Summary Basis of Decision for Multaq ™
Review decision
The Summary Basis of Decision explains why the product was approved for sale in Canada. The document includes regulatory, safety, effectiveness and quality (in terms of chemistry and manufacturing) considerations.
Product type:
MultaqTM
Dronedarone, as dronedarone hydrochloride, 400 mg, Tablet, Oral
sanofi-aventis Canada Inc.
Submission control no: 121065
Date issued: 2010-01-07
Foreword
Health Canada's Summary Basis of Decision (SBD) documents outline the scientific and regulatory considerations that factor into Health Canada regulatory decisions related to drugs and medical devices. SBDs are written in technical language for stakeholders interested in product-specific Health Canada decisions, and are a direct reflection of observations detailed within the evaluation reports. As such, SBDs are intended to complement and not duplicate information provided within the Product Monograph.
Readers are encouraged to consult the 'Reader's Guide to the Summary Basis of Decision - Drugs' to assist with interpretation of terms and acronyms referred to herein. In addition, a brief overview of the drug submission review process is provided in the Fact Sheet entitled 'How Drugs are Reviewed in Canada'. This Fact Sheet describes the factors considered by Health Canada during the review and authorization process of a drug submission. Readers should also consult the 'Summary Basis of Decision Initiative - Frequently Asked Questions' document.
The SBD reflects the information available to Health Canada regulators at the time a decision has been rendered. Subsequent submissions reviewed for additional uses will not be captured under Phase I of the SBD implementation strategy. For up-to-date information on a particular product, readers should refer to the most recent Product Monograph for a product. Health Canada provides information related to post-market warnings or advisories as a result of adverse events (AE).
For further information on a particular product, readers may also access websites of other regulatory jurisdictions. The information received in support of a Canadian drug submission may not be identical to that received by other jurisdictions.
Other Policies and Guidance
Readers should consult the Health Canada website for other drug policies and guidance documents. In particular, readers may wish to refer to the 'Management of Drug Submissions Guidance'.
1 Product and submission information
Brand name:
Manufacturer/sponsor:
Medicinal ingredient:
International non-proprietary Name:
Strength:
Dosage form:
Route of administration:
Drug identification number(DIN):
- 02330989
Therapeutic Classification:
Non-medicinal ingredients:
Tablet core
Colloidal anhydrous silica, crospovidone, hypromellose, lactose monohydrate, magnesium stearate, maize starch, poloxamer 407
Tablet coating
Carnauba wax, hypromellose, macrogol 6000, titanium dioxide
Submission type and control no:
Date of Submission:
Date of authorization:
2 Notice of decision
On August 11, 2009, Health Canada issued a Notice of Compliance to sanofi-aventis Canada Inc. for the drug product, Multaq.
Multaq contains the medicinal ingredient dronedarone classified as an antiarrhythmic agent.
Multaq is indicated for the treatment of patients with a history of, or current atrial fibrillation to reduce the risk of cardiovascular hospitalization due to atrial fibrillation.
Multaq has both heart rate and rhythm control properties.
The market authorization was based on quality, non-clinical, and clinical information submitted. The pivotal trial showing the efficacy and safety of Multaq was a multicentre, multinational, double-blind placebo-controlled study of 4628 patients. All patients had to be in sinus rhythm and have at least one documented episode of atrial fibrillation or atrial flutter. Patients were randomized to either Multaq 400 mg (2301 patients) or matching placebo (2327 patients) taken twice daily. Maximum duration of therapy was 30 months. Treatment with Multaq brought about a significant decrease in cardiovascular hospitalization. This was due to a decrease in the recurrence of atrial fibrillation and other supraventricular rhythm disorders. Evidence of efficacy in the treatment of atrial flutter was lacking. No unexpected or unknown safety issues arose in the course of the study. Multaq was seen as having demonstrated an acceptable level of efficacy and safety in the reduction of recurrences of atrial fibrillation.
Multaq (400 mg, dronedarone, as dronedarone hydrochloride) is presented in tablet form. The recommended dosage is 400 mg twice daily in adults. Multaq should be taken as one tablet with the morning meal and one tablet with the evening meal. Treatment with class I or III antiarrhythmics (such as flecainide, propafenone, quinidine, disopyramide, dofetilide, sotalol, amiodarone) must be stopped before starting Multaq.
Multaq is contraindicated for patients with:
- Severe congestive heart failure [Stage NYHA IV according to the New York Heart Association (NYHA) functional classification system] and other unstable hemodynamic conditions;
- Second- or third- degree atrioventricular (AV) block or sick sinus syndrome (except when used in conjunction with a functioning pacemaker);
- Bradycardia <50 beats per minute;
- Co-administration with strong cytochrome P450 (CYP) 3A4 inhibitors, such as ketoconazole, itraconazole, voriconazole, cyclosporin, telithromycin, clarithromycin, nefazodone and ritonavir;
- Co-administration with drugs inducing torsades de pointes such as phenothiazines, tricyclic antidepressants, and certain oral macrolides, class I and III antiarrhythmics;
- QTc Bazett interval ≥500 msec;
- Severe hepatic impairment;
- Pregnancy;
- Lactation;
- History of hypersensitivity reactions to dronedarone or any of its excipients or component of the container.
Multaq should be used with caution in patients with NYHA III failure.
Priority Review status was granted for the evaluation of Multaq on the basis that there was evidence of a significant increase in efficacy and/or significant decrease in risk compared to other medications currently used in the treatment of atrial fibrillation. Atrial fibrillation is a serious condition not adequately managed by the drugs marketed in Canada.
Based on the Health Canada review of data on quality, safety, and efficacy, Health Canada considers that the benefit/risk profile of Multaq is favourable for the treatment of patients with a history of, or current atrial fibrillation to reduce the risk of cardiovascular hospitalization due to atrial fibrillation.
3 Scientific and Regulatory Basis for Decision
3.1 Quality Basis for Decision
3.1.1 Drug Substance (Medicinal Ingredient)
Manufacturing Process and Process Controls
The medicinal ingredient of Multaq, dronedarone (as dronedarone hydrochloride), is manufactured via a multi-step synthesis. Each step of the manufacturing process is considered to be controlled within acceptable limits:
- The sponsor has provided information on the quality and controls for all materials used in the manufacture of the drug substance.
- The drug substance specifications are found to be satisfactory. Impurity limits meet International Conference on Harmonisation (ICH) requirements.
- The processing steps have been evaluated and the appropriate ranges for process parameters have been established.
Characterization
The structure of dronedarone hydrochloride has been adequately elucidated and the representative spectra have been provided. Physical and chemical properties have been described and are found to be satisfactory.
Impurities and degradation products arising from manufacturing and/or storage were reported and characterized. The proposed limits are considered adequately qualified [that is (i.e.) within ICH limits and/or qualified from toxicological studies]. Control of the impurities and degradation products is therefore considered acceptable.
Control of Drug Substance
The drug substance specifications and analytical methods used for quality control of dronedarone hydrochloride are considered acceptable.
Batch analysis results were reviewed and all results comply with the specifications and demonstrate consistent quality of the batches produced.
The drug substance packaging is considered acceptable.
Stability
Stability study results based on accelerated, long-term and stress testing, show that dronedarone hydrochloride is a stable compound when packaged as proposed over the proposed storage period.
3.1.2 Drug Product
Description and Composition
Multaq tablets contain dronedarone hydrochloride equivalent to 400 mg dronedarone. The tablets are provided as white film-coated tablets for oral administration, oblong-shaped, engraved with a double wave marking on one side and "4142" on the other side. The tablets are packaged in bottles of 60 tablets, 180 tablets, 500 tablets, and in boxes of 4 blisters (15 tablets per blister).
Multaq tablets contain the following non-medicinal ingredients in the tablet core: colloidal anhydrous silica, crospovidone, hypromellose, lactose monohydrate, magnesium stearate, maize starch, poloxamer 407. The tablet coating/polishing consists of carnauba wax, hypromellose, macrogol 6000, and titanium dioxide.
All non-medicinal ingredients (excipients) found in the drug product are acceptable for use in drugs according to the Food and Drug Regulations. The compatibility of dronedarone hydrochloride with the excipients is demonstrated.
Pharmaceutical Development
Changes to the manufacturing process and formulation made throughout the pharmaceutical development are considered acceptable upon review.
Manufacturing Process and Process Controls
The method of manufacturing is considered acceptable and the process is considered adequately controlled within justified limits.
The specifications for all of the ingredients are approved in accordance with United States Pharmacopeia/National Formulary (USP/NF) or European Pharmacopoeia (Ph. Eur.) standards.
Control of Drug Product
Validation results of the analytical methods used for the determination of assay, degradation products, dissolution, and microbial quality are considered acceptable.
Data from final batch analyses were reviewed and are considered to be acceptable according to the specifications of the drug product.
Stability
Based on the long-term, stress, and accelerated stability data submitted, the proposed shelf-life at 15-30°C for Multaq is considered acceptable.
The compatibility of the drug product with the container closure system was demonstrated. The container closure system met all validation test acceptance criteria.
3.1.3 Facilities and Equipment
The design, operations, and controls of the facilities and equipment that are involved in the production of Multaq are considered suitable for the activities and products manufactured. All sites are compliant with Good Manufacturing Practices (GMP).
3.1.4 Adventitious Agents Safety Evaluation
Safety of the sources of lactose and magnesium stearate has been adequately addressed.
3.1.5 Conclusion
The Chemistry and Manufacturing information submitted for Multaq has demonstrated that the drug substance and drug product can be consistently manufactured to meet the approved specifications. Proper development and validation studies were conducted, and adequate controls are in place for the commercial processes.
3.2 Non-Clinical Basis for Decision
3.2.1 Pharmacodynamics
The non-clinical pharmacodynamic studies were performed in a wide variety of animals: rats, guinea pigs, rabbit, pigs, and dogs. A large panel of experimental conditions as well as pathophysiological models were studied. Study results regarding the non-clinical in vitro and in vivo pharmacology activities of dronedarone are described in the Multaq Product Monograph. Dronedarone appears to be a multi-channel blocker considering the various effects of dronedarone on the electrophysiological parameters. In in vitro studies, dronedarone prevented atrial fibrillation or restored normal sinus rhythm. Dronedarone also prevented ventricular tachycardia and ventricular fibrillation in several animal models.
Although dronedarone did not seem to be proarrhythmic, and even prevented the occurrence of pharmacology-induced Torsade de Pointes (TdP), dronedarone may have promoted the occurrence of ventricular tachycardia in response to programmed electrical stimulation in post-infarcted conscious dogs. These changes are linked to the electrophysiological effect of dronedarone and should not reflect toxicity.
In the non-clinical studies, no signals suggestive of significant safety concerns relating to the use of dronedarone for the proposed indication were identified.
3.2.2 Pharmacokinetics
Absorption
The time to maximum plasma concentration (tmax) after oral administration of dronedarone is between 1 to 4 hours whatever the species.
Steady-state plasma concentrations were generally achieved at most on Day 14 of the multiple-dose studies in mice, rats and dogs, and minimal drug accumulation was observed (2 to 3-fold increase).
In rats and dogs, the absolute bioavailability of dronedarone was low (14-22%).
Distribution
Dronedarone was highly bound to rat, dog, mouse, rabbit, and human plasma proteins (>99.5%). Binding was similar between species and was not concentration dependent.
Radiolabelled dronedarone was rapidly and extensively distributed in rats with the liver, spleen, lung, and kidney being the main tissues involved in the distribution of the drug and/or metabolites. The data showed an affinity with melanin-containing tissues (uveal tract, eye, and pigmented skin), as well as an affinity to the mesenteric lymph nodes at higher doses when compared to circulating plasma levels and other lymph nodes.
Metabolism
Dronedarone was extensively metabolized after oral administration. The main circulating metabolites were SR35021 (N-debutyl metabolite) in mice, SR90154 (propanoic acid derivative) and oxidated derivatives of dronedarone in rats and dogs, and oxidated derivatives of dronedarone in rabbits. SR35021 has shown antiarrhythmic, electrophysiological, and haemodynamic activities similar to those of dronedarone but is less potent than dronedarone, and therefore may contribute to the pharmacological activity of dronedarone, while SR90154 has shown very little or no pharmacological activity.
Excretion
Dronedarone was primarily eliminated by metabolic clearance. Metabolism followed by biliary excretion was the main pathway of elimination.
3.2.3 Toxicology
Toxicokinetic evaluations were conducted in many studies and included the determination of the major N-debutyl metabolite (SR35021) which has pharmacologic activity, but which is significantly less potent than dronedarone.
Single-Dose Toxicity
Dronedarone showed a low order of acute oral toxicity. Single-dose oral gavage administration of dronedarone did not result in mortality or treatment-related clinical signs in mice or rats at doses of ≤ 2000 mg/kg.
Repeat-Dose Toxicity
The principal finding of the repeat-dose oral general toxicity studies was general health deterioration at high doses associated with mortality/moribundity (mortality was observed in rodents only), cardiac effects, phospholipidosis, and hepatic effects.
Cardiac effects (observed mainly in ECG evaluations conducted in rats and dogs) are assumed to be related to the antiarrhythmic pharmacology and therefore are an expected finding. Gastrointestinal effects were observed mainly at the highest doses tested in rats and dogs. Slight and reversible phospholipidosis was observed in mesenteric lymph nodes mainly in the rats, however this is considered specific to this species and not relevant to humans. Hepatic effects were seen mainly in rodents at exposures 10X the human therapeutic level. In the repeat-dose studies, dronedarone was well-tolerated up to and including 60 mg/kg/day in the 3-month rat and 3-month dog studies, up to 50 mg/kg/day in the 6-month rat study, and up to 45 mg/kg/day in the one-year dog study.
Genotoxicity
Dronedarone showed no genotoxicity in the battery of in vivo and in vitro genetic toxicity tests performed.
Carcinogenicity
Oral administration of dronedarone in the 2-year carcinogenicity studies was associated with an increased incidence of mammary tumours and histiocytic sarcoma in mice; and non-proliferative and proliferative changes (including angiomatous hyperplasia, haemangioma and/or haemangiosarcoma) in mesenteric lymph nodes in mice and rats, at the high-dose levels used in the mouse and rat studies (300 mg/kg/day and 70 mg/kg/day, respectively). These findings do not pose a carcinogenic risk to humans based on the biology of the findings and/or extrapolated safety margins.
Reproductive and Developmental Toxicity
At 100 mg/kg/day, dronedarone caused litter effects, and embryo-foetal toxicity including teratogenicity in rats. In rabbits, severe maternal toxicity occurred at 200 mg/kg/day, and while there was no evidence of teratogenicity, few animals survived for appropriate evaluation at that dose level. Exposure in rabbits at the 200 mg/kg/day lethal dose ranged from 2-7 times the human therapeutic levels. Because of teratogenicity in rats at high doses, Multaq is contraindicated in pregnant women. The results of the fertility, and pre-and post-natal studies did not show significant effects on mating, sperm count/function, fertility, gestation, parturition, or first generation (F1) behaviour and reproductive function.
Photosensitivity
Dronedarone was shown to be slightly phototoxic, but not photoallergic in guinea pigs.
Immunotoxicity
Dronedarone was not immunotoxic in a special rat study that included a T-cell dependent antibody response, and in the general toxicology studies that included evaluation of immune function.
3.2.4 Conclusion
The non-clinical studies for this drug submission are considered acceptable, and support the use of Multaq for the proposed indication. The pharmacology and toxicology program demonstrated that the compound is relatively safe for humans. Adequate statements are in place in the Product Monograph to address the identified safety concerns.
3.3 Clinical basis for decision
3.3.1 Pharmacodynamics
Dronedarone induced electrocardiogram (ECG) changes consistent with the electrophysiological properties of the compound.
Two pharmacodynamic (PD) studies were conducted to study the effects of dronedarone on renal function. Dronedarone 400 mg administered twice a day (BID) for 7 days in healthy subjects decreased the renal creatinine clearance without significantly changing the sinistrin clearance, a marker of glomerular filtration rate. Furthermore, the significant decrease in the clearance of N-methylnicotinamide (NMN), a marker of tubular secretion, confirmed that the decrease in creatinine clearance was actually due to the inhibition of the tubular secretion of creatinine.
In healthy subjects that received dronedarone 400 mg BID for 14 days, increased levels of serum creatinine were observed within 2 days after administration, and values remained stable during treatment and returned to baseline within 3 days after treatment discontinuation. The observed increase in serum creatinine appears to be due to the inhibition of tubular secretion of creatinine, rather than a decrease in glomerular filtration rate.
3.3.2 Pharmacokinetics
Absorption
The Cmax and Area Under the Curve (AUC) drug exposure values of dronedarone and its debutylated metabolite SR35021 increased in more than a dose-proportional manner. A 2-fold increase in dose resulted in a 2.5- to 3.0-fold increase in Cmax or AUC. Concomitant food intake significantly increased Cmax and AUC. The clinical studies were conducted with food, therefore, the Product Monograph recommends taking Multaq with food.
Distribution
Dronedarone is excessively bound to plasma proteins at 99.7% and was non-saturable in plasma. The binding was mainly to albumin. The volume of distribution at steady-state was 1200-1400 L.
Metabolism
Dronedarone is extensively metabolized in humans. The metabolic pathway includes N-debutylation to form the main circulating active metabolite, SR35021, followed by oxidation, oxidative deamination to form the inactive propanoic acid metabolite (SR90154), followed by oxidation, and direct oxidation. The N-debutylation of dronedarone appears to be catalyzed by the cytochrome P450 isozyme, CYP3A4.
Ketoconazole (a potent inhibitor of CYP3A4) increased the plasma levels of dronedarone in a highly significant manner, therefore co-administration of Multaq with strong inhibitors of CYP3A4 is contraindicated. A complete list of potential drug-drug interactions are listed in the Product Monograph.
Elimination
Dronedarone is extensively metabolized to a variety of different metabolites which are excreted in the urine and faeces. The primary route of excretion was the faeces.
Special Populations
The Cmax and AUC levels were significantly higher in elderly males as compared to young males indicating an age effect, and significantly higher in elderly females as compared to elderly males indicating a gender effect. However, there were no gender- or age-related safety differences detected and consistent efficacy has been shown.
Moderate hepatic impairment modifies the pharmacokinetics of dronedarone, but only moderately. The effects on patients with severe hepatic impairment were not assessed.
Pharmacokinetic parameters for dronedarone and its metabolite SR35021 were similar in patients with normal, mild, moderate, and severe impairment of kidney function.
3.3.3 Clinical Efficacy
The clinical efficacy and safety were evaluated in the ATHENA study, a multicentre, multinational, double-blind placebo-controlled study of 4628 patients. Patients could be in atrial fibrillation/atrial flutter or in sinus rhythm after spontaneous conversion or following any procedures. Patients were randomized to either Multaq 400 mg (2301 patients) or matching placebo (2327 patients) taken twice daily. Maximum duration of therapy was 30 months.
The primary endpoint of this pivotal study was the time to first hospitalization for cardiovascular reasons or death from any cause. With few exceptions, the 17 components comprising "cardiovascular hospitalization" included components not generally accepted as being causally related to atrial fibrillation. Secondary endpoints evaluated were time to death from any cause, time to first hospitalization for 'cardiovascular reasons'. Other endpoints included time to cardiovascular death and time to sudden death.
Throughout the two-year study period, Multaq compared to placebo decreased significantly the primary efficacy parameter by 24.2%, with a 1-year absolute risk reduction of 7.4%. However, the study failed to show efficacy in "death from any cause", a component of the primary endpoint. Efficacy was demonstrated in the other component "time to any cardiovascular hospitalization" with a one-year 7.2% absolute reduction in the cumulative incidence of such hospitalization compared to placebo. This reduction was mainly driven by a decrease in admission for atrial fibrillation and other supraventricular rhythm disorders. Compared with placebo, Multaq resulted in an absolute decrease in such hospitalisations of approximately 7% at both the one-and two-year time points of the study.
The study demonstrated an acceptable level of efficacy and safety in the reduction of recurrences of atrial fibrillation when Multaq is used under conditions as outlined in the Product Monograph. Evidence of efficacy in the treatment of atrial flutter was lacking.
3.3.4 Clinical Safety
In the pivotal study (ATHENA), patients had a median duration of exposure of approximately 18 months. The overall incidence of treatment-emergent AEs, including serious AEs was similar in the two treatment groups (69.3% placebo, 72.0% Multaq). The most frequently reported treatment-emergent AEs were gastrointestinal in nature (diarrhoea and nausea). The overall incidence of serious treatment-emergent AEs was similar between the two treatment groups (21.1% placebo, 19.9% Multaq).
In all of the clinical studies submitted, no unexpected or unknown safety issues were noted. Gastrointestinal disorders (especially diarrhoea) were the commonest treatment-emergent AE. Increases in QT interval were common. A small study carried out in patients with significant degrees of heart failure (NYHA III and IV) and unstable haemodynamic conditions was discontinued prematurely due to increased deaths in the dronedarone group. The presence of severe congestive heart failure (NYHA IV) is now recognized as a contraindication to the use of the drug.
Owing to the drug's metabolism via the CYP3A4 pathway, there are numerous potential drug-drug interactions. A mild increase in mean serum creatinine was seen in patients in the Multaq group, which is consistent with previous observations. An increase in plasma creatinine levels related to inhibition of creatinine secretion at the renal tubular level can be expected, but the increase is not reflective of any decrease in renal function. All of these issues are adequately addressed in the Product Monograph.
3.4 Benefit/Risk Assessment and Recommendation
3.4.1 Benefit/Risk Assessment
Priority Review status was granted for the evaluation of Multaq on the basis that there was evidence of a significant increase in efficacy and significant decrease in risk compared to other medications currently used in the treatment of atrial fibrillation.
Overall, Multaq is seen as showing evidence of acceptable efficacy and safety in the treatment of patients with a history of, or current atrial fibrillation to reduce the risk of cardiovascular hospitalization due to atrial fibrillation, when used under the conditions outlined in the Product Monograph. Given the serious nature of atrial fibrillation and the current lack of any approved effective treatment for the disorder, coupled with the lack of any significant safety signal in any of the studies submitted, Multaq is seen as having an acceptable benefit/risk ratio if prescribed in accordance with the known contraindications and drug-drug interactions.
3.4.2 Recommendation
Based on the Health Canada review of data on quality, safety and efficacy, Health Canada considers that the benefit/risk profile of Multaq is favourable in the treatment of patients with a history of, or current atrial fibrillation to reduce the risk of cardiovascular hospitalization due to atrial fibrillation. The New Drug Submission complies with the requirements of sections C.08.002 and C.08.005.1 and therefore Health Canada has granted the Notice of Compliance pursuant to section C.08.004 of the Food and Drug Regulations.
4 Submission Milestones
Submission Milestones: MultaqTM
| Submission Milestone | Date |
|---|---|
| Pre-submission meeting: | 2008-07-09 |
| Request for priority status | |
| Filed: | 2008-07-30 |
| Approval issued: | 2008-08-29 |
| Submission filed: | 2008-09-02 |
| Screening | |
| Screening Acceptance Letter issued: | 2008-10-03 |
| Review | |
| Biopharmaceutics Evaluation complete: | 2009-03-05 |
| Quality Evaluation complete: | 2009-03-31 |
| Clinical Evaluation complete: | 2009-07-30 |
| Labelling Review complete: | 2009-07-29 |
| Notice of Decision issued by Director General: | 2009-08-11 |
Related Drug Products
| Product name | DIN | Company name | Active ingredient(s) & strength |
|---|---|---|---|
| MULTAQ | 02330989 | SANOFI-AVENTIS CANADA INC | DRONEDARONE (DRONEDARONE HYDROCHLORIDE) 400 MG |