Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2017 Publisher: Mercury Pharma International Ltd, 4045, Kingswood Road, City West Business Park, Co Dublin, Ireland
Hypersensitivity to the active substance(s) or other digitalis glycosides or to any of the excipients listed in section 6.1.
Digoxin is contraindicated in:
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 in 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 6 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. Several 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 nanograms/ml (0.64 nanomol/l) to 1.0 nanograms/ml (1.28 nanomol/l).
Digoxin toxicity is more commonly associated with serum digoxin concentration greater than 2 nanograms/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 of 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. For example, atrial tachycardia with varying atrioventricular block requires particular 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. However, 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 with caution 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. There is also some published information indicating that digoxin may inhibit the uptake of thiamine in myocytes in beri beri heart disease.
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.
Patients with severe respiratory disease may have an increased myocardial sensitivity to digitalis glycosides.
Hypokalaemia sensitises the myocardium to the actions of cardiac glycosides.
Hypoxia, Hypomagnesaemia and marked hypercalcaemia 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.
Although many patients with chronic congestive cardiac failure benefit from acute administration of digoxin, there are some in whom 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.
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.
These may arise from effects on the renal excretion, tissue binding, plasma protein binding and distribution within the body, gut absorptive capacity, P-glycoprotein activity and sensitivity to digoxin. The best precaution is to consider the possibility of an interaction whenever concomitant therapy is contemplated and to check on serum digoxin concentration when any doubt exists.
Digoxin is a substrate of P-glycoprotein. Thus, inhibitors of P-glycoprotein 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.
Digoxin, in association with beta-adrenoceptor blocking drugs, may increase atrio-ventricular conduction time.
Agents causing hypokalaemia or intracellular potassium deficiency may cause increased sensitivity to digoxin; they include lithium salts, corticosteroids, carbenoxolone and some diuretics. Co-administration with diuretics such as loop or hydrochlorothiazide should be under close monitoring of serum electrolytes and renal function.
Calcium, particularly if administered rapidly by the intravenous route, may produce serious arrhythmias in digitalized patients.
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.
Alprazolam, amiodarone, flecainide, gentamicin, indomethacin, itraconazole, prazosin, propafenone, quinidine, quinine, spironolactone, macrolide antibiotics (e.g. erythromycin and clarithromycin), tetracycline (and possibly other antibiotics), trimethoprim, propantheline, atorvastatin, ciclosporin, epoprostenol (transient), carvedilol, nefazodone, vasopressin receptor antagonists (tolvaptan and conivaptan), ritonavir/ritonavir containing regimens, taleprevir, dronedarone, ranolazine, telmisartan, lapatinib, 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.
Drugs that modify afferent and efferent arteriole vascular tone may alter glomerular filtration. Angiotensin converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) decrease angiotensin II-mediated efferent arteriole vasoconstriction, while non-steroidal anti-inflammatory drugs (NSAIDs) and cyclooxygenase-2 enzyme (COX-2) inhibitors decrease prostaglandin-mediated afferent arteriole vasodilation. ARBs, ACEIs, NSAIDs, and COX- 2 inhibitors did not significantly alter digoxin pharmacokinetics or did not alter PK parameters in a consistent manner. However, these drugs may modify renal function in some patients, resulting in a secondary increase in digoxin.
Calcium channel blocking agents may either increase or cause no change in serum digoxin levels. Verapamil, felodipine and tiapamil increase serum digoxin levels. Nifedipine and diltiazem may increase or have no effect on serum digoxin levels. Isradipine causes no change in serum digoxin levels. Calcium channel blockers are also known to have depressant effects on sinoatrial and atrioventricular nodal conduction, particularly diltiazem and verapamil.
Adrenaline (epinephrine), antacids, kaolin-pectin, some bulk laxatives, cholestyramine, acarbose, salbutamol, sulfasalazine, neomycin, rifampicin, some cytostatics, phenytoin, metoclopramide, penicillamine, the herbal remedy 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.
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 of digoxin 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 birth weight, a contributing role of the underlying cardiac disease cannot be excluded. Maternally administered digoxin has been successfully used to treat foetal tachycardia 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.
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.
Since central nervous system and visual disturbances have been reported in patients receiving digoxin, patients should exercise caution before driving, using machinery or participating in dangerous activities.
In general, the adverse reactions of digoxin are dose-dependent and occur at doses higher than those needed to achieve a therapeutic effect.
Hence, adverse reactions are less common when digoxin is used within the recommended dose range or therapeutic serum concentration range and when there is careful attention to concurrent medications and conditions.
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 (≥1/1,000 and <1/100)
Rare (≥1/10,000 and <1/1,000)
Very rare (<1/10,000), including isolated reports
Very common, common and uncommon events were generally determined from clinical trial data. The incidence in placebo was taken into account. Adverse drug reactions identified through post-marketing surveillance were considered to be rare or very rare (including isolated reports).
Very rare: Thrombocytopaenia
Very rare: Anorexia
Uncommon: Depression
Very rare: Psychosis, apathy, confusion
Common: CNS disturbances, dizziness
Very rare: Headache
Common: Visual disturbances (blurred or yellow vision)
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
Common: Nausea, vomiting, diarrhoea
Very rare: Intestinal ischaemia, intestinal necrosis
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
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.
Not applicable.
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