Dronedarone

137-145

149-153 °C

MW: 360.53. Crystals from hexane, mp 126-130 °C. Specific optical rotation: + 24 deg at 25 °C/D /Propionate/

Specific optical rotation: +32 deg at 25 °C/D (ethanol)

Danger

H360 (50%): May damage fertility or the unborn child [Danger Reproductive toxicity]；H373 (50%): May causes damage to organs through prolonged or repeated exposure [Warning Specific target organ toxicity, repeated exposure]；H400 (50%): Very toxic to aquatic life [Warning Hazardous to the aquatic environment, acute hazard]；H410 (75%): Very toxic to aquatic life with long lasting effects [Warning Hazardous to the aquatic environment, long-term hazard]

P203, P260, P273, P280, P318, P319, P391, P405, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 4 reports by companies from 4 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.；Information may vary between notifications depending on impurities, additives, and other factors. The percentage value in parenthesis indicates the notified classification ratio from companies that provide hazard codes. Only hazard codes with percentage values above 10% are shown. For more detailed information, please visit ECHA C&L website.

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including dronedarone hydrochloride, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Dronedarone hydrochloride/

SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.

SRP: At the time of review, regulatory criteria for small quantity disposal are subject to significant revision, however, household quantities of waste pharmaceuticals may be managed as follows: Mix with wet cat litter or coffee grounds, double bag in plastic, discard in trash.

Dronedarone can increase plasma concentrations of tacrolimus, sirolimus, and other CYP 3A substrates with a narrow therapeutic range when given orally. Monitor plasma concentrations and adjust dosage appropriately.

Dronedarone increased simvastatin/simvastatin acid exposure by 4- and 2-fold, respectively. Because of multiple mechanisms of interaction with statins (CYPs and transporters), follow statin label recommendations for use with CYP 3A and P-gP inhibitors such as dronedarone.

Pantoprazole, a drug that increases gastric pH, did not have a significant effect on dronedarone pharmacokinetics.

Verapamil and diltiazem are moderate CYP 3A inhibitors and increase dronedarone exposure by approximately 1.4-to 1.7-fold.

For more Interactions (Complete) data for Dronedarone (16 total), please visit the HSDB record page.

Chronic therapy with dronedarone has been associated with mild serum enzyme elevations in up to 12% of patients, but similar rates were found in comparator arms and even in placebo recipients. The serum aminotransferase elevations that occur during chronic dronedarone therapy are generally mild-to-moderate in severity and asymptomatic, rarely requiring discontinuation or dose modification. In preapproval clinical trials, clinically apparent liver injury was not described. Since its approval and more wide scale use, however, dronedarone has been linked to several cases of clinically apparent liver injury with jaundice, some of which have been severe and some fatal. The onset of injury ranged from 2 to 11 months and the clinical presentation was similar to acute viral hepatitis, with symptoms of fatigue and abdominal discomfort followed by jaundice and a hepatocellular pattern of serum enzyme elevations. Several instances have resulted in acute liver failure requiring emergency liver transplantation. The liver injury associated with dronedarone is distinctly different from that related to amiodarone. The injury is typically hepatocellular rather than cholestatic or mixed. The latency to onset of amiodarone associated liver injury can be quite long, several years and rarely shorter than 6 months. In contrast, dronedarone liver injury typically arises within 2 to 6 months. Therapy with amiodarone has been associated with cirrhosis and histologic findings resembling alcoholic liver disease. Dronedarone has not been implicated in causing cirrhosis, and the injury is more typical of moderate to severe idiosyncratic, hepatocellular drug induced liver injury.；Likelihood score: B (likely rare cause of clinically apparent liver injury).

/SIGNS AND SYMPTOMS/ Postmarketing cases of new onset and worsening heart failure have been reported during treatment with Multaq. Advise patients to consult a physician if they develop signs or symptoms of heart failure, such as weight gain, dependent edema, or increasing shortness of breath. If heart failure develops or worsens, consider the suspension or discontinuation of Multaq.

/SIGNS AND SYMPTOMS/ Hepatocellular liver injury, including acute liver failure requiring transplant, has been reported in patients treated with MULTAQ in the post-marketing setting. Advise patients treated with Multaq to report immediately symptoms suggesting hepatic injury (such as anorexia, nausea, vomiting, fever, malaise, fatigue, right upper quadrant pain, jaundice, dark urine, or itching). Consider obtaining periodic hepatic serum enzymes, especially during the first 6 months of treatment. It is not known whether routine periodic monitoring of serum enzymes will prevent the development of severe liver injury. If hepatic injury is suspected, promptly discontinue Multaq and test serum enzymes, aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase, as well as serum bilirubin, to establish whether there is liver injury. If liver injury is found, institute appropriate treatment and investigate the probable cause. Do not restart Multaq in patients without another explanation for the observed liver injury.

/CASE REPORTS/ A 47-year-old male with a history of heart failure with New York Heart Association class III-IV symptoms presented to our institution with ventricular fibrillation and ventricular tachycardia storm. Torsade de pointes secondary to a combination of dofetilide and hypokalemia was determined to be the etiology. Upon stabilization, the patient was initiated on dronedarone 400 mg orally twice daily by the electrophysiology service for atrial fibrillation. The patient had a questionable history of amiodarone intolerance. By hospital day 9 (day 4 of dronedarone therapy), the patient demonstrated a clinical picture consistent with acute renal and hepatic failure possibly due to worsening heart failure. Dronedarone was discontinued on hospital day 10. He was subsequently transferred to an outside hospital where he required milrinone therapy for cardiogenic shock. Laboratory markers of renal and hepatic function improved over the remainder of his hospitalization and he was discharged on hospital day 20. Dronedarone is a newly approved antiarrhythmic agent with multichannel blocking properties similar to amiodarone. Use of the Naranjo probability scale determined that this patient's worsening heart failure leading to acute renal and hepatic failure was possibly caused by dronedarone. The implication from the ANDROMEDA trial as well as our experience in this case is that dronedarone should be used cautiously in patients with heart failure and avoided in patients specifically outlined in the product labeling.

/EPIDEMIOLOGY STUDIES/ In a multicenter study with a double-blind design, 1000 patients who were hospitalized with symptomatic heart failure and severe left ventricular systolic dysfunction /were randomly assigned/ to receive 400 mg of dronedarone twice a day or placebo. The primary end point was the composite of death from any cause or hospitalization for heart failure. After inclusion of 627 patients (310 in the dronedarone group and 317 in the placebo group), the trial was prematurely terminated for safety reasons, at the recommendation of the data and safety monitoring board, in accordance with the board's predefined rules for termination of the study. During a median follow-up of 2 months, 25 patients in the dronedarone group (8.1%) and 12 patients in the placebo group (3.8%) died (hazard ratio in the dronedarone group, 2.13; 95% confidence interval (CI), 1.07 to 4.25; P=0.03). The excess mortality was predominantly related to worsening of heart failure--10 deaths in the dronedarone group and 2 in the placebo group. The primary end point did not differ significantly between the two groups; there were 53 events in the dronedarone group (17.1%) and 40 events in the placebo group (12.6%) (hazard ratio, 1.38; 95% CI, 0.92 to 2.09; P=0.12). More increases in the creatinine concentration were reported as serious adverse events in the dronedarone group than in the placebo group.

Drug-Induced Liver Injury Severity and Toxicity (DILIst)

dronedarone

DILI Positive

Oral

DOI:10.1016/j.drudis.2019.09.022

/LABORATORY ANIMALS: Acute Exposure/ Single-dose toxicity studies with oral (1500 and 2000 mg/kg) administration were performed in mice and rats of both sexes (5 animals/sex/group). The maximum nonlethal dose in the mouse and the rat was 2000 mg/kg. A single oral administration of 2000 mg/kg of dronedarone caused some clinical signs in rats (prostration, piloerection, ptyalism, and soiled urogenital areas), and a decrease in body weight gain in both species.

/LABORATORY ANIMALS: Acute Exposure/ On the hydroelectrolytic balance, the only observed effects in the rat were a decrease in endogenous creatinine clearance (from 30 mg/kg in females and at 100 mg/kg in males), a decrease in urinary volume associated with slight changes in excreted quantities of electrolytes (100 mg/kg only in both sexes).

/LABORATORY ANIMALS: Acute Exposure/ The respiratory function was assessed both in conscious guinea-pigs and in anesthetized dogs. In the guinea pig, dronedarone administered orally did not affect respiratory function up to and including the dose of 100 mg/kg. Single doses of 12.5 or 25 mg/kg dronedarone were administered by intraduodenal administration to groups of 5 anesthetized dogs of either sex. An increase in the respiratory frequency and flow was observed after the administration of the dose of 25 mg/kg.

/LABORATORY ANIMALS: Acute Exposure/ In anesthetized dog, administered by the intraduodenal route, dronedarone induced at 12.5 and 25 mg/kg a dose-dependent decrease in mean arterial blood pressure associated with a vasodilator effect, an increase in stroke volume and cardiac output associated with a decrease in total peripheral resistances. No ECG changes were observed. Single doses of dronedarone (1 and 5 mg/kg) were administered by intravenous infusion in pentobarbital-anesthetized mongrel dogs of either sex. At 5 mg/kg the main effects consisted of a biphasic decrease in blood pressure, limb peripheral resistances and left ventricular pressure, a negative chronotropic effect (-22%), a decrease in total peripheral resistances (-43%) and moderate increase (39%) in cardiac output associated with a marked increase (54%) in stroke volume.

For more Non-Human Toxicity Excerpts (Complete) data for Dronedarone (11 total), please visit the HSDB record page.

Multaq is contraindicated in patients with New York Heart Association (NYHA) Class IV heart failure, or NYHA Class II - III heart failure with a recent decompensation requiring hospitalization or referral to a specialized heart failure clinic. In a placebo-controlled study in patients with severe heart failure requiring recent hospitalization or referral to a specialized heart failure clinic for worsening symptoms (the ANDROMEDA Study), patients given dronedarone had a greater than two-fold increase in mortality. Such patients should not be given dronedarone

Dronedarone has not been studied in patients with severe hepatic impairment and limited clinical experience is available in patients with moderate hepatic impairment. No dosage adjustment is required in patients with moderate hepatic impairment. Dronedarone is contraindicated in patients with severe hepatic impairment. In patients with moderate hepatic impairment, the mean exposure to dronedarone increased by 1.3-fold compared with that in individuals with normal hepatic function, and the mean exposure to the N-debutyl metabolite decreased by about 50%. The pharmacokinetics of dronedarone have not been studied in patients with severe hepatic impairment.

/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/

/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/

/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including dronedarone hydrochloride, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Dronedarone hydrochloride/

C - Cardiovascular system；C01 - Cardiac therapy；C01B - Antiarrhythmics, class i and iii；C01BD - Antiarrhythmics, class iii；C01BD07 - Dronedarone

QC - Cardiovascular system；QC01 - Cardiac therapy；QC01B - Antiarrythmics, class i and iii；QC01BD - Antiarrhythmics, class iii；QC01BD07 - Dronedarone

Dronedarone is an antiarrhythmic agent that restores normal sinus rhythm and reduces heart rate in atrial fibrillation. In another model, it prevents ventricular tachycardia and ventricular fibrillation. Dronedarone moderately prolongs the QTc interval by about 10 ms on average. Dronedarone decreases arterial blood pressure and reduces oxygen consumption. It reduces myocardial contractility with no change in left ventricular ejection fraction. Dronedarone vasodilates coronary arteries through activation of the nitric oxide pathway. In clinical studies, dronedarone reduced incidence of hospitalizations for acute coronary syndromes and reduced incidence of stroke. Dronedarone exhibits antiadrenergic effects by reducing alpha-adrenergic blood pressure response to epinephrine and beta 1 and beta 2 responses to isoproterenol. Dronedarone was shown to inhibit triiodothyronine (T3) signalling by binding to TRα1 but much less so to TRβ1. The treatment of dronedarone in patients with severe heart failure and left ventricular systolic dysfunction was associated with increased early mortality related to the worsening of heart failure. In animal studies, the use of dronedarone at doses equivalent to the recommended human doses was associated with fetal harm. In clinical studies and postmarketing reports, dronedarone was shown to cause hepatocellular liver injury and pulmonary toxicities, such as interstitial lung disease, pneumonitis, and pulmonary fibrosis. Compared to its related compound [amiodarone], dronedarone has a faster onset and offset of actions with a shorter elimination half-life and low tissue accumulation.

Atrial fibrillation is the most common type of arrhythmia that is caused by abnormal electrical activity in the atria. In atrial fibrillation, tachyarrhythmia, or fast heart rate, can either be paroxysmal (less than 7 days) or persistent (more than 7 days). Atrial fibrillation causes turbulent and abnormal blood flow through the heart chambers, leading to decreased the effectiveness of the heart to pump blood and an increased likelihood of thrombus formation within the atria which can ultimately dislodge and cause a stroke. Dronedarone achieves heart rate and rhythm control in atrial fibrillation. _In vitro_, dronedarone decreased the maximum rate of the rise of an action potential in a concentration- and frequency-dependent manner. Cardiac action potentials are generated by ionic currents of multiple voltage-gated ion channels, including potassium, sodium, and calcium channels. Dronedarone is a multichannel blocker that meets the criteria of all four Vaughan Williams antiarrhythmic drug classes but the contribution of each of these activities to the drug's antiarrhythmic effect is unknown. Dronedarone inhibits rapid Na+ currents rate-dependently (class Ib), non-competitively antagonizes α– and β-adrenergic receptors (class II), blocks K+ outward currents (class III) and blocks slow Ca2+ inward currents (class IV). More specifically, it decreases delayed-rectifier K+ current (IKr), slowly activating delayed-rectifier K+ current (IKs), inward rectifier potassium current (IK1), peak Na+ current (INa) and L-type Ca2+ current (ICa (L)). Dronedarone ultimately increases refractory periods, decelerates cardiac conduction, and prolongs cardiac action potential and refractory periods.

Pharmacological inhibition of human-ether-a-go-go-related gene (HERG) K(+) channels by structurally and therapeutically diverse drugs is associated with the 'acquired' form of long QT syndrome and with potentially lethal cardiac arrhythmias. Two aromatic amino-acid residues (Y652 and F656) on the inner (S6) helices are considered to be key constituents of a high affinity drug binding site within the HERG channel pore cavity. Using wild-type (WT) and mutant HERG channels expressed in mammalian cell lines, we have investigated HERG channel current (I(HERG)) blockade at 37+/-1 degrees C by dronedarone a non-iodinated analogue of the Class III antiarrhythmic agent amiodarone. Under our conditions WT I(HERG) tails, measured at -40 mV following activating pulses to +30 mV, were blocked with IC(50) values of approximately 59 and 70 nM for dronedarone and amiodarone, respectively. I(HERG) inhibition by dronedarone was contingent upon channel gating, with block developing rapidly on membrane depolarization, but with no preference for activated over inactivated channels. High external [K(+)] (94 mM) reduced the potency of I(HERG) inhibition by both dronedarone and AMIOD. Strikingly, mutagenesis to alanine of the S6 residue F656 (F656A) failed to eliminate blockade by both dronedarone and amiodarone, whileY652A had comparatively little effect on dronedarone but some effect on amiodarone. These findings demonstrate that high affinity drug blockade of I(HERG) can occur without a strong dependence on the Y652 and F656 aromatic amino-acid residues.

In animals, dronedarone prevents atrial fibrillation or restores normal sinus rhythm depending on the model used. It also prevents ventricular tachycardia and ventricular fibrillation in several animal models. These effects most likely result from its electrophysiological properties belonging to all four Vaughan-Williams classes. Dronedarone is a multichannel blocker inhibiting the potassium currents (including IK(Ach), IKur, IKr, IKs) and thus prolonging cardiac action potential and refractory periods (Class III). It also inhibits the sodium currents (Class Ib) and the calcium currents (Class IV). It noncompetitively antagonises adrenergic activities (Class II).

The elimination half life ranges from 13 to 19 hours.

The terminal elimination half-life of dronedarone is around 25-30 hours and that of its N-debutyl metabolite around 20-25 hours.

Dronedarone predominantly undergoes CYP3A-mediated hepatic metabolism. Initial metabolism of dronedarone involves N-debutylation to form the N-debutyl-dronedarone, which retains 1/10 to 1/3 of pharmacological activity of the parent compound. N-debutyl-dronedarone can be further metabolized to phenol-dronedarone via O-dealkylation and propanoic acid-dronedarone via oxidative deamination. Dronedarone can also be metabolized by CYP2D6 to form benzofuran-hydroxyl-dronedarone. Other detectable metabolites include C-dealkyl-dronedarone and dibutylamine-hydroxyl-dronedarone, along with other minor downstream metabolites with undetermined chemical structures.

Dronedarone is extensively metabolised, mainly by CYP 3A4 (see section 4.5). The major metabolic pathway includes N-debutylation to form the main circulating active metabolite followed by oxidation, oxidative deamination to form the inactive propanoic acid metabolite, followed by oxidation, and direct oxidation. The N-debutyl metabolite exhibits pharmacodynamic activity but is 3 to 10-times less potent than dronedarone. This metabolite contributes to the pharmacological activity of dronedarone in humans.

JQZ1L091Y2

DRONEDARONE

Established Pharmacologic Class [EPC] - Antiarrhythmic

Dronedarone is an Antiarrhythmic.

DRONEDARONE

Antiarrhythmic [EPC]; P-Glycoprotein Inhibitors [MoA]; Cytochrome P450 3A Inhibitors [MoA]; Cytochrome P450 2D6 Inhibitors [MoA]

Agents used for the treatment or prevention of cardiac arrhythmias. They may affect the polarization-repolarization phase of the action potential, its excitability or refractoriness, or impulse conduction or membrane responsiveness within cardiac fibers. Anti-arrhythmia agents are often classed into four main groups according to their mechanism of action: sodium channel blockade, beta-adrenergic blockade, repolarization prolongation, or calcium channel blockade.

Dronedarone is well absorbed after oral administration (>70%). It displays low systemic bioavailability due to extensive first-pass metabolism. The absolute bioavailability of dronedarone without and with a high-fat meal is 4% and 15%, respectively. The peak plasma concentrations of dronedarone and its main circulating N-debutyl metabolite are reached within 3 to 6 hours after administration with food. Following repeated administration of 400 mg dronedarone twice daily, the steady-state was reached within 4 to 8 days of initial treatment. The steady-state Cmax and systemic exposure to the N-debutyl metabolite are similar to that of the parent compound.

Following oral administration, about 84% of the labeled dose is excreted in feces and 6% is excreted in urine, mainly as metabolites. Unchanged parent compound and the N-debutyl metabolite accounted for less than 15% of the total radioactivity in the plasma.

The volume of distribution at steady-state ranges from 1200 to 1400 L following intravenous administration.

Following intravenous administration, the clearance ranged from 130 to 150 L/h.

The in vitro plasma protein binding of dronedarone and its N-debutyl metabolite is 99.7% and 98.5% respectively and is not saturable. Both compounds bind mainly to albumin. After intravenous administration the volume of distribution at steady state (Vss) ranges from 1,200 to 1,400 L.

Following oral administration in fed condition, dronedarone is well absorbed (at least 70%). However due to presystemic first pass metabolism, the absolute bioavailability of dronedarone (given with food) is 15%. Concomitant intake of food increases dronedarone bioavailability by on average 2- to 4- fold. After oral administration in fed conditions, peak plasma concentrations of dronedarone and the main circulating active metabolite (N-debutyl metabolite) are reached within 3 to 6 hours. After repeated administration of 400 mg twice daily, steady state is reached within 4 to 8 days of treatment and the mean accumulation ratio for dronedarone ranges from 2.6 to 4.5. The steady state mean dronedarone Cmax is 84-147 ng/mL and the exposure of the main N-debutyl metabolite is similar to that of the parent compound. The pharmacokinetics of dronedarone and its N-debutyl metabolite both deviate moderately from dose proportionality: a 2-fold increase in dose results in an approximate 2.5- to 3.0-fold increase with respect to Cmax and AUC.