LANOXIN (Page 5 of 9)

7.3 Potentially Significant Pharmacodynamic Drug Interactions

Because of considerable variability of pharmacodynamic interactions, the dosage of digoxin should be individualized when patients receive these medications concurrently.

Drugs that Affect Renal Function A decline in GFR or tubular secretion, as from ACE inhibitors, angiotensin receptor blockers, nonsteroidal anti-inflammatory drugs [NSAIDS], COX-2 inhibitors may impair the excretion of digoxin.
Antiarrthymics Dofetilide Concomitant administration with digoxin was associated with a higher rate of torsades de pointes
Sotalol Proarrhythmic events were more common in patients receiving sotalol and digoxin than on either alone; it is not clear whether this represents an interaction or is related to the presence of CHF, a known risk factor for proarrhythmia, in patients receiving digoxin.
Dronedarone Sudden death was more common in patients receiving digoxin with dronedarone than on either alone; it is not clear whether this represents an interaction or is related to the presence of advanced heart disease, a known risk factor for sudden death in patients receiving digoxin.
Parathyroid Hormone Analog Teriparatide Sporadic case reports have suggested that hypercalcemia may predispose patients to digitalis toxicity. Teriparatide transiently increases serum calcium.
Thyroid supplement Thyroid Treatment of hypothyroidism in patients taking digoxin may increase the dose requirements of digoxin.
Sympathomimetics EpinephrineNorepinephrine Dopamine Can increase the risk of cardiac arrhythmias
Neuromuscular Blocking Agents Succinylcholine May cause sudden extrusion of potassium from muscle cells causing arrhythmias in patients taking digoxin.
Supplements Calcium If administered rapidly by intravenous route, can produce serious arrhythmias in digitalized patients.
Beta-adrenergic blockers and calcium channel blockers Additive effects on AV node conduction can result in bradycardia and advanced or complete heart block.
Hyperpolarization-activated cyclic nucleotide-gated channel blocker Ivabradine Can increase the risk of bradycardia

7.4 Drug/Laboratory Test Interactions

Endogenous substances of unknown composition (digoxin-like immunoreactive substances, [DLIS]) can interfere with standard radioimmunoassays for digoxin. The interference most often causes results to be falsely positive or falsely elevated, but sometimes it causes results to be falsely reduced. Some assays are more subject to these failings than others. Several LC/MS/MS methods are available that may provide less susceptibility to DLIS interference. DLIS are present in up to half of all neonates and in varying percentages of pregnant women, patients with hypertrophic cardiomyopathy, patients with renal or hepatic dysfunction, and other patients who are volume-expanded for any reason. The measured levels of DLIS (as digoxin equivalents) are usually low (0.2-0.4 ng/mL), but sometimes they reach levels that would be considered therapeutic or even toxic.

In some assays, spironolactone, canrenone, and potassium canrenoate may be falsely detected as digoxin, at levels up to 0.5 ng/mL. Some traditional Chinese and Ayurvedic medicine substances like Chan Su, Siberian Ginseng, Asian Ginseng, Ashwagandha or Dashen can cause similar interference.

Spironolactone and DLIS are much more extensively protein-bound than digoxin. As a result, assays of free digoxin levels in protein-free ultrafiltrate (which tend to be about 25% less than total levels, consistent with the usual extent of protein binding) are less affected by spironolactone or DLIS. It should be noted that ultrafiltration does not solve all interference problems with alternative medicines. The use of an LC/MS/MS method may be the better option according to the good results it provides, especially in terms of specificity and limit of quantization.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary
Experience with digoxin in pregnant women over several decades, based on published retrospective clinical studies and case reports, has not led to the identification of a drug associated risk of major birth defects, miscarriage or adverse maternal and fetal outcomes. Untreated underlying maternal conditions, such as heart failure and atrial fibrillation, during pregnancy pose a risk to mother and fetus (see clinical consideration). Animal reproduction studies have not been conducted with digoxin.
The estimated background risk of major birth defects and miscarriage for the indicated population(s) are unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%-4% and 15%-20%, respectively.


Clinical Considerations
Disease-associated maternal and/or embryo/fetal risk
Pregnant women with heart failure are at increased risk of preterm birth. Clinical classification of heart disease may worsen with pregnancy and lead to maternal or fetal death.
Pregnant women with atrial fibrillation are at increased risk of delivering a low birth weight infant. Atrial fibrillation may worsen with pregnancy and can lead to maternal or fetal death.
Fetal/neonatal adverse reactions
Digoxin has been shown to cross the placenta and is found in amniotic fluid. Monitor neonates for signs and symptoms of digoxin toxicity, including vomitting, cardiac arrhythmias [see Warning and Precautions (5.3)].
Dose adjustments during pregnancy and the postpartum period
LANOXIN requirements may increase during pregnancy and decrease in the postpartum period. Monitor serum digoxin levels during pregnancy and postpartum period [see Dosage and Administration (2.5)].
Labor or delivery
Risk of arrhythmias may increase duing labor and delivery. Monitor patients continously during labor and delivery [see Warnings and Precautions (5.1and 5.2)].

8.2 Lactation

Risk Summary
The digoxin dose received through breastfeeding is upto 4% of the neonatal maintenance dosage, which is unlikely to be clinically relevant. There are no data on the effects of digoxin on the breastfed infant or effects on milk production.
Data Based on data from two lactation studies in a total of 13 breastfed infants, the digoxin concentrations in breast milk were between 0.4 — 1.0 ng/ml following 0.25 mg once daily dose of digoxin in the lactating mother. Thus, the amount of digoxin ingested daily by the infants is estimated to be between 0.03 to 0.16 μg/kg/day. This translates to relative infant dose of digoxin between 1 to 7% of maternal weight-adjusted dose and about 0.2 to 4% of the neonatal maintenance dose.

8.4 Pediatric Use

The safety and effectiveness of LANOXIN in the control of ventricular rate in children with atrial fibrillation have not been established.

The safety and effectiveness of LANOXIN in the treatment of heart failure in children have not been established in adequate and well-controlled studies. However, in published literature of children with heart failure of various etiologies (e.g., ventricular septal defects, anthracycline toxicity, patent ductus arteriosus), treatment with digoxin has been associated with improvements in hemodynamic parameters and in clinical signs and symptoms.

Newborn infants display considerable variability in their tolerance to digoxin. Premature and immature infants are particularly sensitive to the effects of digoxin, and the dosage of the drug must not only be reduced but must be individualized according to their degree of maturity.

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