Lanoxin Injection

  • Name:

    Lanoxin Injection

  • Company:
    info
  • Active Ingredients:

    Digoxin

  • Legal Category:

    Product subject to medical prescription which may not be renewed (A)

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Summary of Product Characteristics last updated on medicines.ie: 22/1/2019

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Medicine Name Lanoxin 250 microgram tablets Active Ingredients Digoxin
Medicine Name Lanoxin Injection Active Ingredients Digoxin
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Medicine Name Lanoxin PG Tablets Active Ingredients Digoxin
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1 - 0 of 63 items.Total: Infinity pages

When a pharmaceutical company changes any document, a new version is published on medicines.ie. For each version, we show the dates it was published on medicines.ie and the reasons for change.

Updated on 28 March 2019 PIL

Reasons for updating

  • Change to section 6 - manufacturer
  • Change to section 6 - date of revision

Updated on 22 January 2019 PIL

Reasons for updating

  • Change to section 2 - interactions with other medicines, food or drink
  • Change to section 2 - excipient warnings
  • Change to section 6 - date of revision

Updated on 22 January 2019 SmPC

Reasons for updating

  • Change to section 4.1 - Therapeutic indications
  • Change to section 4.3 - Contraindications
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.6 - Pregnancy and lactation
  • Change to Section 4.8 – Undesirable effects - how to report a side effect
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Updated on 10 May 2018 SmPC

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  • New SmPC for new product

Legal category: Product subject to medical prescription which may not be renewed (A)

Updated on 24 April 2017 SmPC

Reasons for updating

  • New SmPC for new product

Legal category: Product subject to medical prescription which may not be renewed (A)

Updated on 24 April 2017 SmPC

Reasons for updating

  • Change to section 4.1 - Therapeutic indications
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.3 - Contraindications
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.8 - Undesirable effects
  • Change to Section 4.8 – Undesirable effects - how to report a side effect
  • Change to section 4.9 - Overdose
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 6.3 - Shelf life
  • Change to section 6.6 - Special precautions for disposal and other handling
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

Text in red = new text
Text strikethrough = deleted text

 

4.1 Therapeutic indications

 

Cardiac failure

Digoxin is indicated in the management of chronic cardiac failure where the dominant problem is systolic dysfunction.  Its therapeutic benefit is greatest in those patients with ventricular dilatation.

 

Digoxin is specifically indicated where cardiac failure is accompanied by atrial fibrillation.

 

Supraventricular arrhythmias

Digoxin is indicated in the management of certain supraventricular arrhythmias, particularly chronic atrial flutter and fibrillation.

 

 

 

4.2 Posology and method of administration

 

Posology:

The dose of digoxin for each patient has to be tailored individually according to age, lean body weight and renal function

 

 

 

Adults and paediatric populations over 10 years

Parenteral loading:

Parenteral loading should only be used in patients who have not been given cardiac glycosides within the preceding two weeks.

 

The total loading dose of parenteral digoxin is 500 to 1000 micrograms (0.5 to 1.0 mg) depending on age, lean body weight and renal function. The total loading dose should be administered in divided doses with approximately half of the total dose given as the first dose and further fractions of the total dose given at intervals of four to eight hours. An assessment of clinical response should be performed before giving each additional dose.  

 

Each dose should be given by I.V. infusion (see Method of Administration, below) over 10 to 20 mins.

 

 

 

Maintenance dose = Peak body stores x daily loss in percent

 

 

 

100

 

Where:

Peak body stores = personalised loading dose

 

 

daily loss (in percent) = 14 + creatinine clearance (Ccr)/5

 

 

Ccr is creatinine clearance corrected to 70 kg bodyweight or 1.73 m2 body surface area.  If only serum creatinine (Scr) concentrations are available, a Ccr (corrected to 70 kg bodyweight) may be estimated in men as

 

 

 

Ccr =

(140 - age)

 

 

 

Scr (in mg/100 ml)

 

 

NOTE:  Where serum creatinine values are obtained in micromol/l, these may be converted to mg/100 ml (mg %) as follows:

 

 

Scr(mg/100 ml) =

Scr (micromol/l) x 113.12

 

 

 

10,000

 

 

       =

Scr (micromol/l)

 

 

 

88.4

Where 113.12 is the molecular weight of creatinine.

 

For women, this result should be multiplied by 0.85.

 

N.B. These formulae cannot be used for creatinine clearance in children.

 

Neonates, infants and paediatric populations up to 10 years of age

 

 

Preterm neonates less than 1.5 kg

-

20 micrograms/kg over 24 h.

Preterm neonates 1.5 kg to 2.5 kg

-

30 micrograms/kg over 24 h.

Term neonates to 2 years

-

35 micrograms/kg over 24 h.

2 to 5 years

-

35 micrograms/kg over 24 h.

5 to 10 years

-

25 micrograms/kg over 24 h.

 

 

The loading dose should be administered in divided doses with approximately half the total dose given as the first dose and further fractions of the total dose given at intervals of four to eight hours, assessing clinical response before giving each additional dose.  Each dose should be given by I.V. infusion (see Method of Administration, below) over 10 to 20 mins.

 

Maintenance dose:

The maintenance dose should be administered in accordance with the following schedule:

 

Preterm neonates:

 

daily dose = 20 % of 24 h loading dose.

 

Term neonates and children up to 10 years:

 

daily dose = 25 % of 24 h loading dose.

 

 

 

Elderly

The possibility of reduced renal function and lower lean body mass should be taken into account when dealing with elderly patients. If necessary, the dosage should be reduced and adjusted to the changed pharmacokinetics to prevent elevated serum dioxin levels and the risk of toxicity. The serum dioxin levels should be checked regularly and hypokalaemia should be avoided. A reduction in both initial and maintenance doses should be considered (See Section 4.4).

 

 

A reduction in both initial and maintenance doses should be considered (See Section 4.4).

 

Method of administration:

 

Dilution of digoxin injection:

 

Digoxin injection can be administered undiluted or diluted with a 4-fold or greater volume of 0.9% Sodium Chloride Injection, 0.18 % Sodium Chloride/4% Glucose Injection or 5% Glucose Injection.  A 4-fold volume of diluent equates to adding one 2 ml ampoule of digoxin to 6 ml of injection solution. The use of less than a 4-fold volume of diluent could lead to precipitation of digoxin.

 

Digoxin injection, when diluted in the ratio of 1 to 250 is known to be compatible with the following infusion solutions and stable for up to 48 h at room temperature (20 to 25 C):

·       Sodium Chloride I.V. Infusion, B.P., 0.9 % w/v.

·       Sodium Chloride (0.18 % w/v) and Glucose (4 % w/v) I.V. Infusion, B.P.

·       Glucose I.V. Infusion, B.P., 5 % w/v.

A ratio of 1 to 250 can be obtained for example by diluting one 2 ml ampoule with 500 ml of infusion solution.

 

Dilution should be carried out either under full aseptic conditions or immediately before use.  Any unused solution should be discarded (see Section 6.6).

 

Administration of digoxin injection:

 

Each dose should be given by I.V. infusion over 10 to 20 mins.

 

The total loading dose should be administered in divided doses with approximately half of the total dose given as the first dose and further fractions of the total dose given at intervals of four to eight hours. An assessment of clinical response should be performed before giving each additional dose.

 

 

 

4.3 Contraindications

 

Digoxin is contraindicated in:

 

-        hypertrophic obstructive cardiomyopathy, unless there is concomitant atrial fibrillation and heart failure but even then caution should be exercised if digoxin is to be used.

-        patients known to be hypersensitive to the active substance, other digitalis glycosides or to any of the excipients listed in section 6.1.

 

 

4.4 Special warnings and precautions for use

 

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.

 

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

 

Sinoatrial disorder

 

Cardiac amyloidosis

 

Myocarditis

 

Beri-beri heart disease

 

Constrictive pericarditis

 

Exercise tolerance

 

Withdrawal

 

Electrocardiograhy

 

 

Severe respiratory disease

 

Hypokalaemia

 

Thyroid disease

 

Malabsorption

 

 

Chronic congestive cardiac failure

 

Direct current cardioversion:

 

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 h 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.

 

 

4.5 Interaction with other medicinal products and other forms of interaction

 

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. 

 

Combinations that should be avoided

 

Combinations which can increase effects of digoxin when co-administered:

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 I.V. route, may produce serious arrhythmias in digitalised 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.

 

Combinations requiring caution

 

Combinations which can increase the effects of digoxin when co-administered:

amiodarone, flecainide, prazosin, propafenone, quinidine, spironolactone, macrolide antibiotics e.g. erythromycin and clarythromycin, tetracycline (and possibly other antibiotics), gentamicin, itraconazole, quinine, trimethoprim, alprazolam, indomethacin, propantheline, nefazodone, atorvastatin, ciclosporine, epoprostenol (transient), vasopressin receptor antagonists (tolvaptan and conivaptan), carvedilol, 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 while isradipine causes no change. Calcium channel blockers are also known to have depressant effects on sinoatrial and atrioventricular nodal conduction, particularly diltiazem and verapamil.    

 

Combinations which can decrease the effects of digoxin when co-administered:

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.

  

Other interactions

 

 

4.8 Undesirable effects

 

Summary of the safety profile

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.

 

Tabulated list of adverse reactions

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.

 

 

System Organ Class

Frequency

Side effects

Blood and lymphatic system disorders

Very rare

Thrombocytopaenia

Metabolism and nutrition disorders

Very rare

Anorexia

Psychiatric disorders

Uncommon

Depression

Very rare

Psychosis, apathy, confusion

Nervous system disorders

Common

CNS disturbances, dizziness

Very rare

Headache

Eye disorders

Common

Visual disturbances (blurred or yellow vision)

Cardiac disorders

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

Gastrointestinal disorders

Common

Nausea, vomiting, diarrhoea

Very rare

Intestinal ischaemia, intestinal necrosis

Skin and subcutaneous tissue Disorders

Common

Skin rashes of urticarial or scarlatiniform character may be accompanied by pronounced eosinophilia

Reproductive system and breast disorders

Very rare

Gynaecomastia can occur with long term administration

General disorders and administration site conditions

Very rare

Fatigue, malaise, weakness

 

 

Reporting of suspected adverse reactions

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 national reporting system

 

 

4.9 Overdose

 

(see Section 4.2). In patients undergoing haemodialysis, digoxin use is associated with increased mortality; patients with low pre-dialysis potassium concentrations are most at risk.

 

 

 

 

Non-cardiac manifestations

The frequent non-cardiac manifestations are similar to those seen in adults are gastrointestinal, CNS and visual. However, nausea and vomiting are not frequent in infants and small children.

 

In addition to the undesirable effects seen with recommended doses, weight loss in older age groups and failure to thrive in infants, abdominal pain due to mesenteric artery ischaemia, drowsiness and behavioural disturbances including psychotic manifestations have been reported in overdose.

 

Treatment

After recent ingestion, such as accidental or deliberate self-poisoning, the load available for absorption may be reduced by gastric lavage. Gastric lavage increases vagal tone and may precipitate or worsen arrhythmias. Consider pre-treatment with atropine if gastric lavage is performed. Treatment with digitalis Fab antibody usually renders gastric lavage unnecessary. In the rare instances in which gastric lavage is indicated, it should only be performed by individuals with proper training and expertise.

 

 

5.1 Pharmacodynamic properties

 

Pharmacotherapeutic group:

Cardiac therapy, cardiac glycosides, digitalis glycosides.

 

ATC code:

C01AA05

 

Mechanism of action

 

Digoxin exerts the same fundamental effect of inhibition of the Na+-K+ exchange mechanism on cells of the autonomic nervous system, stimulating them to exert indirect cardiac activity. Increases in efferent vagal impulses result in reduced sympathetic tone and diminished impulse conduction rate through the atria and atrio-ventricular node. Thus, the major beneficial effect of digoxin is reduction of ventricular rate.

 

Intravenous administration of a loading dose produces an appreciable pharmacological effect within 5 to 30 mins, while using the oral route the onset of effect occurs in 0.5 to 2 hours.

 

Pharmacodynamic effects

The PROVED trial designed to determine the effectiveness of digoxin in 88 patients with chronic, stable mild to moderate heart failure. Withdrawal of digoxin or its continuation  was performed in a prospective, randomised, double-blind, placebo-controlled multicentre trial of patients with chronic, stable mild to moderate heart failure secondary to left ventricular systolic dysfunction who had normal sinus rhythm and were receiving long-term treatment with diuretic drugs and digoxin. Patients withdrawn from digoxin therapy showed worsened maximal exercise capacity (p = 0.003) an increased incidence of treatment failures (p = 0.039) and a decreased time to treatment failure (p = 0.037). Patients who continued to receive digoxin had a lower body weight (p = 0.044) and heart rate (p = 0.003) and a higher left ventricular ejection fraction (p = 0.016). The overall percentage of participants having one or more adverse event was similar in the two groups: 59 % in the placebo group and 69 % in the digoxin group. The types of adverse event were unspecified

 

The RADIANCE trial examined the effects of discontinuation of digoxin in stable NYHA class II and III patients who were receiving diuretics and ACE inhibitors. The 178 patients were initially stabilised on a combination of captopril or enalapril, diuretics and digoxin, then randomised to continue digoxin therapy or change to placebo. The relative risk of worsening disease in the placebo group was 5.9 compared to the digoxin group. Withdrawal of digoxin was accompanied by worsening symptoms, reduced exercise tolerance, and a deteriorating quality of life, indicating that patients with CHF were at considerable risk from discontinuation of the drug in spite of the continuation of therapy with diuretics and ACE inhibitors. Approximately 56 % in the placebo group and 49% in the digoxin group experienced unspecified side effects.

 

In the DIG trial, 6800 patients with heart failure were randomised to receive digoxin or placebo. No difference was found in all-cause mortality between patients who were treated with digoxin and those who were given placebo. In the digoxin group, there was a trend toward a decrease in the risk of death attributed to worsening heart failure (risk ratio, 0.88; 95% confidence interval, 0.77 to 1.01; p = 0.06). However, the patients who received digoxin had significantly (p<0.001) fewer hospital admissions when the drug was given in addition to diuretics and ACE inhibitors. Digoxin therapy was most beneficial in patients with ejection fractions of ≤25%, patients with enlarged hearts (cardiothoracic ratio of >0.55), and patients in NYHA functional class III or IV. In the DIG study, 11.9 % of patients in the digoxin arm and 7.9 % of patients in the placebo arm were suspected of having digoxin toxicity, the most common symptoms being new episodes of ventricular fibrillation, supraventricular arrhythmia, tachycardia, or advanced atrioventricular block.

 

The AFFIRM study involved a total of 4060 patients recruited to a randomised, multicentre comparison of two treatment strategies in patients with atrial fibrillation and a high risk of stroke or death. The primary end point was overall mortality. There were 356 deaths among the patients assigned to rhythm-control therapy (amiodarone, disopyramide, flecainide, moricizine, procainamide, propafenone, quinidine, sotalol, and combinations of these drugs) and 310 deaths among those assigned to rate-control [β-blockers, calcium-channel blockers (verapamil and diltiazem), digoxin, and combinations of these drugs) therapy (mortality at five years, 23.8% and 21.3%, respectively; hazard ratio, 1.15 [95% confidence interval, 0.99 to 1.34]; p=0.08). More patients in the rhythm-control group than in the rate-control group were hospitalised, and there were more adverse drug effects in the rhythm-control group as well.

 

 

 

5.2 Pharmacokinetic properties

 

Absorption

The Tmax following IV administration is approximately 1 to 5 hours, while the Tmax for oral administration is 2 to 6 hours.  Upon oral administration, digoxin is absorbed from the stomach

 

 

Biotransformation

The majority of digoxin is excreted by the kidneys as an intact drug, although a small fraction of the dose is metabolised to pharmacologically active and inactive metabolites.

 

The terminal elimination half-life of digoxin in patients with normal renal function is 30 to 40 h.

 

 

Paediatric population

In the newborn period, renal clearance of digoxin is diminished and suitable dosage adjustments must be observed.  This is especially pronounced in the premature infant since renal clearance reflects maturation of renal function.  Digoxin clearance has been found to be 65.6 ± 30 ml/min/1.73m2 at three months, compared to only 32 ± 7 ml/min/1.73m2 at one week.  By 12 months digoxin clearance of 88 ± 43 ml / min / 1.73m2 has been reported. Beyond the immediate newborn period, children generally require proportionally larger doses than adults on the basis of body weight and body surface area.

 

 

Renal impairment

The terminal elimination half-life of digoxin is prolonged in patients with impaired renal function, and in anuric patients may be of the order of 100 h.

 

Hepatic impairment

Hepatic impairment has little effect on digoxin clearance.

 

Elderly

Age-related declines in renal function in elderly patients can result in a lower rates of digoxin clearance than in younger subjects, with reported digoxin clearance rates in the elderly of 53 ml/min/1.73m2.

 

Gender

Digoxin clearance is 12% – 14% less in females than males and may need to be considered in dosing calculations

 

5.3 Preclinical safety data

 

Carcinogenesis, mutagenesis

Digoxin showed no genotoxic potential in in vitro studies (Ames test and mouse lymphoma). No data are available on the carcinogenic potential of digoxin.

 

6.3 Shelf life

 

Unopened:                    5 years

After first opening:       Once opened use immediately and discard any unused contents.

After dilution:              48 hours

 

When Lanoxin injection is diluted at a ratio of 1 to 250, it is stable for up to 48 hours at room temperature (20 to 25 °C).

 

 

 

6.6 Special precautions for disposal and other handling

Digoxin injection:

Digoxin injection can be administered undiluted or diluted with a 4-fold or greater volume of 0.9% Sodium Chloride Injection, 0.18 % Sodium Chloride/4% Glucose Injection or 5% Glucose Injection. A 4-fold volume of diluent equates to adding one 2 ml ampoule of digoxin to 6 ml of injection solution

 

·        Sodium Chloride I.V. Infusion, B.P., 0.9 % w/v.

·        Sodium Chloride (0.18 % w/v) and Glucose (4 % w/v) I.V. Infusion, B.P.

·        Glucose I.V. Infusion, B.P., 5 % w/v.

A ratio of 1 to 250 can be obtained for example by diluting one 2 ml ampoule with 500 ml of infusion solution.

 

Dilution should be carried out either under full aseptic conditions immediately before use. Any unused solution should be discarded.

 

 

 

10. DATE OF REVISION OF THE TEXT

 

April 2017  2014

 

 

 

 

 

 

 

Updated on 18 April 2017 PIL

Reasons for updating

  • New PIL for new product

Updated on 18 April 2017 PIL

Reasons for updating

  • Change to section 1 - what the product is used for
  • Change to section 2 - what you need to know - contraindications
  • Change to section 2 - what you need to know - warnings and precautions
  • Change to section 2 - use in children and adolescents
  • Change to section 2 - interactions with other medicines, food or drink
  • Change to section 2 - pregnancy, breast feeding and fertility
  • Change to section 2 - driving and using machines
  • Change to section 3 - dose and frequency
  • Change to section 3 - use in children/adolescents
  • Change to section 3 - how to take/use
  • Change to section 3 - duration of treatment
  • Change to section 3 - overdose, missed or forgotten doses
  • Change to section 4 - possible side effects
  • Change to section 4 - how to report a side effect
  • Change to section 6 - date of revision

Updated on 22 April 2014 SmPC

Reasons for updating

  • Change to section 7 - Marketing authorisation holder
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

 

Text in red = new text
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7 MARKETING AUTHORISATION HOLDER

12/13 Exchange Place

I.F.S.C Dublin 1

3016 Lake Drive,

Citywest Business Campus

Dublin 24

10 DATE OF REVISION OF THE TEXT

October April 20143

Updated on 9 April 2014 PIL

Reasons for updating

  • Change to date of revision
  • Change to MA holder contact details

Updated on 16 December 2013 SmPC

Reasons for updating

  • Change to section 2 - Qualitative and quantitative composition
  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.3 - Contraindications
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.5 - Interaction with other medicinal products and other forms of interaction
  • Change to section 4.8 - Undesirable effects
  • Change to section 4.9 - Overdose
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 6.3 - Shelf life
  • Change to section 6.5 - Nature and contents of container
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

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2 QUALITATIVE AND QUANTITATIVE COMPOSITION

 

Excipients with known effect:

Contains 0.104ml/ml ethanol (96%) 0.104mg/ml and less than 1 mmol (23 mg) sodium.

 

For the a full list of excipients, see section 6.1.

 

4.1 Therapeutic Iindications

 

Monitoring

Digoxin toxicity is more commonly associated with serum digoxin concentrations greater than 2 ng/mL. However, 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 Overdose).

 

Scr (micromol/L) x 113.12

 

Maintenance d Dose

 

The elderly

The tendency to impaired renal function and low lean body mass in the elderly influences the pharmacokinetics of dixogin LANOXIN such that high serum digoxin levels and associated toxicity can occur quite readily, unless doses of LANOXIN dixogin lower than those in non-elderly patients are used. Serum digoxin levels should be checked regularly and hypokalaemia avoided.

 

Dose rRecommendations in specific patient groups Renal Disorder or with Diuretic Therapy:

 

See section 4.4 Special warnings and precautions for use

 

4.3 Contraindications

 

 

LANOXIN is contraindicated in intermittent complete heart block or second degree atrioventricular block, especially if there is a history of Stokes-Adams attacks.

 

LANOXIN is contraindicated in intermittent complete heart block or second degree atrioventricular block, especially if there is a history of Stokes-Adams attacks.

 

4.4 Special warnings and precautions for use

Herbal preparations containing St. John’s Wort (Hypericum Pperforatum) should not be used while taking Lanoxin due to the risk of decreased plasma concentrations and reduced clinical effects of Lanoxin (see section 4.5 –Interaction with other medicinal products and other forms of interaction).

 

This medicinal product contains small amounts of ethanol (alcohol), less than 100mg per dose. This medicinal product contains less than 1 mmol sodium (23 mg) per ampoule, i.e. essentially ‘sodium- free’.

4.5 Interaction with other medicinal products and other forms of interaction

Calcium particularly if administered rapidly by the intravenous route, may produce serious arrhythmias in digitalised patients (see also section 4.4 Special wWarnings and Special Pprecautions for uUse).

Serum levels of digoxin may be INCREASED by concomitant administration of the following:

-          amiodarone, flecainide, prazosin, propafenone, quinidine, spironolactone, macrolide, antibiotics e.g. erythromycin and clarithromycin, tetracycline (and possibly other antibiotics), gentamicin, itraconazole, quinine, trimethoprim, alprazolam, indomethacin, propantheline, nefazodone, atorvastatin, and ciycclosporin, epoprostenol (transient) and carvedilol.

Serum levels of digoxin may be REDUCED by concomitant administration of the following:

-          antacids, some bulk laxatives, kaolin-pectin, acarbose, neomycin, penicillamine, rifampicin, some cytostatics, metoclopramide, sulfphasalazine, salbutamol, adrenaline, cholestyramine, phenytoin and St John's Wort (Hypericum perforatum)

 

Serum levels of digoxin can be reduced by concomitant use of the herbal preparations, St, John's Wort (Hypericum perforatum). This is due to induction of drug metabolising enzymes and/or P-glycoprotein by St. John's Wort. Herbal preparations containing St. John"'s Wort should therefore not be combined with Lanoxin.

 

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 (sSee section 5.2 Pharmacokinetics properties).

 

4.8 Undesirable effects

Adverse reactions are listed below by system organ class and frequency.

Frequenciesy are defined as: very common (³ >1/10), common (³>1/100 and <1/10), uncommon (³>1/1,000 and <1/100), rare (³>1/10,000 and <1/1,000), very rare (<1/10,000), including isolated reports.

Skin and subcutaneous tissue  disorders

 

4.9 Overdose

 

Symptoms and sSigns

 

The symptoms and signs of toxicity are generally similar to those described in the Adverse reactions section but may be more frequent and can be more severe.

Signs and symptoms of digoxin toxicity become more frequent with levels above 2.0 nanograms/mL (2.56 nanomol/L) although there is considerable interindividual variation.

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 section 4.2 Posology Dosage and method of administration).

Cardiac manifestations


Premature ventricular contractions (PVCs) are often the earliest and most common arrhythmia. Bigeminy or trigeminy also occur frequently.

Sinus bradycardia and other bradyarrhythmias are very common.

First, second, third degree heart block and AV dissoeciation are also common.

Early toxicity may only be manifested by prolongation of the PR interval.

Ventricular tachycardia may also be a manifestation of toxicity.

Cardiac arrest from asystole or ventricular fibrillation due to digoxin toxicity is usually fatal.

 

Acute massive digoxin overdosage can result in mild to pronounced hyperkalaemia due to inhibition of the sodium­potassium (Na+-K+) pump. Hypokalaemia may contribute to toxicity (see section 4.4 Special warnings and Pprecautions for use).

 

5.2 Pharmacokinetic properties

 

Absorption

Intravenous administration of a loading dose produces an appreciable pharmacological effect within 5 to 30 minutes; this reaches a maximum in 1 to 5 hours. Upon oral administration, digoxin is absorbed from the stomach and upper part of the small intestine.

When digoxin is taken after meals, the rate of absorption is slowed, but the total amount of digoxin absorbed is usually unchanged. When taken with meals high in fibre, however, the amount absorbed from an oral dose may be reduced.

Using the oral route the onset of effect occurs in 0.5 to 2 hours and reaches its maximum at 2 to 6 hours. The bioavailability of orally administered digoxin is approximately 63% in tablet form and 75% as paediatric elixiroral oral solution.

 

Distribution

The initial distribution of digoxin from the central to the peripheral compartment generally lasts from 6 to 8 hours. This is followed by a more gradual decline in serum digoxin concentration, which is dependent upon digoxin elimination from the body. The volume of distribution is large (Vdss = 510 litres in healthy volunteers), indicating digoxin to be extensively bound to body tissues. The highest digoxin concentrations are seen in the heart, liver and kidney, that in the heart averaging 30-fold that in the systemic circulation.

 

 

Elimination

The major route of elimination is renal excretion of the unchanged drug.

 

Digoxin is a substrate for P-glycoprotein. As an efflux protein on the apical membrane of enterocytes, P-glycoprotein may limit the absorption of digoxin. P-glycoprotein in renal proximal tubules appears to be an important factor in the renal elimination of digoxin (Ssee section 4.5 Interaction with other medicinal products and other forms of interaction).

 

Following intravenous i.v. administration to healthy volunteers, between 60 and 75% of a digoxin dose is recovered unchanged in the urine over a 6 day follow-up period. Total body clearance of digoxin has been shown to be directly related to renal function, and percent daily loss is thus a function of creatinine clearance, which in turn may be estimated from a stable serum creatinine. The total and renal clearances of digoxin have been found to be 193 +/-± 25 ml/min and 152 +/- ± 24 ml/min in a healthy control population.

 

In a small percentage of individuals, orally administered digoxin is converted to cardioinactive reduction products (digoxin reduction products or DRPs) by colonic bacteria in the gastrointestinal tract. In these subjects over 40% of the dose may be excreted as DRPs in the urine. Renal clearances of the two main metabolites, dihydrodigoxin and digoxygenin, have been found to be 79 +/ ± 13 ml/min and 100+/ ±26 ml/min, respectively. In the majority of cases however, the major route of digoxin elimination is renal excretion of the unchanged drug. The terminal elimination half-life of digoxin in patients with normal renal function is 30 to 40 hours. 

Since most of the drug is bound to the tissues rather than circulating in the blood, digoxin is not effectively removed from the body during cardiopulmonary by-pass. Furthermore, only about 3% of a digoxin dose is removed from the body during 5 hours of haemodialysis.

 

Special patient populations

 

Neonates, infants and children up to 10 years of age

In the newborn period, renal clearance of digoxin is diminished and suitable dosage adjustments must be observed. This is especially pronounced in the premature infant since renal clearance reflects maturation of renal function. Digoxin clearance has been found to be 65.6 +/± 30ml/min/1.73m2 at 3 months, compared to only 32 +/± 7 ml/min/1.73m2 at 1 week. Beyond the immediate newborn period, children generally require proportionally larger doses than adults on the basis of body weight and body surface area.

Renal impairment

The terminal elimination half-life is prolonged in patients with impaired renal function, and in anuric patients may be of the order of 100 hours.

 

Since most of the drug is bound to the tissues rather than circulating in the blood, digoxin is not effectively removed from the body during cardiopulmonary by-pass. Furthermore, only about 3% of a digoxin dose is removed from the body during 5 hours of haemodialysis.

 

6.3 Shelf life

 

Unopened:                   5 years

After first opening:      Once opened use immediately and discard any unused contents.

After dilution:              48 hours

 

6.6 Special precautions for disposal of a used medicinal product or waste materials derived from such medicinal product and other handling of the product

 

 

10 DATE OF REVISION OF THE TEXT

 

December 2012 October 2013

 

 

Updated on 19 November 2013 PIL

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 1. Trade NAME OF THE MEDICINAL PRODUCT

 

 

Lanoxin Digoxin 500micrograms/2ml Solution for Injection

 

 

 

4. CLINICAL PARTICULARS

 

4.1 Therapeutic iIndications

 

Cardiac Failure:

Lanoxin is indicated in the management of chronic cardiac failure where the dominant problem is systolic dysfunction. Its therapeutic benefit is greatest in those patients with ventricular dilatation.

 

Lanoxin is specifically indicated where cardiac failure is accompanied by atrial fibrillation.

 

Supraventricular Arrhythmias:-

Lanoxin is indicated in the management of certain supraventricular arrhythmias, particularly atrial flutter and fibrillation, where a major beneficial effect is reduction of the ventricular rate.

 

4.2 Posology and Mmethod of Aadministration

 

The dose of LANOXIN digoxin for each patient has to be tailored individually according to age, lean body weight and renal function.

Suggested doses are intended only as an initial guide.

 

The difference in bioavailability between injectable LANOXIN digoxin and oral formulations must be considered when changing from one dosage form to another. For example if patients are switched from oral to the i.v. formulation the dosage should be reduced by approximately 33 %.

 

Monitoring

Serum concentrations of digoxin may be expressed in Conventional Units of nanograms/ml or SI Units of nanomol/l Tto 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. 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 ng/mL (0.64 nanomol/L) to 1.0 ng/mL (1.28 nanomol/L).

 

Digoxin toxicity is more commonly associated with serum digoxin concentration greater than 2 ng/mL. However, 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 Overdose).

 

Other glycosides, 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.

 

Dilution of digoxin injection:

Digoxin injection can be administered undiluted or diluted with a 4-fold or greater volume of diluent. The use of less than a 4-fold volume of diluent could lead to precipitation of digoxin. Digoxin injection, 250 micrograms per ml when diluted in the ratio of 1 to 250 (i.e. one 2 ml ampoule containing 500 micrograms added to 500 ml of infusion solution) is known to be compatible with the following infusion solutions and stable for up to 48 h at room temperature (20 to 25°C).

 

Sodium cChloride I.V. Infusion, B.P., 0.9 % w/v.

Sodium Chloride (0.18 % w/v) and Glucose (4 % w/v) Intravenous Infusion, B.P.

Glucose I.V. Infusion, B.P., 5 % w/v.

 

Dilution should be carried out either under full aseptic conditions or immediately before use.

Any unused solution should be discarded.

 

Populations

 

Adults and Children over 10 years:

 

Parenteral Lloading

NOTE: For use in patients who have not been given cardiac glycosides within the preceding two weeks. The total loading dose of parenteral digoxin is 500 to 1000 micrograms (0.5 to 1.0 mg) depending on age, lean body weight and renal function. The total loading dose should be administered in divided doses with approximately half of the total dose given as the first dose and further fractions of the total dose given at intervals of four to eight hours. An assessment of clinical response should be performed before giving each additional dose. Each dose should be given by i.v. infusion (see dilution of digoxin injection) over 10 to 20 mins.

 

Maintenance Dose:

The maintenance dosage should be based upon the percentage of the peak body stores lost each day through elimination. The following formula has had wide clinical use:

Maintenance dose        =          Peak body stores          x          daily loss in percent

                                                                                                            100

 

Where:                                     Peak body stores = loading dose

daily loss (in percent) = 14 + creatinine clearance (Ccr)/5

 

Ccr is creatinine clearance corrected to 70 kg bodyweight or 1.73 m2 body surface area. If only serum creatinine (Scr) concentrations are available, a Ccr (corrected to 70 kg bodyweight) may be estimated in men as

 

Ccr                                =          (140 - age)

Scr (in mg/100 ml)

 

NOTE: Where serum creatinine values are obtained in micromol/L, these may be converted to mg/100 ml (mg %) as follows:

 

Scr(mg/100 ml)                         =          Scr (micromol /Ll) x 113.12

10,000

 

=          Scr (micromol l/Ll) x 113.12

88.4

 

Where 113.12 is the molecular weight of creatinine.

 

For women, this result should be multiplied by 0.85.

 

NOTE B: These formulae cannot be used for creatinine clearance in children.

 

In practice, this will mean that most patients with heart failure will be maintained on 125 to 250 micrograms (0.125 to 0.25 mg) digoxin daily; however in those who show increased sensitivity to the adverse effects of digoxin, a dose of 62.5 micrograms (0.0625 mg) daily or less may suffice. Conversely, some patients may require a higher dose.

 

Neonates, infants and children up to 10 years of age (if cardiac glycosides have not been given in the preceding two weeks):

If cardiac glycosides have been given in the two weeks preceding commencement of digoxin therapy, it should be anticipated that optimum loading doses of digoxin will be less than those recommended below.

In the newborn, particularly in the premature infant, renal clearance of digoxin is diminished and suitable dose reductions must be observed, over and above general dosage instructions.

Beyond the immediate newborn period, children generally require proportionally larger doses than adults on the basis of body weight or body surface area, as indicated in the schedule below. Children over ten years of age require adult dosages in proportion to their body weight.

 

Parenteral Loading dose:

The intravenous i.v loading dose in the above groups should be administered in accordance with the following schedule:

 

Preterm neonates < 1.5 kg        -          20 micrograms/kg over 24 hours.

Preterm neonates 1.5 kg - 2.5 kg          -          30 micrograms/kg over 24 hours.

Term neonates to 2 years                     -          35 micrograms/kg over 24 hours.

2 to 5 years                                          -          35 micrograms/kg over 24 hours.

5 to 10 years                                        -          25 micrograms/kg over 24 hours.

 

The loading dose should be administered in divided doses with approximately half the total dose given as the first dose and further fractions of the total dose given at intervals of 4 four to 8 eight hours, assessing clinical response before giving each additional dose. Each dose should be given by

intravenous infusion i.v (see Dilution) over 10 to 20 minutes.

 

Maintenance:

The maintenance dose should be administered in accordance with the following schedule:

 

Preterm neonates:

daily dose = 20 % of 24 hour loading dose

(intravenous or oral).

 

Term neonates and children up to 10 years:

daily dose = 25 % of 24 hour loading dose

(intravneous i.v or oral).

 

These dosage schedules are meant as guidelines and careful clinical observation and monitoring of serum digoxin levels (see Monitoring) should be used as a basis for adjustment of dosage in these paediatric patient groups.

 

The elderly

The tendency to impaired renal function and low lean body mass in the elderly influences the pharmacokinetics of LANOXIN digoxin such that high serum digoxin levels and associated toxicity can occur quite readily, unless doses of LANOXIN digoxin lower than those in non-elderly patients are used. Serum digoxin levels should be checked regularly and hypokalaemia avoided.

 

Dose recommendations in Renal Disorder or with Diuretic Therapy special patient groups

 

See Special Warnings and Special Precautions for use.

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.

4.5 Interaction with other mMedicinalaments products and oOther forms of iInteraction

 

These may arise from effects on the renal excretion, tissue binding, plasma protein binding, distribution within the body, gut absorptive capacity and sensitivity to Lanoxin. Consideration of the possibility of an interaction whenever concomitant therapy is contemplated is the best precaution and a check on serum digoxin concentration is recommended when any doubt exists.

 

 

4.6 Fertility, pPregnancy and lLactation

 

Teratogenicity:

No data are available on whether or not digoxin has teratogenic effects.

4.7 Effects on aAbility to dDrive and uUse mMachines

 

Since central nervous system and visual disturbances have been reported in patients receiving Lanoxin, patients should exercise caution before driving, using machinery or participating in dangerous activities.

 

4.8 Undesirable effects

 

In general, the adverse reactions of digoxin are dose-dependent and occur at doses higher than those needed to achieve a therapeutic effect.

 

 

 

5.2 Pharmacokinetic pProperties

 

Absorption

Intravenous administration of a loading dose produces an appreciable pharmacological effect within 5 to 30 minutes; this reaches a maximum in 1 to 5 hours. Upon oral administration, digoxin is absorbed from the stomach and upper part of the small intestine.

 

When digoxin is taken after meals, the rate of absorption is slowed, but the total amount of digoxin absorbed is usually unchanged. When taken with meals high in fibre, however, the amount absorbed from an oral dose may be reduced.

 

Using the oral route the onset of effect occurs in 0.5 to 2 h and reaches its maximum at 2 to 6 hours. The bioavailability of orally administered digoxin is approximately 63% in tablet form and 75% as oral solution.

 

Distribution

The initial distribution of digoxin from the central to the peripheral compartment generally lasts from 6 to 8 hours. This is followed by a more gradual decline in serum digoxin concentration, which is dependent upon digoxin elimination from the body. The volume of distribution is large (Vdss = 510 litres in healthy volunteers), indicating digoxin to be extensively bound to body tissues. The highest digoxin concentrations are seen in the heart, liver and kidney that in the heart averaging 30- fold that in the systemic circulation.

Elimination

The major route of elimination is renal excretion of the unchanged drug. Digoxin is a substrate for P-glycoprotein. As an efflux protein on the apical membrane of enterocytes, P-glycoprotein may limit the absorption of digoxin. P-glycoprotein in renal proximal tubules appears to be an important factor in the renal elimination of digoxin (See Interaction).

 

Following i.v. intravenous administration to healthy volunteers, between 60 and 75% of a digoxin dose is recovered unchanged in the urine over a 6 day follow-up period. Total body clearance of digoxin has been shown to be directly related to renal function, and percent daily loss is thus a function of creatinine clearance, which in turn may be estimated from a stable serum creatinine. The total and renal clearances of digoxin have been found to be 193 +/- 25 ml/min and 152 +/- 24 ml/min in a healthy control population.

The terminal elimination half-life of digoxin in patients with normal renal function is 30 to 40 hours.

Since most of the drug is bound to the tissues rather than circulating in the blood, digoxin is not effectively removed from the body during cardiopulmonary by-pass. Furthermore, only about 3% of a digoxin dose is removed from the body during 5 fivehours of haemodialysis.

Special patient populations

 

Neonates, infants and children up to 10 years of age

In the newborn period, renal clearance of digoxin is diminished and suitable dosage adjustments must be observed. This is especially pronounced in the premature infant since renal clearance reflects maturation of renal function.

Digoxin clearance has been found to be 65.6 +/- 30ml/min/1.73m2 at 3 months, compared to only 32 +/- 7 ml/min/1.73m2 at 1 week. Beyond the immediate newborn period, children generally require proportionally larger doses than adults on the basis of body weight and body surface area.

 

6. PHARMACEUTICAL PARTICULARS

 

6.1 List of eExcipients

 

Ethanol (96%)

Propylene glycol

Citric acid monohydrate

Sodium phosphate anhydrous

OR Sodium phosphate

Water for injections

6.3 Shelf lLife

 

Unopened:                   5 years

After first opening:      Once opened use immediately and discard any unused contents.

 

6.4 Special precautions for storage

 

Unopened:       Do not store above 25°C. Keep the ampoules in the outer carton to protect from light.

After dilution:  See section 6.6

 

6.5 Nature and contents of container

 

Box of 5 x 2ml neutral, type I glass ampoules.

 

6.6 Special precautions for disposal of a used medicinal product or waste materials derived from such medicinal products and other handling of the product

For single use only. Discard any unused contents.

For single use only. Discard any unused contents.

 

After first opening: Once opened, use immediately and discard any unused contents.

After dilution: Lanoxin Injection 250 micrograms per ml when diluted in the ratio of 1 to 250 (i.e. One 2ml ampoule containing 500 micrograms added to 500ml of infusion solution) is known to be compatible with the following infusion solutions and stable for up to 48 hours at room temperature (20 to 25°C):

Sodium Chloride Intravenous Infusion BP 0.9% w/v

Sodium chloride (0.18% w/v) and Glucose (4% w/v) intravenous infusion BP

Glucose intravenous Infusion BP 5% w/v

 

10. DATE OF (Partial) REVISION OF THE TEXT

Updated on 28 January 2013 PIL

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Updated on 14 January 2013 SmPC

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Updated on 27 May 2011 PIL

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Updated on 18 March 2010 SmPC

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Updated on 15 March 2010 PIL

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4.4 Special Warnings and Special Precautions for Use

 

Addition of “However, the benefit of digoxin in patients with supraventricular arrhythmias is most evident at rest, less evident with exercise.

 

 

4.5 Interaction with Other Medicaments and Other Forms of Interaction

Serum levels of digoxin may be INCREASED by concomitant administration of the following:

 Addition of “epoprostenol (transient) and carvedilol.

Updated on 28 August 2007 PIL

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4.9 Overdose

Symptoms and Signs

The symptoms and signs of toxicity are generally similar to those described in the Adverse Reactions section but may be more frequent and can be more severe.

Signs and symptoms of digoxin toxicity become more frequent with levels above 2.0 nanograms/mL (2.56 nanomol/L) although there is considerable interindividual variation. However, in deciding whether a patient's symtoms are due to digoxin, the clinical state, together with serum electrolyte levels and thyroid function are important factors (see Dosage and Administration).

Updated on 10 July 2006 PIL

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Updated on 5 July 2006 SmPC

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4.2:

......Monitoring:

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. 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 ng/mL (0.64 nanomol/L) to 1.0 ng/mL (1.28 nanomol/L).

Digoxin toxicity is more commonly associated with serum digoxin concentration greater than 2 ng/mL. However, 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 Overdose). .......

 

......Rapid oral loading:

If medically appropriate, rapid digitalisation may be achieved in a number of ways, such as the following:

750 to 1500 micrograms (0.75 to 1.5 mg) as a single dose.

Where there is less urgency, or greater risk of toxicity e.g. in the elderly, the oral loading dose should be given in divided doses six hours apart, with approximately half the total dose given as the first dose.

Clinical response should be assessed before giving each additional dose (see Warnings and Precautions).

Slow oral loading:

In some patients, for example those with mild heart failure, digitalisation may be achieved more slowly with doses of 250 to 750 micrograms (0.25 to 0.75 mg) daily for one week followed by an appropriate maintenance dose. A clinical response should be seen within one week.

NOTE: The choice between slow and rapid oral loading depends on the clinical state of the patient and the urgency of the condition.

Parenteral Loading

NOTE: For use in patients who have not been given cardiac glycosides within the preceding two weeks.

The total loading dose of parenteral digoxin is 500 to 1000 micrograms (0.5 to 1.0 mg) depending on age, lean body weight and renal function. The total loading dose should be administered in divided doses with approximately half of the total dose given as the first dose and further fractions of the total dose given at intervals of four to eight hours. An assessment of clinical response should be performed before giving each additional dose. Each dose should be given by i.v. infusion (see Dilution of digoxin injection) over 10 to 20 mins.........

.....In practice, this will mean that most patients with heart failure will be maintained on 125 to 250 micrograms (0.125 to 0.25 mg) digoxin daily; however in those who show increased sensitivity to the adverse effects of digoxin, a dose of 62.5 micrograms (0.0625 mg) daily or less may suffice. Conversely, some patients may require a higher dose......

4.3 Contraindications

.....Digoxin is contraindicated in patients known to be hypersensitive to digoxin, other digitalis glycosides or to any component of the preparation.

4.4 Warnings & precautions

...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 .......

4.8 Undesirable effects

......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.

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).

Blood and lymphatic system disorders

Very rare:Thrombocytopaenia

Metabolism and nutrition disorders

Very Rare: Anorexia

Psychiatric disorders

Uncommon:Depression

Very rare:Psychosis, apathy, confusion

Nervous system disorders

Common: CNS disturbances, dizziness

Very rare:Headache

Eye disorders

Common: Visual disturbances (blurred or yellow vision)

Cardiac disorders

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

Gastrointestinal disorders

Common: Nausea, vomiting, diarrhoea

Very rare:Intestinal ischaemia, intestinal necrosis

Skin disorders

Common: Skin rashes of urticarial or scarlatiniform character may be accompanied by pronounced eosinophilia

Reproductive system and breast disorders

Very rare:Gynaecomastia can occur with long term administration

General disorders and administration site conditions

Very rare:Fatigue, malaise, weakness

 

4.9 Overdose

Symptoms and Signs

The symptoms and signs of toxicity are generally similar to those described in the Adverse Reactions section but may be more frequent and can be more severe.

Signs and symptoms of digoxin toxicity become more frequent with levels above 3.0 nanograms/mL (3.84 nanomol/L) although there is considerable interindividual variation. However, in deciding whether a patient's symtoms are due to digoxin, the clinical state, together with serum electrolyte levels and thyroid function are important factors (see Dosage and Administration).

Adults

In adults without heart disease, clinical observation suggests that an overdose of digoxin of 10 to 15 mg was the dose resulting in death of half of the patients. If more than 25 mg of digoxin was ingested by an adult without heart disease, death or progressive toxicity responsive only to digoxin-binding Fab antibody fragments resulted.

Cardiac manifestations

Cardiac manifestations are the most frequent and serious sign of both acute and chronic toxicity. Peak cardiac effects generally occur 3 to 6 hours following overdosage and may persist for the ensuing 24 hours or longer. Digoxin toxicity may result in almost any type of arrhythmia. Multiple rhythm disturbances in the same patient are common. These include paroxysmal atrial tachycardia with variable atrioventricular (AV) block, accelerated junctional rhythm, slow atrial fibrillation (with very little variation in the ventricular rate) and bi directional ventricular tachycardia.

Premature ventricular contractions (PVCs) are often the earliest and most common arrhythmia. Bigeminy or trigeminy also occur frequently.

Sinus bradycardia and other bradyarrhythmias are very common.

First, second, third degree heart blocks and AV disocciation are also common.

Early toxicity may only be manifested by prolongation of the PR interval.

Ventricular tachycardia may also be a manifestation of toxicity.

Cardiac arrest from asystole or ventricular fibrillation due to digoxin toxicity is usually fatal.

Acute massive digoxin overdosage can result in mild to pronounced hyperkalaemia due to inhibition of the sodium-potassium (Na+-K+) pump. Hypokalaemia may contribute to toxicity (see Warnings and Precautions).

Non-cardiac manifestations

Gastrointestinal symptoms are very common in both acute and chronic toxicity. The symptoms precede cardiac manifestations in approximately half of the patients in most literature reports. Anorexia, nausea and vomiting have been reported with an incidence up to 80%. These symptoms usually present early in the course of an overdose.

Neurologic and visual manifestations occur in both acute and chronic toxicity. Dizziness, various CNS disturbances, fatigue and malaise are very common. The most frequent visual disturbance is an aberration of colour vision (predominance of yellow green). These neurological and visual symptoms may persist even after other signs of toxicity have resolved.

In chronic toxicity, non-specific extracardiac symptoms, such as malaise and weakness, may predominate.

Children

In children aged 1 to 3 years without heart disease, clinical observation suggests that an overdose of digoxin of 6 to 10 mg was the dose resulting in death in half of the patients. If more than 10 mg of digoxin was ingested by a child aged 1 to 3 years without heart disease, the outcome was uniformly fatal when Fab fragment treatment was not given.

Most manifestations of toxicity in children occur during or shortly after the loading phase with digoxin.

Cardiac manifestations

The same arrhythmias or combination of arrhythmias that occur in adults can occur in paediatrics. Sinus tachycardia, supraventricular tachycardia, and rapid atrial fibrillation are seen less frequently in the paediatric population.

Paediatric patients are more likely to present with an AV conduction disturbance or a sinus bradycardia.

Ventricular ectopy is less common, however in massive overdose, ventricular ectopy, ventricular tachycardia and verntricular fibrillation have been reported.

In neonates, sinus bradycardia or sinus arrest and/or prolonged PR intervals are frequent signs of toxicity. Sinus bradycardia is common in young infants and children. In older children, AV blocks are the most common conduction disorders.

Any arrhythmia or alteration in cardiac conduction that develops in a child taking digoxin should be assumed to be caused by digoxin, until further evaluation proves otherwise.

Extracardiac manifestations

The frequent extracardiac manifestations similar to those seen in adults are gastrointestinal, CNS and visual. However, nausea and vomiting are not frequent in infants and small children.

In addition to the undesirable effects seen with recommended doses, weight loss in older age groups and failure to thrive in infants, abdominal pain due to mesenteric artery ischaemia, drowsiness and behavioural disturbances including psychotic manifestations have been reported in overdose.

Treatment

After recent ingestion, such as accidental or deliberate self-poisoning, the load available for absorption may be reduced by gastric lavage.

Patients with massive digitalis ingestion should receive large doses of activated charcoal to prevent absorption and bind digoxin in the gut during enteroenteric recirculation.

If hypokalaemia is present, it should be corrected with potassium supplements either orally or intravenously, depending on the urgency of the situation. In cases where a large amount of digoxin has been ingested hyperkalaemia may be present due to release of potassium from skeletal muscle. Before administering potassium in digoxin overdose the serum potassium level must be known.

Bradyarrhythmias may respond to atropine but temporary cardiac pacing may be required. Ventricular arrhythmias may respond to lignocaine or phenytoin.

Dialysis is not particularly effective in removing digoxin from the body in potentially life-threatening toxicity.

Digoxin-specific antibody Fab is a specific treatment for digoxin toxicity and is very effective. Rapid reversal of the complications that are associated with serious poisoning by digoxin, digitoxin and related glycosides has followed i.v. administration of digoxin-specific (ovine) antibody fragments (Fab). For details, consult the literature supplied with antibody fragments.

Updated on 5 July 2006 SmPC

Reasons for updating

  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.3 - Contraindications
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.8 - Undesirable effects
  • Change to section 4.9 - Overdose

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

4.2:

......Monitoring:

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. Several post hoc analyses of heart failure patients in the Digitalis Investigation Group trial suggest that the optimal trough difoxin serum level may be 0.5 ng/mL (0.64 nanomol/L) to 1.0 ng/mL (1.28 nanomol/L).

Digoxin toxicity is more commonly associated with serum digoxin concentration greater than 2 ng/mL. However, 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 Overdose). .......

 

......Rapid oral loading:

If medically appropriate, rapid digitalisation may be achieved in a number of ways, such as the following:

750 to 1500 micrograms (0.75 to 1.5 mg) as a single dose.

Where there is less urgency, or greater risk of toxicity e.g. in the elderly, the oral loading dose should be given in divided doses six hours apart, with approximately half the total dose given as the first dose.

Clinical response should be assessed before giving each additional dose (see Warnings and Precautions).

Slow oral loading:

In some patients, for example those with mild heart failure, digitalisation may be achieved more slowly with doses of 250 to 750 micrograms (0.25 to 0.75 mg) daily for one week followed by an appropriate maintenance dose. A clinical response should be seen within one week.

NOTE: The choice between slow and rapid oral loading depends on the clinical state of the patient and the urgency of the condition.

Parenteral Loading

NOTE: For use in patients who have not been given cardiac glycosides within the preceding two weeks.

The total loading dose of parenteral digoxin is 500 to 1000 micrograms (0.5 to 1.0 mg) depending on age, lean body weight and renal function. The total loading dose should be administered in divided doses with approximately half of the total dose given as the first dose and further fractions of the total dose given at intervals of four to eight hours. An assessment of clinical response should be performed before giving each additional dose. Each dose should be given by i.v. infusion (see Dilution of digoxin injection) over 10 to 20 mins.........

.....In practice, this will mean that most patients with heart failure will be maintained on 125 to 250 micrograms (0.125 to 0.25 mg) digoxin daily; however in those who show increased sensitivity to the adverse effects of digoxin, a dose of 62.5 micrograms (0.0625 mg) daily or less may suffice. Conversely, some patients may require a higher dose......

4.3 Contraindications

.....Digoxin is contraindicated in patients known to be hypersensitive to digoxin, other digitalis glycosides or to any component of the preparation.

4.4 Warnings & precautions

...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 .......

4.8 Undesirable effects

......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.

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).

Blood and lymphatic system disorders

Very rare:Thrombocytopaenia

Metabolism and nutrition disorders

Very Rare: Anorexia

Psychiatric disorders

Uncommon:Depression

Very rare:Psychosis, apathy, confusion

Nervous system disorders

Common: CNS disturbances, dizziness

Very rare:Headache

Eye disorders

Common: Visual disturbances (blurred or yellow vision)

Cardiac disorders

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

Gastrointestinal disorders

Common: Nausea, vomiting, diarrhoea

Very rare:Intestinal ischaemia, intestinal necrosis

Skin disorders

Common: Skin rashes of urticarial or scarlatiniform character may be accompanied by pronounced eosinophilia

Reproductive system and breast disorders

Very rare:Gynaecomastia can occur with long term administration

General disorders and administration site conditions

Very rare:Fatigue, malaise, weakness

 

4.9 Overdose

Symptoms and Signs

The symptoms and signs of toxicity are generally similar to those described in the Adverse Reactions section but may be more frequent and can be more severe.

Signs and symptoms of digoxin toxicity become more frequent with levels above 3.0 nanograms/mL (3.84 nanomol/L) although there is considerable interindividual variation. However, in deciding whether a patient's symtoms are due to digoxin, the clinical state, together with serum electrolyte levels and thyroid function are important factors (see Dosage and Administration).

Adults

In adults without heart disease, clinical observation suggests that an overdose of digoxin of 10 to 15 mg was the dose resulting in death of half of the patients. If more than 25 mg of digoxin was ingested by an adult without heart disease, death or progressive toxicity responsive only to digoxin-binding Fab antibody fragments resulted.

Cardiac manifestations

Cardiac manifestations are the most frequent and serious sign of both acute and chronic toxicity. Peak cardiac effects generally occur 3 to 6 hours following overdosage and may persist for the ensuing 24 hours or longer. Digoxin toxicity may result in almost any type of arrhythmia. Multiple rhythm disturbances in the same patient are common. These include paroxysmal atrial tachycardia with variable atrioventricular (AV) block, accelerated junctional rhythm, slow atrial fibrillation (with very little variation in the ventricular rate) and bi directional ventricular tachycardia.

Premature ventricular contractions (PVCs) are often the earliest and most common arrhythmia. Bigeminy or trigeminy also occur frequently.

Sinus bradycardia and other bradyarrhythmias are very common.

First, second, third degree heart blocks and AV disocciation are also common.

Early toxicity may only be manifested by prolongation of the PR interval.

Ventricular tachycardia may also be a manifestation of toxicity.

Cardiac arrest from asystole or ventricular fibrillation due to digoxin toxicity is usually fatal.

Acute massive digoxin overdosage can result in mild to pronounced hyperkalaemia due to inhibition of the sodium-potassium (Na+-K+) pump. Hypokalaemia may contribute to toxicity (see Warnings and Precautions).

Non-cardiac manifestations

Gastrointestinal symptoms are very common in both acute and chronic toxicity. The symptoms precede cardiac manifestations in approximately half of the patients in most literature reports. Anorexia, nausea and vomiting have been reported with an incidence up to 80%. These symptoms usually present early in the course of an overdose.

Neurologic and visual manifestations occur in both acute and chronic toxicity. Dizziness, various CNS disturbances, fatigue and malaise are very common. The most frequent visual disturbance is an aberration of colour vision (predominance of yellow green). These neurological and visual symptoms may persist even after other signs of toxicity have resolved.

In chronic toxicity, non-specific extracardiac symptoms, such as malaise and weakness, may predominate.

Children

In children aged 1 to 3 years without heart disease, clinical observation suggests that an overdose of digoxin of 6 to 10 mg was the dose resulting in death in half of the patients. If more than 10 mg of digoxin was ingested by a child aged 1 to 3 years without heart disease, the outcome was uniformly fatal when Fab fragment treatment was not given.

Most manifestations of toxicity in children occur during or shortly after the loading phase with digoxin.

Cardiac manifestations

The same arrhythmias or combination of arrhythmias that occur in adults can occur in paediatrics. Sinus tachycardia, supraventricular tachycardia, and rapid atrial fibrillation are seen less frequently in the paediatric population.

Paediatric patients are more likely to present with an AV conduction disturbance or a sinus bradycardia.

Ventricular ectopy is less common, however in massive overdose, ventricular ectopy, ventricular tachycardia and verntricular fibrillation have been reported.

In neonates, sinus bradycardia or sinus arrest and/or prolonged PR intervals are frequent signs of toxicity. Sinus bradycardia is common in young infants and children. In older children, AV blocks are the most common conduction disorders.

Any arrhythmia or alteration in cardiac conduction that develops in a child taking digoxin should be assumed to be caused by digoxin, until further evaluation proves otherwise.

Extracardiac manifestations

The frequent extracardiac manifestations similar to those seen in adults are gastrointestinal, CNS and visual. However, nausea and vomiting are not frequent in infants and small children.

In addition to the undesirable effects seen with recommended doses, weight loss in older age groups and failure to thrive in infants, abdominal pain due to mesenteric artery ischaemia, drowsiness and behavioural disturbances including psychotic manifestations have been reported in overdose.

Treatment

After recent ingestion, such as accidental or deliberate self-poisoning, the load available for absorption may be reduced by gastric lavage.

Patients with massive digitalis ingestion should receive large doses of activated charcoal to prevent absorption and bind digoxin in the gut during enteroenteric recirculation.

If hypokalaemia is present, it should be corrected with potassium supplements either orally or intravenously, depending on the urgency of the situation. In cases where a large amount of digoxin has been ingested hyperkalaemia may be present due to release of potassium from skeletal muscle. Before administering potassium in digoxin overdose the serum potassium level must be known.

Bradyarrhythmias may respond to atropine but temporary cardiac pacing may be required. Ventricular arrhythmias may respond to lignocaine or phenytoin.

Dialysis is not particularly effective in removing digoxin from the body in potentially life-threatening toxicity.

Digoxin-specific antibody Fab is a specific treatment for digoxin toxicity and is very effective. Rapid reversal of the complications that are associated with serious poisoning by digoxin, digitoxin and related glycosides has followed i.v. administration of digoxin-specific (ovine) antibody fragments (Fab). For details, consult the literature supplied with antibody fragments.

Updated on 31 January 2006 PIL

Reasons for updating

  • Improved electronic presentation

Updated on 18 January 2006 SmPC

Reasons for updating

  • Change to section 1 - Name of medicinal product

Legal category: Product subject to medical prescription which may not be renewed (A)

Updated on 26 August 2005 PIL

Reasons for updating

  • Change of manufacturer

Updated on 13 July 2005 PIL

Reasons for updating

  • Change to drug interactions

Updated on 26 May 2005 PIL

Reasons for updating

  • New PIL for medicines.ie

Updated on 22 February 2005 SmPC

Reasons for updating

  • New SPC for medicines.ie

Legal category: Product subject to medical prescription which may not be renewed (A)