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CLINICAL PHARMACOLOGY

Mechanism Of Action

The mechanism of action of dronedarone is unknown. Dronedarone has antiarrhythmic properties belonging to all four Vaughan-Williams classes, but the contribution of each of these activities to the clinical effect is unknown.

Pharmacodynamics

Electrophysiological effects

Dronedarone exhibits properties of all four Vaughn-Williams antiarrhythmic classes, although it is unclear which of these are important in producing dronedarone's clinical effects. The effect of dronedarone on 12-lead ECG parameters (heart rate, PR, and QTc) was investigated in healthy subjects following repeated oral doses up to 1600 mg once daily or 800 mg twice daily for 14 days and 1600 mg twice daily for 10 days. In the dronedarone 400 mg twice daily group, there was no apparent effect on heart rate; a moderate heart rate lowering effect (about 4 bpm) was noted at 800 mg twice daily. There was a clear dose-dependent effect on PR-interval with an increase of +5 ms at 400 mg twice daily and up to +50 ms at 1600 mg twice daily. There was a moderate dose related effect on the QTc-interval with an increase of +10 ms at 400 mg twice daily and up to +25 ms with 1600 mg twice daily.

DAFNE study

DAFNE was a dose-response study in patients with recurrent AF, evaluating the effect of dronedarone in comparison with placebo in maintaining sinus rhythm. The doses of dronedarone in this study were 400, 600, and 800 mg twice a day. In this small study, doses above 400 mg were not more effective and were less well tolerated.

Pharmacokinetics

Dronedarone is extensively metabolized and has low systemic bioavailability; its bioavailability is increased by meals. Its elimination half life is 13-19 hours.

Absorption

Because of presystemic first pass metabolism the absolute bioavailability of dronedarone without food is low, about 4%. It increases to approximately 15% when dronedarone is administered with a high fat meal. 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 Cmax and 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.

Distribution

The in vitro plasma protein binding of dronedarone and its N-debutyl metabolite is > 98 % and not saturable. Both compounds bind mainly to albumin. After intravenous (IV) administration the volume of distribution at steady state is about 1400 L.

Metabolism

Dronedarone is extensively metabolized, mainly by CYP 3A. The initial metabolic pathway includes N-debutylation to form the active N-debutyl metabolite, oxidative deamination to form the inactive propanoic acid metabolite, and direct oxidation. The metabolites undergo further metabolism to yield over 30 uncharacterized metabolites. The N-debutyl metabolite exhibits pharmacodynamic activity but is 1/10 to 1/3 as potent as dronedarone.

Excretion/Elimination

In a mass balance study with orally administered dronedarone (14C-labeled) approximately 6% of the labeled dose was excreted in urine, mainly as metabolites (no unchanged compound excreted in urine), and 84% was excreted in feces, mainly as metabolites. Dronedarone and its N-debutyl active metabolite accounted for less than 15% of the resultant radioactivity in the plasma.

After IV administration the plasma clearance of dronedarone ranges from 130 to 150 L/h. The elimination half-life of dronedarone ranges from 13 to 19 hours.

Special populations

Gender

Dronedarone exposures are on average 30% higher in females than in males.

Race

Pharmacokinetic differences related to race were not formally assessed. However, based on a cross study comparison, following single dose administration (400 mg), Asian males (Japanese) have about a 2-fold higher exposure than Caucasian males. The pharmacokinetics of dronedarone in other races has not been assessed.

Elderly

Of the total number of subjects in clinical studies of dronedarone, 73% were 65 years of age and over and 34% were 75 and over. In patients aged 65 years old and above, dronedarone exposures are 23% higher than in patients less than 65 years old [see Use In Specific Populations].

Hepatic Impairment

In subjects with moderate hepatic impairment, the mean dronedarone exposure increased by 1.3fold relative to subjects with normal hepatic function and the mean exposure of the N-debutyl metabolite decreased by about 50%. Pharmacokinetic data were significantly more variable in subjects with moderate hepatic impairment.

The effect of severe hepatic impairment on the pharmacokinetics of dronedarone was not assessed [see CONTRAINDICATIONS].

Renal Impairment

Consistent with the low renal excretion of dronedarone, no pharmacokinetic difference was observed in subjects with mild or moderate renal impairment compared to subjects with normal renal function [see Use in Specific Populations]. No pharmacokinetic difference was observed in patients with mild to severe renal impairment in comparison with patients with normal renal function.

Drug Interactions

Dronedarone is metabolized primarily by CYP 3A and is a moderate inhibitor of CYP 3A and CYP 2D6. Dronedarone has no significant potential to inhibit CYP 1A2, CYP 2C9, CYP 2C19, CYP 2C8 and CYP 2B6. It has the potential to inhibit P-glycoprotein (P-gp) transport. Dronedarone inhibits in vivo the tubular secretion of creatinine a substrate of the organic cation transporter (OCT2) [see WARNINGS AND PRECAUTIONS]. In vitro studies demonstrate that dronedarone or its metabolites are weak inhibitors of organic cation transporter (OCT1), organic anion transporting polypeptide (OATP1B1, OATP1B3), and organic anion transporter (OAT3). Monamine oxidases contribute partially to the metabolism of the active metabolite of dronedarone.

Pharmacokinetic measures indicating the magnitude of these interactions are presented in Figure 1 (impact of co-administered drugs on dronedarone) and Figure 2 (impact of dronedarone on coadministered drugs).

Figure 1: The impact of co-administered drugs on the pharmacokinetics of dronedarone and recommendations for dronedarone coadministration or dose adjustment

The impact of co-administered drugs on the pharmacokinetics of dronedarone - Illustration

Figure 2: The impact of dronedarone on co-administered drugs and recommendations for dose adjustment of co-administered drug

The impact of dronedarone on co-administered drugs - Illustration

Developmental Toxicity

Dronedarone was teratogenic in rats given oral doses ≥ 80 mg/kg/day (a dose equivalent to the maximum recommended human dose [MHRD] on a mg/m² basis), with fetuses showing external, visceral and skeletal malformations (cranioschisis, cleft palate, incomplete evagination of pineal body, brachygnathia, partially fused carotid arteries, truncus arteriosus, abnormal lobation of the liver, partially duplicated inferior vena cava, brachydactyly, ectrodactylia, syndactylia, and anterior and/or posterior club feet). In rabbits, dronedarone caused an increase in skeletal abnormalities (anomalous ribcage and vertebrae, pelvic asymmetry) at doses ≥ 20 mg/kg (the lowest dose tested and approximately half the MRHD on a mg/m² basis).

Clinical Studies

Athena

ATHENA was a multicenter, multinational, double blind, and randomized placebo-controlled study of dronedarone in 4628 patients with a recent history of AF/AFL who were in sinus rhythm or who were to be converted to sinus rhythm. The objective of the study was to determine whether dronedarone could delay death from any cause or hospitalization for cardiovascular reasons.

Initially patients were to be ≥ 70 years old, or < 70 years old with at least one risk factor (including hypertension, diabetes, prior cerebrovascular accident, left atrial diameter ≥ 50 mm or LVEF < 0.40). The inclusion criteria were later changed such that patients were to be ≥ 75 years old, or ≥ 70 years old with at least one risk factor. Patients had to have both AF/AFL and sinus rhythm documented within the previous 6 months. Patients could have been in AF/AFL or in sinus rhythm at the time of randomization, but patients not in sinus rhythm were expected to be either electrically or chemically converted to normal sinus rhythm after anticoagulation.

Subjects were randomized and treated for up to 30 months (median follow-up: 22 months) with either MULTAQ 400 mg twice daily (2301 patients) or placebo (2327 patients), in addition to conventional therapy for cardiovascular diseases that included beta-blockers (71%), ACE inhibitors or angiotensin II receptor blockers (ARBs) (69%), digoxin (14%), calcium antagonists (14%), statins (39%), oral anticoagulants (60%), aspirin (44%), other chronic antiplatelet therapy (6%) and diuretics (54%).

The primary endpoint of the study was the time to first hospitalization for cardiovascular reasons or death from any cause. Time to death from any cause, time to first hospitalization for cardiovascular reasons, and time to cardiovascular death and time to all causes of death were also explored.

Patients ranged in age from 23 to 97 years; 42% were 75 years old or older. Forty-seven percent (47%) of patients were female and a majority was Caucasian (89%). Approximately seventy percent (71%) of those enrolled had no history of heart failure. The median ejection fraction was 60%. Twenty-nine percent (29%) of patients had heart failure, mostly NYHA class II (17%). The majority had hypertension (86%) and structural heart disease (60%).

Results are shown in Table 3. MULTAQ reduced the combined endpoint of cardiovascular hospitalization or death from any cause by 24.2% when compared to placebo. This difference was entirely attributable to its effect on cardiovascular hospitalization, principally hospitalization related to AF.

Other endpoints, death from any cause and first hospitalization for cardiovascular reasons, are shown in Table 3. Secondary endpoints count all first events of a particular type, whether or not they were preceded by a different type of event.

Table 3: Incidence of Endpoint Events

  Placebo (N= 2327) MULTAQ 400mg BID (N= 2301) HR 95% CI p-Value
Primary endpoint
Cardiovascular hospitalization or death from any cause 913 (39.2%) 727 (31.6%) 0.76 [0.68 -0.83] <0.0001
Components of the endpoint (as first event)
  Cardiovascular hospitalization 856 (36.8%) 669 (29.1%)      
   Death from any cause 57 (2.4%) 58 (2.5%)      
Secondary endpoints (any time in study)
   Death from any cause 135 (5.8%) 115 (5.0%) 0.86 [0.67 -1.11] 0.24
   Cardiovascular hospitalization 856 (36.8%) 669 (29.1%) 0.74 [0.67 -0.82] < 0.0001
Components of the cardiovascular hospitalization endpoint (as first event)
   AF and other supraventricular rhythm disorders 456 (19.6%) 292 (12.7%) 0.61 [0.53 -0.71] < 0.0001
   Other 400 (17.2%) 377 (16.4%) 0.89 [0.77 -1.03] 0.11

The Kaplan-Meier cumulative incidence curves showing the time to first event are displayed in Figure 3. The event curves separated early and continued to diverge over the 30 month follow-up period.

Figure 3:Kaplan-Meier Cumulative Incidence Curves from Randomization to First Cardiovascular Hospitalization or Death from any Cause

Kaplan-Meier Cumulative Incidence Curves - Illustration

Reasons for hospitalization included major bleeding (1% in both groups), syncope (1% in both groups), and ventriculararrhythmia ( < 1% in both groups). The reduction in cardiovascular hospitalization or death from anycausewasgenerallyconsistent in all subgroupsbased onbaseline characteristicsor medications (ACE inhibitors or ARBs; beta-blockers, digoxin, statins, calcium channel blockers, diuretics) (see Figure4).

Figure 4: Relative Risk (MULTAQ versus placebo) Estimates with 95% Confidence Intervals According to Selected Baseline Characteristics: First Cardiovascular Hospitalization or Death from any Cause.

Relative Risk (MULTAQ versus placebo) Estimates with 95% Confidence Intervals - Illustration

a Determined from Cox regression model

b P-value of interaction between baseline characteristics and treatment based on Cox regression model c Calcium antagonists with heart rate lowering effects restricted to diltiazem, verapamil and bepridil

EURIDIS And ADONIS

In EURIDIS and ADONIS, a total of 1237 patients in sinus rhythm with a prior episode of AF or AFL were randomized in an outpatient setting and treated with either MULTAQ 400 mg twice daily (n=828) or placebo (n=409) on top of conventional therapies (including oral anticoagulants, beta-blockers, ACE inhibitors or ARBs, chronic antiplatelet agents, diuretics, statins, digoxin, and calcium channel blockers). Patients had at least one ECG-documented AF/AFL episode during the 3 months prior to study entr y but were in sinus rhythm for at least one hour. Patients ranged in age from 20 to 88 years, with the majority being Caucasian (97%), male (70%) patients. The most common co-morbidities were hypertension (56.8%) and structural heart disease (41.5%), including coronar y heart disease (21.8%). Patients were followed for 12 months.

In the pooled data from EURIDIS and ADONIS as well as in the individual trials, dronedarone delayed the time to first recurrence of AF/AFL (primary endpoint), lowering the risk of first AF/AFL recurrence during the 12-month study period by about 25%,with an absolute difference in recurrence rate of about 11% at 12 months.

Andromeda

Patients recently hospitalized with symptomatic heart failure and severe left ventricular systolic dysfunction (wall motion index ≤ 1.2) were randomized to either MULTAQ 400 mg twice daily or matching placebo, with a primary composite end point of all-cause mortality or hospitalization for heart failure. Patients enrolled in ANDROMEDA were predominantly NYHA Class II (40%) and III (57%), and only 25% had AF at randomization. After enrollment of 627 patients and a median follow-up of 63 days, the trial was terminated because of excess mortality in the dronedarone group. Twenty-five (25) patients in the dronedarone group died versus 12 patients in the placebo group (hazard ratio 2.13; 95% CI: 1.07 to 4.25). The main reason for death was worsening heart failure. Baseline digoxin therapy was reported in 6/16 dronedarone patients vs. 1/16 placebo patients who died of arrhythmia. In patients without baseline use of digoxin, no excess risk of arrhythmic death was observed in the dronedarone vs. placebo groups.

There were also excess hospitalizations for cardiovascular reasons in the dronedarone group (71 versus 51 for placebo) [see BOXED WARNING and CONTRAINDICATIONS].

Pallas

Patients with permanent AF (AF documented in 2 weeks prior to randomization and at least 6 months prior to randomization in whom cardioversion had failed or was not planned) and additional risk factors for thromboembolism (coronary artery disease, prior stroke or TIA, symptomatic heart failure, LVEF < 40%, peripheral arterial occlusive disease, or age > 75 with hypertension and diabetes) were randomized to dronedarone 400 mg twice daily or placebo. After enrollment of 3236 patients (placebo=1617 and dronedarone=1619) and a median follow up of 3.7 months for placebo and 3.9 for dronedarone, the study was terminated because of a significant increase in

  • Mortality: 25 dronedarone vs. 13 placebo (HR, 1.94; CI, 0.99 to 3.79). The majority of deaths in the dronedarone group were classified as arrhythmic/sudden deaths (HR, 3.26; CI: 1.06 to 10.0). Baseline digoxin therapy was reported in 11/13 dronedarone patients who died of arrhythmia. None of the arrhythmic deaths on placebo (4) reported use of digoxin. In patients without baseline use of digoxin, no excess risk of arrhythmic death was observed in the dronedarone vs. placebo groups.
  • Stroke: 23 dronedarone vs. 10 placebo (HR, 2.32; CI: 1.11 to 4.88). The increased risk of stroke observed with dronedarone was observed in the first two weeks of therapy (10 dronedarone vs. 1 placebo), most of the subjects treated with dronedarone did not have an INR of 2.0 to 3.0 [see WARNINGS AND PRECAUTIONS].
  • Hospitalizations for heart failure in the dronedarone group: 43 dronedarone vs. 24 placebo (HR, 1.81; CI: 1.10 to 2.99).

Last reviewed on RxList: 2/10/2014
This monograph has been modified to include the generic and brand name in many instances.

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