levels are significantly reduced.
Nefazodone, trazodone: Plasma levels of digoxin are increased by concomitant administration of nefazodone or trazodone and it may be necessary to reduce the dose of digoxin. Phenytoin increases total clearance of digoxin and reduces its elimination half-life, resulting in a decrease in plasma levels. Intravenous phenytoin should not be used to treat digitalis induced arrhythmias or in patients with a high degree of heart block or marked bradycardia because of the risk of cardiac arrest.
Topiramate: co-administration of digoxin and topiramate reduces the bioavailability of digoxin and patients should be monitored. Alprazolam and diazepam can decrease digoxin clearance, resulting in increased plasma concentrations. Patients should be monitored for digoxin toxicity, especially those aged over 65. Digoxin may have detrimental effects on the short term control of bipolar disorder in patients treated with lithium.
Potassium depletion due to acetazolamide, loop diuretics and thiazide diuretics potentiates the effects of digoxin on the myocardium and may also have a small effect on reducing the renal tubular secretion of digoxin. Patients should be monitored for hypokalaemia and given potassium supplements when necessary. Spironolactone decreases renal excretion of digoxin, increasing plasma levels. The dose of digoxin should be decreased in susceptible patients.
Antacids and adsorbents, such as kaolin, can inhibit the absorption of digoxin from the gastrointestinal tract, resulting in a fall in digoxin plasma levels. The interaction can be prevented by separating the doses by about 2 hours. Carbenoxolone may cause fluid retention and hypokalaemia which can increase susceptibility to digoxin toxicity. Metabolism of digoxin in the gastrointestinal tract is inhibited by omeprazole, resulting in increased plasma levels of digoxin. Smaller effects have been seen with pantoprazole and rabeprazole. Sucralfate decreases the absorption of digoxin from the gastrointestinal tract, lowering plasma levels. Plasma levels of digoxin may be reduced by co-administration with sulfasalazine because of decreased absorption. Patients receiving both drugs should be monitored. No interaction has been seen between digoxin and another mesalazine prodrug, balsalazide.
Increases in plasma levels of digoxin have been observed in patients taking atorvastatin and it may be necessary to reduce the dose of digoxin. Although fluvastatin, pravastatin and simvastatin do not appear to cause significant increases in plasma digoxin levels it is prudent to monitor the effects of co-administration. Colestipol and colestyramine bind to digoxin in the gastrointestinal tract, reducing its absorption and lowering plasma digoxin levels. The interaction can be prevented by separating the doses of digoxin and anion exchange resin by about 2 hours.
Edrophonium should not be given to patients with atrial flutter and tachycardia who are taking digoxin as the combination may cause excessive bradycardia and atrioventricular block. Serious cardiac arrhythmias can develop in patients taking digoxin if they are given suxamethonium and pancuronium due to rapid removal of potassium from myocardial cells. Concomitant use should be avoided. Tizanidine may potentiate hypotension and bradycardia when administered concurrently with digoxin.
NSAIDs have the potential to cause renal impairment, reducing the renal clearance of digoxin with a subsequent increase in plasma levels. Aspirin, azapropazone, diclofenac, fenbufen, ibuprofen, indometacin and tiaprofenic acid have all been shown to increase plasma concentrations of digoxin but this may only be clinically significant in patients with impaired renal function. Etoricoxib, ketoprofen, meloxicam, piroxicam and rofecoxib do not appear to increase plasma digoxin levels. Patients being treated with digoxin often need to take NSAIDs and digoxin plasma concentrations should be monitored whenever an NSAID is initiated or discontinued. Phenylbutazone stimulates hepatic metabolism of digoxin so plasma levels should be monitored in these drugs are given concurrently.
Acarbose inhibits the absorption of digoxin in the gastrointestinal tract, resulting in lower plasma levels. Plasma levels of digoxin are increased by concomitant administration of prazosin. Carbimazole or penicillamine may reduce plasma levels of digoxin. Changes in thyroid function may affect sensitivity to digoxin independently of plasma levels. Increased plasma digoxin levels have been reported when ciclosporin has been administered to patients taking digoxin due to reduced renal elimination. Patients should be monitored closely and the digoxin dose adjusted when required. Corticosteroids cause potassium loss and sodium and water retention which increase the risk of digoxin toxicity and heart failure. Patients taking prolonged courses of corticosteroids should be monitored closely. Many cytotoxic drugs damage the intestinal lining, impairing the absorption of digoxin and decreasing plasma levels. The effect is reversed shortly after discontinuing cytotoxic drug administration. Selective beta2 agonists may cause hypokalaemia which can increase susceptibility to digoxin induced arrhythmias. Concurrent administration of salbutamol has also been associated with increases in plasma digoxin levels.
Sympathomimetic drugs have direct positive chronotropic effects that can promote cardiac arrhythmias and may also lead to hypokalaemia, which can lead to or worsen cardiac arrhythmias. Concomitant use of digoxin and sympathomimetics may increase the risk of cardiac arrhythmias.
Propantheline, epoprostenol (transient), vasopressin receptor antagonists (tolvaptan and conivaptan), carvedilol, ritonavir/ritonavir containing regimens, taleprevir, dronedarone, ranolazine, lapatinib and ticagrelor.
The concomitant use of digoxin and sennosides may be associated with a moderate increase in the risk of digoxin toxicity in heart failure patients.
Patients receiving digoxin are more susceptible to the effects of suxamethonium-exacerbated hyperkalaemia.
Co-administration of lapatinib with orally administered digoxin resulted in an increase in the AUC of digoxin.
Caution should be exercised when dosing digoxin concurrently with lapatinib.
Antacids, some bulk laxatives, kaolin-pectin, acarbose, neomycin, penicillamine, rifampicin, some cytostatics, metoclopramide, sulfasalazine, adrenaline, salbutamol, cholestyramine, phenytoin, St John’s wort (Hypericum perforatum), bupropion and supplemental enteral nutrition.
Bupropion and its major circulating metabolite, with and without digoxin, stimulated OATP4C1-mediated digoxin transport. Digoxin has been identified as a substrate for aOATP4C1 in the basolateral side of the proximal renal tubules. Binding of bupropion and its metabolites to OATP4C1 could possibly increase the transport of digoxin and therefore, increase the renal secretion of digoxin.
Milrinone does not alter steady-state serum digoxin levels.
No data are available on whether or not digoxin has teratogenic effects.
There is no information available on the effect of digoxin on human fertility.
The use of digoxin in pregnancy is not contraindicated, although the dosage and control may be less predictable in pregnant than in non-pregnant women with some requiring an increased dosage of digoxin during pregnancy. As with all drugs, use should be considered only when the expected clinical benefit of treatment to the mother outweighs any possible risk to the developing foetus.
Despite extensive antenatal exposure to digitalis preparations, no significant adverse effects have been observed in the foetus or neonate when maternal serum digoxin concentrations are maintained within the normal range. Although it has been speculated that a direct effect of digoxin on the myometrium may result in relative prematurity and low birthweight, a contributing role of the underlying cardiac disease cannot be excluded. Maternally administered digoxin has been used successfully to treat foetal bradycardia and congestive heart failure.
Adverse foetal effects have been reported in mothers with digitalis toxicity.
Although digoxin is excreted in breast milk, the quantities are minute and breast feeding is not contraindicated.
There is no information available on the effect of digoxin on human fertility.
No data are available on whether or not digoxin has teratogenic effects.
Neurological adverse effects and visual disturbances have been reported in patients receiving digoxin. Patients should make sure they are not affected before they drive or operate machinery.
The adverse effects produced by digoxin are frequently due to the narrow margin between therapeutic and toxic doses. Plasma levels in excess of 2nmol.L-1 indicate that the patient is at special risk, although there is considerable interindividual variation. Special care should be taken in patients at high risk of developing digoxin toxicity, such as the elderly and those with renal impairment or thyroid disease (see Special warnings, above). In addition, care should be taken when digoxin is taken with other medications as many have the potential to affect plasma digoxin concentrations or electrolytes and cause toxicity (see section 4.5).
Adverse reactions are listed below by system organ class and frequency. Frequencies are defined as:
Very common ≥1/10
Common ≥1/100 and <1/10
Uncommon ≥1/1000 and <1/100
Rare ≥1/10,000 and <1/1000
Very rare <1/10,000, including isolated reports
Rare: Agranulocytosis
Very rare: Thrombocytopaenia
Not known: Hypersensitivity reactions (pruritus, erythematous rashes, papules, vesicles and angioedema)
Very rare: Anorexia
Uncommon: Depression
Rare: Epilepsy
Very rare: Psychosis, confusion
Not Known: Disorientation, amnesia, delirium, visual and auditory hallucinations (especially in elderly patients)
Common: CNS disturbances, dizziness
Very rare: Headache, apathy
Not known: Fatigue, weakness, drowsiness, bad dreams, restlessness, nervousness, agitation
Common: Visual disturbances
Not Known: Blurred vision, photophobia, colour vision may be affected infrequently, with objects appearing yellow or, less frequently, green, red, blue, brown or white
Common: Arrhythmia, conduction disturbances, bigeminy, trigeminy, PR prolongation, sinus bradycardia
Very rare: Supraventricular tachyarrhythmia, atrial tachycardia (with or without block), junctional (nodal) tachycardia, ventricular arrhythmia, ventricular premature contraction, ST segment depression
Not Known: Heart failure or aggravation of heart failure, superventricular tachycardia, extrasystoles, sinoatrial block
Common: Nausea, vomiting, diarrhoea
Very rare: Intestinal ischaemia, intestinal necrosis
Not Known: Anorexia, abdominal pain
Common: Skin rashes of urticarial or scarlatiniform character may be accompanied by pronounced eosinophilia
Very rare: Gynaecomastia can occur with long term administration
Very rare: Fatigue, malaise, weakness
Children are especially sensitive to the effects of digoxin (see section 4.2). Anorexia, nausea, vomiting, diarrhoea and CNS disturbances may occur but they are rarely the initial symptoms of overdose. Cardiac arrhythmias are the most frequent sign of excessive dosing with digoxin. The most common are conduction disturbances or superventricular tachyarrhythmias, such as atrial tachycardia with or without block. Ventricular arrhythmias are less common. Sinus bradycardia may indicate digoxin toxicity, especially in infants.
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme; website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
None known.
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