Detailed View: Safety Labeling Changes Approved By FDA Center for Drug Evaluation and Research (CDER)
Serious Symptomatic Bradycardia When Co-administered with Ledipasvir/Sofosbuvir or with Sofosbuvir with Simeprevir
- Postmarketing cases of symptomatic bradycardia, some requiring pacemaker insertion and at least one fatal, have been reported when ledipasvir/sofosbuvir or sofosbuvir with simeprevir were initiated in patients on amiodarone. Bradycardia generally occurred within hours to days, but in some cases up to 2 weeks after initiating antiviral treatment. Bradycardia generally resolved after discontinuation of antiviral treatment. The mechanism for this effect is unknown. Monitor heart rate in patients taking or recently discontinuing amiodarone when starting antiviral treatment.
- Amiodarone can cause fetal harm when administered to a pregnant woman. Fetal exposure may increase the potential for adverse experiences including cardiac, thyroid, neurodevelopmental, neurological and growth effects in neonate. Inform the patient of the potential hazard to the fetus if Cordarone is administered during pregnancy or if the patient becomes pregnant while taking Cordarone.
- Amiodarone and desethylamiodarone cross the placenta.
- Reported risks include:
- neonatal bradycardia, QT prolongation, and periodic ventricular extrasystoles
- neonatal hypothyroidism (with or without goiter) detected antenatally or in the newborn and reported even after a few days of exposure
- neonatal hyperthyroxinemia
- neurodevelopmental abnormalities independent of thyroid function, including speech delay and difficulties with written language and arithmetic, delayed motor development, and ataxia.
- jerk nystagmus with synchronous head titubation
- fetal growth retardation
- premature birth.
- Amiodarone and one of its major metabolites, DEA, are excreted in human milk, suggesting that breast-feeding could expose the nursing infant to a significant dose of the drug. Nursing offspring of lactating rats administered have been shown to be less viable and have reduced body-weight gains. The risk of exposing the infant to amiodarone and DEA must be weighed against the potential benefit of arrhythmia suppression in the mother. Advise the mother to discontinue nursing.
- …serious symptomatic bradycardia has been reported in patients taking amiodarone who initiate treatment with ledipasvir/sofosbuvir or with sofosbuvir with simeprevir…
- added...The risk of exacerbation may be increased when other risk factors are present such as electrolytic disorders or use of concomitant antiarrhythmics or other interacting drugs (See “Drug Interactions, Other reported interactions with amiodarone”).
- added...Correct hypokalemia, hypomagnesemia or hypocalcemia whenever possible before initiating treatment with CORDARONE, as these disorders can exaggerate the degree of QTc prolongation and increase the potential for TdP. Give special attention to electrolyte and acid-base balance in patients experiencing severe or prolonged diarrhe or in patients receiving concomitant diuretics and laxatives, systemic corticosteroids, amphotericin B (IV) or other drugs affecting electrolyte levels.
- Sentence edited...Elevations in liver enzymes (aspartate aminotransferase and alanine aminotransferase) can occur.
The following sections have undergone significant edits:
- Pharmacodynamic interactions
- Pharmocokinetic interactions
- Effects of other medicinal products on amiodarone
- Effects of amiodarone on other medicinal products
- Hypothyroidism has been reported in 2 to 10% of patients receiving amiodarone and may be primary or subsequent to resolution of preceding amiodarone-induced hyperthyroidism. This condition may be identified by clinical symptoms and elevated serum TSH levels. Cases of severe hypothyroidism and myxedema coma, sometimes fatal, have been reported in association with amiodarone therapy. In some clinically hypothyroid amiodarone-treated patients, free thyroxine index values may be normal. Manage hypothyroidism by reducing the dose of or discontinuing Cordarone and considering the need for thyroid hormone supplement.
- In Postmarketing surveillance…acute pancreatitis…bullous dermatitis…and dry mouth…
- added: acute respiratory distress syndrome in the post-operative setting
HMG-CoA reductase inhibitors:
- Limit the dose of simvastatin in patients on amiodarone to 20 mg daily. Limit the daily dose of lovastatin to 40 mg. Lower starting and maintenance doses of other CYP3A4 substrates (e.g., atorvastatin) may be required as amiodarone may increase the plasma concentration of these drugs.
- drug rash with eosinophilia and systemic symptoms (DRESS)