Amiodarone intravenous

Amiodarone is a substrate for CYP3A and CYP2C8, so inhibitors and inducers affect amiodarone exposure ( 7 ) Amiodarone inhibits p-glycoprotein and CYP1A2, CYP2C9, CYP2D6, and CYP3A, increasing exposure to other drugs ( 7 )

7.1 Pharmacodynamic Interactions Drugs Prolonging the QT Interval Co-administration of drugs prolonging the QT interval (such as class I and III antiarrhythmics, lithium, certain phenothiazines, tricyclic antidepressants, certain fluoroquinolone and macrolide antibiotics, azole antifungals, halogenated inhalation anesthetic agents) increases the risk of Torsade de Pointes. In general, avoid concomitant use of drugs that prolong the QT interval [see Warnings and Precautions (5.4) ] .

Drugs That Slow Heart Rate Concomitant use of drugs with depressant effects on the sinus and AV nodes (e.g., digoxin, beta blockers, verapamil, diltiazem, ivabradine, clonidine) can potentiate the electrophysiologic and hemodynamic effects of amiodarone, resulting in bradycardia, sinus arrest, and AV block. Monitor heart rate in patients on amiodarone and concomitant drugs that slow heart rate.

7.2 Pharmacokinetic Interactions Effect of Other Drugs on Amiodarone Amiodarone is metabolized to the active metabolite desethylamiodarone (DEA) by the cytochrome P450 (CYP450) enzyme group, specifically CYP3A and CYP2C8. Amiodarone has the potential for interactions with drugs or substances that may be substrates, inhibitors or inducers of CYP450 enzymes (e.g., inhibitors such as protease inhibitors , grapefruit juice , certain fluoroquinolone and macrolide antibiotics , azole antifungals and inducers such as St. John’s Wort ) or P-glycoprotein.

In view of the long and variable half- life of amiodarone, potential for drug interactions exists not only with concomitant medications but also with drugs administered after discontinuation of amiodarone [see Clinical Pharmacology (12.3) ] . Patients should avoid grapefruit juice beverages while taking amiodarone because exposure to amiodarone is significantly increased [see Clinical Pharmacology (12.3) ] . Effect of amiodarone on other drugs Amiodarone and DEA are inhibitors of P-glycoprotein and certain CYP450 enzymes, including CYP1A2, CYP2C9, CYP2D6, and CYP3A [see Clinical Pharmacology (12.3)].

Antiarrhythmics The metabolism of quinidine , procainamide , and flecainide can be inhibited by amiodarone. In general, initiate any added antiarrhythmic drug at a lower than usual dose and monitor the patient carefully. During transfer to oral amiodarone, reduce the dose levels of previously administered antiarrhythmic agents by 30% to 50% several days after the addition of oral amiodarone. Review the continued need for the other antiarrhythmic agent after the effects of amiodarone have been established, and attempt discontinuation [see Clinical Pharmacology (12.3) ].

Digoxin In patients receiving digoxin therapy, administration of oral amiodarone results in an increase in serum digoxin concentration. Reduce dose of digoxin by half or discontinue digoxin. If digitalis treatment is continued, monitor serum levels closely and observe patients for clinical evidence of toxicity [see Clinical Pharmacology (12.3) ] . 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.

Anticoagulants Potentiation of warfarin -type (CYP2C9 and CYP3A substrate) anticoagulant response is almost always seen in patients receiving amiodarone and can result in serious or fatal bleeding. Since the concomitant administration of warfarin with amiodarone increases INR by 100% after 3 to 4 days, reduce the dose of the anticoagulant by one-third to one-half, and monitor INR closely. Cyclosporine (CYP3A Substrate) Administered in combination with oral amiodarone has been reported to produce persistently elevated plasma concentrations of cyclosporine resulting in elevated creatinine, despite reduction in dose of cyclosporine.

Monitor cyclosporine drug levels and renal function in patients taking both drugs. Increased steady-state levels of phenytoin during concomitant therapy with amiodarone have been reported. Monitor phenytoin levels in patients taking both drugs.

7.3 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.

Drug Interactions Effect of Other Drugs on Amiodarone: Cimetidine inhibits CYP3A and can increase serum amiodarone levels. Grapefruit juice given to healthy volunteers increased amiodarone AUC by 50% and Cmax by 84%, resulting in increased plasma levels of amiodarone. Cholestyramine reduces enterohepatic circulation of amiodarone thereby increasing its elimination. This results in reduced amiodarone serum levels and half-life. Effect of Amiodarone on Other Drugs: Amiodarone taken concomitantly with quinidine increases the quinidine serum concentration by 33% after two days.

Amiodarone taken concomitantly with procainamide for less than seven days increases plasma concentrations of procainamide and n-acetyl procainamide by 55% and 33%, respectively. Loratadine , a non-sedating antihistaminic, is metabolized primarily by CYP3A and its metabolism can be inhibited by amiodarone. Metabolism of lidocaine can be inhibited by amiodarone. Sinus bradycardia has been reported with oral amiodarone in combination with lidocaine (CYP3A substrate) given for local anesthesia. Seizure, associated with increased lidocaine concentrations, has been reported with concomitant administration of intravenous amiodarone.

Amiodarone can inhibit the metabolism of macrolide/ketolide antibiotics (except for azithromycin) and systemic azole antifungal drugs. Amiodarone taken concomitantly with digoxin increases the serum digoxin concentration by 70% after one day. Dextromethorphan is a substrate for both CYP2D6 and CYP3A. Amiodarone inhibits CYP2D6. Chronic (> 2 weeks) oral amiodarone administration impairs metabolism of dextromethorphan can lead to increased serum concentrations. Dabigatran etexilate when taken concomitantly with oral amiodarone can result in elevated serum concentration of dabigatran. Cyclophosphamide is a prodrug , metabolized by CYP450 including CYP3A to an active metabolite.

The metabolism of cyclophosphamide may be inhibited by amiodarone. Clopidogrel , an inactive thienopyridine prodrug, is metabolized in the liver by CYP3A to an active metabolite. A potential interaction between clopidogrel and amiodarone resulting in ineffective inhibition of platelet aggregation has been reported.

8.1 Pregnancy Teratogenic Effects 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 has caused a variety of adverse effects in animals. Amiodarone was given intravenously to rabbits at dosages of 5 mg/kg per day, 10 mg/kg per day, or 25 mg/kg per day (about 0.1, 0.3, and 0.7 times the human intravenous maintenance dose of 0.5 mg/min on a body surface area basis), during gestation days 8 to 16 (organogenesis). The incidence of maternal deaths increased with increasing dose and occurred in all treated groups, and controls.

Mean fetal weights were significantly decreased in the low and middle dose groups and embryotoxicity (as manifested by fewer full- term fetuses and increased resorptions) occurred at dosages of 10 mg/kg and above. There were no significant differences in the number of minor fetal abnormalities and no major fetal abnormalities were observed. Amiodarone was administered by continuous intravenous infusion to rats at dosages of 25 mg/kg per day, 50 mg/kg per day, or 100 mg/kg per day (about 0.3, 0.7, and 1.3 times the human intravenous maintenance dose of 0.5 mg/min on a body surface area basis) during gestation days 8 to 16 (organogenesis).

Maternal toxicity (manifest as reduced weight gain and food consumption) and embryotoxicity (manifest as increased resorptions, decreased live litter size and fetal body weights, and delayed sternal and metacarpal ossification) were observed in the 100 mg/kg group. The delayed ossification was reversible and related to decreased fetal weight. Fetal thyroid tissues appeared normal in all groups. Nonteratogenic Effects Very high concentrations of amiodarone and desethylamiodarone may be found in testes. Elevated follicle-stimulating hormone and luteinizing hormone levels, suggestive of testicular dysfunction, have been reported in men on long-term amiodarone treatment.

While planning pregnancy after discontinuation of amiodarone treatment, consider the long half-life of amiodarone and its metabolite DEA.

8.3 Nursing Mothers Amiodarone and one of its major metabolites, desethylamiodarone (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 amiodarone have demonstrated reduced viability and reduced body weight gains. The risk of exposing the infant to amiodarone must be weighed against the potential benefit of arrhythmia suppression in the mother. Advise the mother to discontinue nursing.