Lanoxin PG Tablets

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 above.

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

See section 4.4 Special w W arnings and p P recautions for u U se.

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.

4.4 Special warnings and precautions for use

Treatment with of digoxin should generally be avoided in patients with heart failure associated with cardiac amyloidosis.

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).

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 disociation dissociation 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

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. It 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.

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.[

10 DATE OF REVISION OF THE TEXT

December 2012 October 2013