Side Effects of Lanoxin (digoxin)

Lanoxin (digoxin) is a cardiac glycoside that increases the strength and efficiency of heart contractions, and is used to treat mild to moderate congestive heart failure and to treat atrial fibrillation, an abnormal heart rhythm. It also is used for increasing myocardial contractility in pediatric patients with heart failure. 

Lanoxin increases the force of contraction of the muscle of the heart by inhibiting the activity of an enzyme (ATPase) that controls movement of calcium, sodium, and potassium into heart muscle. Calcium controls the force of contraction. Inhibiting ATPase increases calcium in heart muscle and therefore increases the force of heart contractions. 

Lanoxin also slows electrical conduction between the atria and the ventricles of the heart and is useful in treating abnormally rapid atrial rhythms such as atrial fibrillation, atrial flutter, and atrial tachycardia. (Abnormally rapid atrial rhythms can be caused by heart attacks, excessive thyroid hormones, alcoholism, infections, and many other conditions.) 

During rapid atrial rhythms, electrical signals from the atria cause rapid contractions of the ventricles. Rapid ventricular contractions are inefficient in pumping blood containing oxygen and nutrients to the body, causing symptoms of

• weakness,
• shortness of breath,
• dizziness, and
• even chest pain.

Lanoxin alleviates these symptoms by blocking the electrical conduction between the atria and ventricles, thus slowing ventricular contractions.

Common side effects of Lanoxin include

• nausea,
• diarrhea,
• vomiting,
• headache,
• dizziness,
• skin rash, and
• mental changes.

Lanoxin has also been associated with

• visual disturbance (blurred or yellow vision),
• abdominal pain, and
• breast enlargement. 

Serious side effects of Lanoxin include

• heart block,
• rapid heartbeat, and
• slow heart rate.

Drug interactions of Lanoxin include gentamicin, tetracycline, ranolazine, verapamil, quinidine, amiodarone, indomethacin, alprazolam, spironolactone, and itraconazole, which can increase Lanoxin levels and the risk of toxicity.

• The co-administration of Lanoxin and beta-blockers or calcium channel blockers or CCBs, which also reduce heart rate, can cause serious heart rate slowing.
• Diuretic-induced (for example, by furosemide) reduction in blood potassium or magnesium levels may predispose patients to Lanoxin-induced abnormal heart rhythms.
• Saquinavir and ritonavir increase the amount of Lanoxin in the body and may cause Lanoxin toxicity.
• Mirabegron increases Lanoxin blood levels.
• The lowest dose of Lanoxin should be used by people who are also using mirabegron.
• Omeprazole and other drugs that reduce stomach acidity may increase blood levels of Lanoxin. 

There are no adequate studies of Lanoxin in pregnant women. Lanoxin is secreted in breast milk at concentrations similar to concentrations in the mother’s blood. However, the total amount of Lanoxin that will be absorbed from breast milk by the infant may not be enough to cause effects. 

Caution should be exercised by nursing mothers who are taking Lanoxin.  Consult your doctor before breastfeeding.

Common side effects include

• nausea,
• diarrhea,
• vomiting,
• headache,
• dizziness,
• skin rash, and
• mental changes.

Many digoxin side effects are dose dependent and happen when blood levels are over the narrow therapeutic range. Therefore, digoxin side effects can be avoided by keeping blood levels within the therapeutic level. Serious side effects associated with digoxin include

• heart block,
• rapid heartbeat, and
• slow heart rate.

Digoxin has also been associated with visual disturbance (blurred or yellow vision), abdominal pain, and breast enlargement. Patients with low blood potassium levels can develop digoxin toxicity even when digoxin levels are not considered elevated. Similarly, high calcium and low magnesium blood levels can increase digoxin toxicity and produce serious disturbances in heart rhythm.

The following adverse reactions are included in more detail in the Warnings and Precautions section of the label:

• Cardiac arrhythmias
• Digoxin Toxicity

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

In general, the adverse reactions of Lanoxin are dose-dependent and occur at doses higher than those needed to achieve a therapeutic effect. Hence, adverse reactions are less common when Lanoxin is used within the recommended dose range, is maintained within the therapeutic serum concentration range, and when there is careful attention to concurrent medications and conditions.

In the DIG trial (a trial investigating the effect of digoxin on mortality and morbidity in patients with heart failure), the incidence of hospitalization for suspected digoxin toxicity was 2% in patients taking Lanoxin compared to 0.9% in patients taking placebo.

The overall incidence of adverse reactions with digoxin has been reported as 5-20%, with 15-20% of adverse events considered serious. Cardiac toxicity accounts for about one-half, gastrointestinal disturbances for about one-fourth, and CNS and other toxicity for about one-fourth of these adverse events.

Gastrointestinal

• In addition to nausea and vomiting, the use of digoxin has been associated with abdominal pain, intestinal ischemia, and hemorrhagic necrosis of the intestines.

CNS

• Digoxin can cause headache, weakness, dizziness, apathy, confusion, and mental disturbances (such as anxiety, depression, delirium, and hallucination).

Other

• Gynecomastia has been occasionally observed following the prolonged use of digoxin.
• Thrombocytopenia and maculopapular rash and other skin reactions have been rarely observed.

• Digoxin has a narrow therapeutic index, increased monitoring of serum digoxin concentrations and for potential signs and symptoms of clinical toxicity is necessary when initiating, adjusting, or discontinuing drugs that may interact with digoxin.
• Prescribers should consult the prescribing information of any drug which is co-prescribed with digoxin for potential drug interaction information.

P-Glycoprotein (PGP) Inducers/Inhibitors

• Digoxin is a substrate of P-glycoprotein, at the level of intestinal absorption, renal tubular section and biliary-intestinal secretion.
• Therefore, drugs that induce/ inhibit P-glycoprotein have the potential to alter digoxin pharmacokinetics.

Pharmacokinetic Drug Interactions

• Pharmacokinetic interactions have been observed and reported primarily when digoxin is coadministered by oral route.
• There are very few studies that have evaluated the drug interaction when digoxin is administered via IV route.
• The magnitude of digoxin exposure change through IV route is generally lower than that through oral route.
• Table below provides available interaction data using digoxin IV formulation (NA means not available).

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.

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.