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LANOXIN INJECTION

Active substance(s): DIGOXIN / DIGOXIN / DIGOXIN

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SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT
Lanoxin Injection.

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Digoxin

3

0.025 % w/v

PHARMACEUTICAL FORM
Solution for Injection.

4

CLINICAL PARTICULARS

4.1

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

4.2

Posology and method of administration
The dose of Lanoxin 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 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 %.
Adults and children over 10 years of age:
Parenteral Loading:
Note: For use in patients who have not been given cardiac glycosides within the
preceding two weeks.
The loading of parenteral Lanoxin is 500 to 1000 micrograms (0.5 to 1.0 mg)
depending on age, lean body weight and renal function.
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 to 8 hours. An assessment of clinical response should be performed
before giving each additional dose. Each dose should be given by intravenous
infusion (Dilution Instructions: see 6.6) over 10 to 20 minutes.
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
100

Where:
Peak Body Stores
% Daily Loss

=
=

Loading Dose
14 + Creatinine Clearance (Ccr)/5.

Ccr is creatinine clearance corrected to 70 kg body weight or 1.73 m2 body surface
area. If only serum creatinine (Scr) concentrations are available, a Ccr (corrected to
70 kg body weight) 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.
NOTE: These formulae cannot be used for creatinine clearance in children.
In practice, this will mean that most patients will be maintained on 0.125 to 0. 25 mg
digoxin daily; however in those who show increased sensitivity to the adverse effects
of digoxin, a dosage of 62.5 microgram (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):

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 10 years of age require adult dosages in
proportion to their body weight.
Parenteral Loading:
The parenteral loading dose in the above groups should be administered in
accordance with the following schedule:
Preterm neonates < 1.5 kg
Preterm neonates 1.5 kg to 2.5 kg
Term neonates to 2 years
2 to 5 years
5 to 10 years

20 microgram/kg over 24 hours
30 microgram/kg over 24 hours
35 microgram/kg over 24 hours
35 microgram/kg over 24 hours
25 microgram/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 to 8 hours. An assessment of clinical response should be performed
before giving each additional dose. Each dose should be given by intravenous
infusion (Dilution instructions: see 6.6) over 10 to 20 minutes.
If cardiac glycosides have been given in the two weeks preceding commencement of
Lanoxin therapy, it should be anticipated that optimum loading doses of Lanoxin will
be less than those recommended above.
Maintenance Dose:
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 (intravenous 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.
If cardiac glycosides have been given in the two weeks preceding commencement of
Lanoxin therapy, it should be anticipated that optimum loading doses of Lanoxin will
be less than those recommended above.
Use in the elderly:
The tendency to impaired renal function and low lean body mass in the elderly
influences the pharmacokinetics of Lanoxin such that high serum digoxin levels and
associated toxicity can occur quite readily, unless doses of Lanoxin 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:

See Special Warnings and Precautions for use.
Monitoring:
Serum concentrations of digoxin may be expressed in conventional units of
nanogram/ml (ng/ml) or SI Units of nanomol/L (nmol/L). To convert ng/ml to
nmol/L, multiply ng/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 Lanoxin. 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
patient's clinical state together with the serum potassium level and thyroid function
are important factors.
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.

4.3

Contraindications
Lanoxin is contra-indicated in intermittent complete heart block or second
degree atrioventricular block, especially if there is a history of Stokes-Adams
attacks.
Lanoxin is contra-indicated in arrhythmias caused by cardiac glycoside
intoxication.
Lanoxin is contra-indicated in supraventricular arrhythmias associated with an
accessory atrioventricular pathway, as in the Wolff-Parkinson-White
syndrome unless the electrophysiological characteristics of the accessory
pathway and any possible deleterious effect of digoxin on these characteristics
has been evaluated. If an accessory pathway is known or suspected to be
present and there is no history of previous supraventricular arrhythmias,
Lanoxin is similarly contra-indicated.
Lanoxin is contra-indicated in ventricular tachycardia or ventricular
fibrillation.
Lanoxin is contra-indicated 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.
Lanoxin is contra-indicated in patients known to be hypersensitive to digoxin,
other digitalis glycosides, or to any component of the preparation.

4.4

Special warnings and 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.
In some cases of sinoatrial disorder (i.e. Sick Sinus Syndrome) digoxin may cause or
exacerbate sinus bradycardia or cause sinoatrial block.
Determination of the serum digoxin concentration may be very helpful in making a
decision to treat with further digoxin, but toxic doses of other glycosides may crossreact in the assay and wrongly suggest apparently satisfactory measurements.
Observations during the temporary withholding of digoxin might be more
appropriate.
In cases where cardiac glycosides have been taken in the preceding two weeks, the
recommendations for initial dosing of a patient should be reconsidered and a reduced
dose is advised.
The dosing recommendations should be reconsidered if patients are elderly or there
are other reasons for the renal clearance of digoxin being reduced. A reduction in
both initial and maintenance doses should be considered.
Hypokalaemia sensitises the myocardium to the actions of cardiac glycosides.
Hypoxia, hypomagnesaemia and marked hypercalcaemia increase myocardial
sensitivity to cardiac glycosides.
Rapid intravenous injection can cause vasoconstriction producing hypertension and/or
reduced coronary flow. A slow injection rate is therefore important in hypertensive
heart failure and acute myocardial infarction.
Administering Lanoxin to a patient with thyroid disease requires care. Initial and
maintenance doses of Lanoxin 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.
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.

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.
The administration of digoxin in the period immediately following myocardial
infarction is not contra-indicated. 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 cardiologically 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 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 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.
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 Lanoxin is continued long-term.

The intramuscular route is painful and is associated with muscle necrosis. This route
cannot be recommended.
Patients with severe respiratory disease may have an increased myocardial sensitivity
to digitalis glycosides.
The packs will carry the following statements:
Do not store above 25°C
Protect from light
For intravenous injection under medical supervision
Keep out of reach of children

4.5

Interaction with other medicinal products and other forms of interaction
Interactions 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.
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 diuretics, lithium salts,
corticosteroids and carbenoxolone.
Patients receiving Digoxin are more susceptible to the effects of
suxamethonium-exacerbated hyperkalaemia.
Calcium, particularly if administered rapidly by the intravenous route, may
produce serious arrhythmias in digitalized patients.
Serum levels of digoxin may be increased by concomitant administration of
the following:
Alprazolam, amiodarone, flecainide, gentamicin, indometacin, itraconazole,
prazosin, propafenone, quinidine, quinine, spironolactone, macrolide
antibiotics (e.g. erythromycin and clarithromycin), tetracycline (and possibly
other antibiotics), trimethoprim, propantheline, atorvastatin, ciclosporin,
epoprostenol (transient) and carvedilol.
Serum levels of digoxin may be reduced by concomitant administration of the
following:
Adrenaline (epinephrine), antacids, kaolin-pectin, some bulk laxatives,
colestyramine, acarbose, salbutamol, sulfasalazine, neomycin, rifampicin,

some cytostatics, phenytoin, metoclopramide, penicillamine and the herbal
remedy St John’s wort (Hypericum perforatum).
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.
Angiotensin converting enzyme (ACE) inhibitors may also increase or cause
no change in serum digoxin concentrations.
Milrinone does not alter steady-state serum digoxin levels.
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 5.2 Pharmacokinetic Properties).
4.6

Fertility, Pregnancy and lactation
No data are available on whether or not digoxin has teratogenic effects.
There is no information available on the effect of digoxin on human fertility.
The use of digoxin in pregnancy is not contra-indicated, although the dosage
and control may be less predictable in pregnant than in non-pregnant women
with some requiring an increased dosage of digoxin during pregnancy. As
with all drugs, use should be considered only when the expected clinical
benefit of treatment to the mother outweighs any possible risk to the
developing foetus.
Despite extensive antenatal exposure to digitalis preparations, no significant
adverse effects have been observed in the foetus or neonate when maternal
serum digoxin concentrations are maintained within the normal range.
Although it has been speculated that a direct effect of digoxin in the
myometrium may result in relative prematurity and low birthweight, a
contributing role of the underlying cardiac disease cannot be excluded.
Maternally administered digoxin has been 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 contra-indicated.

4.7

Effects on ability to drive and use machines

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
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:

4.9

Fatigue, malaise, weakness

Overdose
The symptoms and signs of toxicity are generally similar to those described in
the Undesirable Effects 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 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.
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.
Hypokalaemia may contribute to toxicity (see Warnings and Precautions).
Non-cardiac manifestations
Acute massive digoxin overdosage can result in mild to pronounced
hyperkalaemia due to inhibition of the sodium-potassium (Na+-K+) pump.
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.
.
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 children. 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 ventricular fibrillation have been reported.
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 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 (Digibind®) resulted. 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.
Hypokalaemia should be corrected. In cases where a large amount of Lanoxin
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.
Rapid reversal of the complications that are associated with serious poisoning
by digoxin, digitoxin and related glycosides has followed intravenous
administration of digoxin-specific (ovine) antibody fragments (Fab) when

other therapies have failed. Digibind® is the only specific treatment for digoxin
toxicity.

5

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties
Mode of Action:Digoxin increases contractility of the myocardium by direct activity. This
effect is proportional to dose in the lower range and some effect is achieved
with quite low dosing; it occurs even in normal myocardium although it is
then entirely without physiological benefit. The primary action of digoxin is
specifically to inhibit adenosine triphosphatase, and thus sodium-potassium
(Na+-K+) exchange activity, the altered ionic distribution across the membrane
resulting in an augmented calcium ion influx and thus an increase in the
availability of calcium at the time of excitation-contraction coupling. The
potency of digoxin may therefore appear considerably enhanced when the
extracellular potassium concentration is low, with hyperkalaemia having the
opposite effect.
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 atrioventricular node. Thus, the major beneficial effect of
digoxin is reduction of ventricular rate.
Indirect cardiac contractility changes also result from changes in venous
compliance brought about by the altered autonomic activity and by direct
venous stimulation. The interplay between direct and indirect activity governs
the total circulatory response, which is not identical for all subjects. In the
presence of certain supraventricular arrhythmias, the neurogenically mediated
slowing of AV conduction is paramount.
The degree of neurohormonal activation occurring in patients with heart
failure is associated with clinical deterioration and an increased risk of death.
Digoxin reduces activation of both the sympathetic nervous system and the
(renin-angiotensin) system independently of its inotropic actions, and may
thus favourably influence survival. Whether this is achieved via direct
sympathoinhibitory effects or by re-sensitising baroreflex mechanisms remains
unclear.

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 Lanoxin
is approximately 63% in tablet form and 75% as paediatric elixir.
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.
Although the concentration in skeletal muscle is far lower, this store cannot be
overlooked since skeletal muscle represents 40% of total body weight. Of the
small proportion of digoxin circulating in plasma, approximately 25% is
bound to protein.
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 4.5 Interaction with other medicinal
products and other forms of interaction).
Following 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 mil/min in a healthy control population.
In a small percentage of individuals, orally administered digoxin is converted
to cardioinactivate 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. It is prolonged in patients with impaired renal
function, and in anuric patients may be of the order of 100 hours.
In the newborn period, renal clearance of digoxin is diminished and suitable
dosage adjustments must be observed. This is specially 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 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.
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 five hours of haemodialysis.
5.3

Preclinical safety data
No data are available on whether or not digoxin has mutagenic or carcinogenic
effects.

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Ethanol
Propylene Glycol
Citric Acid Monohydrate
Sodium phosphate anhydrous
or Sodium phosphate
Water for Injections

6.2

Incompatibilities
None known.

6.3

Shelf life
5 years.

6.4

Special precautions for storage
Do not store above 25°C.
Store in the original container

6.5

Nature and contents of container
Neutral glass ampoules

6.6

Special precautions for disposal
Lanoxin 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.
Lanoxin Injection, 250 micrograms/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:
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
Chemical in-use stability has been demonstrated for up to 96 hours at ambient
temperature (20-25°C).
From a microbiological point of view, the product should be used
immediately. If not used immediately, in-use storage times and conditions
prior to use are the responsibility of the user and would normally not be longer
than 24 hours at 2 to 8°C, unless reconstitution / dilution (etc) has taken place
in controlled and validated aseptic conditions.
Any unused solution should be discarded.
Ampoules are equipped with the OPC (one point cut) opening system and
must be opened as follows:

Hold with the hand the bottom part of the ampoule as indicated in Picture 1.
Put the other hand on the top of the ampoule positioning the thumb above the
coloured point and press as indicated in Picture 2.

7.

MARKETING AUTHORISATION HOLDER
Aspen Pharma Trading Limited
3016 Lake Drive
Citywest Business Campus
Dublin 24
Ireland

8

MARKETING AUTHORISATION NUMBER(S)
PL 39699/0006

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
22/06/2010

10

DATE OF REVISION OF THE TEXT
24/01/2014

Expand Transcript

Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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