Summary Basis of Decision for Edarbi
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:
Edarbi
Azilsartan medoxomil, 40 mg and 80 mg, Tablet, Oral
Takeda Canada Inc.
Submission control no: 145305
Date issued: 2012-06-26
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):
- 02381389 - 40 mg
- 02381397 - 80 mg
Therapeutic Classification:
Non-medicinal ingredients:
Submission type and control no:
Date of Submission:
Date of authorization:
2 Notice of decision
On March 8, 2012, Health Canada issued a Notice of Compliance to Takeda Canada, Inc. for the drug product Edarbi.
Edarbi contains the medicinal ingredient azilsartan medoxomil (as azilsartan medoxomil potassium) which is an angiotensin II AT1 receptor blocker.
Edarbi is indicated for the treatment of mild to moderate essential hypertension. Azilsartan medoxomil acts by inhibiting the vasoconstriction and aldosterone-secreting effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT1 receptor.
The market authorization was based on quality, non-clinical, and clinical information submitted. The safety and efficacy of Edarbi were demonstrated primarily in two 6-week randomized, double-blind studies which evaluated Edarbi at two doses, 40 and 80 mg, in comparison to a placebo. More than 1,700 patients were enrolled in both studies. Ambulatory blood pressure monitoring was used for blood pressure measurement and the systolic blood pressure was the primary endpoint. Results showed that Edarbi 40 mg and 80 mg had a statistically significantly greater blood pressure reduction effect compared to placebo.
Edarbi (40 and 80 mg azilsartan medoxomil) is presented in tablet form. The recommended starting dose in adults is 40 mg taken orally once daily. The dose may be increased to a maximum of 80 mg once daily when additional blood pressure reduction is required. Edarbi may be used alone, concomitantly with thiazide diuretics, or concomitantly with calcium channel blockers. The safety and efficacy of concurrent use with angiotension converting enzyme inhibitors have not been established. Further dosing guidelines are available in the Product Monograph.
Edarbi is contraindicated for patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container. Serious warnings and precautions have been identified in the Product Monograph for Edarbi and its use in pregnancy. Angiotensin receptor blockers can cause injury or even death of the developing foetus. When pregnancy is detected Edarbi should be discontinued as soon as possible. Edarbi should be administered under the conditions stated in the Product Monograph taking into consideration the potential risks associated with the administration of this drug product. Detailed conditions for the use of Edarbi are described in the Product Monograph.
Based on the Health Canada review of data on quality, safety, and efficacy, Health Canada considers that the benefit/risk profile of Edarbi is favourable for the treatment of mild to moderate essential hypertension.
3 Scientific and Regulatory Basis for Decision
3.1 Quality Basis for Decision
3.1.1 Drug Substance (Medicinal Ingredient)
General Information
Azilsartan medoxomil (as azilsartan medoxomil potassium) is the medicinal ingredient of Edarbi. Azilsartan medoxomil is an angiotensin II AT1 receptor blocker (ARB).
Edarbi is indicated for the treatment of mild to moderate essential hypertension. Azilsartan acts by inhibiting the vasoconstriction and aldosterone-secreting effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT1 receptor.
Manufacturing Process and Process Controls
The drug substance is synthetically derived.
The manufacturing process is considered to be adequately controlled within justified limits.
Characterization
The structure of azilsartan medoxomil potassium has been adequately elucidated and the representative spectra have been provided. Physical and chemical properties have been described and were found to be satisfactory.
The sponsor has provided a summary of all drug-related impurities. These products were found to be within International Conference on Harmonisation (ICH) established limits and/or were qualified from toxicological studies and therefore, are considered to be acceptable.
Control of Drug Substance
Copies of the analytical methods and, where appropriate, validation reports were provided and are considered satisfactory for all analytical procedures used for release and stability testing of azilsartan medoxomil potassium.
The drug substance packaging is considered acceptable.
Stability
Based on the long-term, real-time, accelerated stability data submitted, the proposed retest period for the drug substance was supported and is considered to be satisfactory.
3.1.2 Drug Product
Description and Composition
Edarbi is supplied as white to nearly white round tablets in the following dosage strengths:
- 40 mg tablets - debossed "ASL" on one side and "40" on the other side;
- 80 mg tablets - debossed "ASL" on one side and "80" on the other side.
Edarbi is available for oral use as tablets. Each Edarbi tablet contains 42.68 mg or 85.36 mg of azilsartan medoxomil potassium, which is equivalent to containing 40 mg or 80 mg respectively, of azilsartan medoxomil. Each tablet also contains the following non-medicinal ingredients: mannitol; fumaric acid; sodium hydroxide; hydroxypropyl cellulose; croscarmellose sodium; microcrystalline cellulose; and magnesium stearate.
Edarbi tablets are supplied in high-density polyethylene (HDPE) bottles with each bottle containing 30 or 90 tablets. The tablets are also contained in aluminum blister strips, with 4 blister strips of 7 tablets each, for each carton.
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 azilsartan medoxomil potassium with the excipients is demonstrated by the stability data presented on the proposed commercial formulation.
Pharmaceutical Development
Changes to the manufacturing process and formulation made throughout the pharmaceutical development were considered acceptable upon review.
Manufacturing Process and Process Controls
The manufacturing process uses conventional manufacturing techniques, namely: granulation; milling; blending; compression; and tablet drying.
The validated process is capable of consistently generating product that meets release specifications.
Control of Drug Product
Edarbi is tested to verify that its identity, appearance, content uniformity, assay, dissolution, and levels of degradation products and drug-related impurities are within acceptance criteria. The test specifications and analytical methods are considered acceptable.
The validation process is considered to be complete. Data from final batch analyses were reviewed and are considered to be acceptable according to the specifications of the drug product.
Although impurities and degradation products arising from manufacturing and/or storage were reported and characterized, these were found to adequately qualified.
Stability
Based on the real-time, long-term, and accelerated stability data submitted, the proposed 36-month shelf-life at 15-30°C for Edarbi is considered acceptable when the product is packaged in the original packaging, and protected from light and moisture.
The compatibility of the drug product with the container closure system was demonstrated through the stability studies. The container closure system met all validation test acceptance criteria.
3.1.3 Facilities and Equipment
The design, operations, and controls of the facility and equipment that are involved in the production of Edarbi are considered suitable for the activities and products manufactured.
3.1.4 Adventitious Agents Safety Evaluation
Not applicable. The excipients used in the drug product formulation are not from animal or human origin.
3.1.5 Conclusion
The Chemistry and Manufacturing information submitted for Edarbi 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
Azilsartan medoxomil is the pro-drug for azilsartan, a competitive reversible antagonist at angiotensin II receptors (AT1). After oral administration, azilsartan medoxomil is hydrolyzed rapidly to azilsartan, in the gastrointestinal tract and/or during the process of absorption. The primary and secondary pharmacology, safety pharmacology, pharmacokinetic, and toxicology characteristics of azilsartan medoxomil and azilsartan have been comprehensively evaluated in non-clinical studies.
The Health Canada assessment of the non-clinical programme was based on review of the sponsor-provided Non-clinical Overview; Pharmacology Written Summary; Pharmacokinetic Written Summary; Toxicology Written Summary; the United States Food and Drug Administration (FDA) Pharmacology Review; and the European Medicines Agency (EMA) Review. Under the provisions of the Draft Guidance Document: The Use of Foreign Reviews by Health Canada, the Canadian regulatory decision on the non-clinical programme was based on a critical.
3.2.1 Pharmacodynamics
The pharmacodynamic studies indicated that azilsartan is a potent antagonist at AT1 receptors in vitro and in vivo across a number of species, and that dosing of azilsartan medoxomil or azilsartan acts to reduce blood pressure in animal models of normo- and supra-renin hypertension. The metabolites of azilsartan, M-I and M-II, demonstrated only weak-binding affinity for AT1 receptors. In secondary pharmacodynamic studies, binding of azilsartan medoxomil and related compounds/metabolites to a spectrum of receptors, channels, and enzymes, occurred at concentrations of at least 10-times higher than that would be anticipated with the maximum recommended human dose (MRHD) of 80 mg azilsartan medoxomil per day.
In safety pharmacology studies, azilsartan medoxomil did not adversely affect the central nervous system or respiratory function in rats (doses up to 2,000 mg/kg taken orally) or cardiovascular parameters (other than the expected decrease in arterial blood pressure) in dogs (doses up to 300 mg/kg taken orally). Results of in vitro studies did not indicate a potential for inhibition of the human-ether-a-go-go-related gene (hERG) channel current by azilsartan or M-II.
3.2.2 Pharmacokinetics
Absorption
Results of the non-clinical pharmacokinetic studies in rats, dogs, and monkeys indicate that azilsartan medoxomil is rapidly and efficiently converted to azilsartan in vivo without any appreciable systemic exposure to azilsartan medoxomil.
Systemic bioavailability of azilsartan after single oral dosing of azilsartan medoxomil in non-fasted animals was approximately 12% in rats and 54% in dogs.
Distribution
Following oral administration of radiolabelled azilsartan in rats, total radioactivity was distributed widely to tissues with relatively high concentrations in the liver. In pregnant rats, the radioactivity was gradually transferred to foetuses via the placenta. Plasma radioactivity was distributed into the milk of lactating rats.
Azilsartan medoxomil and its related compounds were highly protein bound in all species tested, including humans.
Metabolism
Azilsartan was the main component found in plasma following oral administration of azilsartan medoxomil. In vitro studies showed that azilsartan medoxomil was hydrolyzed rapidly to azilsartan in plasma, hepatic S9 fractions, and intestinal S9 fractions from all species tested. In human hepatic microsomes, azilsartan was further decarboxylated to the pharmacologically inactive metabolite M-I by the cytochrome P450 enzyme (CYP) 2C8, or was O-dealkylated to the inactive metabolite M-II by CYP2C9. No metabolites of azilsartan were unique to humans since they were all found in the animal species investigated.
Neither azilsartan nor azilsartan medoxomil induced CYP3A activity in human hepatocytes at concentrations up to 30-100 µmol/L.
The half maximal inhibitory concentration (IC50) values for azilsartan medoxomil for the in vitro inhibition of human hepatic CYP isoforms, CYP2C8, CYP2C9, CYP3A4, CYP2B6, CYP1A2, and CYP2C19 ranged from 3.5 to 66 µmol/L. Since azilsartan showed no significant CYP inhibition in vitro, and given that the expected levels of azilsartan medoxomil in humans are virtually none or below detectable limits, the effects seen with azilsartan medoxomil on CYP inhibition are not expected to be clinically significant.
Based on in vitro data, neither azilsartan medoxomil nor azilsartan is considered as a potential P-glycoprotein substrate or inhibitor in the clinical setting.
Excretion
In rats, dogs, and monkeys, only a small amount of unchanged azilsartan was detected in urine and faeces, indicating that the drug is almost completely metabolized before being eliminated. Excretion occurred mainly via the faeces (≥95%) with only small amount excreted in the urine of the animals tested.
3.2.3 Toxicology
Single-Dose Toxicity
Azilsartan medoxomil (the pro-drug) and azilsartan (the active form of azilsartan medoxomil) had a low order of acute oral toxicity. No deaths were observed in acute oral studies in mice, rats or in dogs (escalating doses).
Repeat-Dose Toxicity
Overall, the repeat-dose general toxicity observed with azilsartan medoxomil and azilsartan across species reflected exaggerated pharmacologic effects of AT1 receptor blockade in normotensive animals. A number of effects were reported as toxicologically significant, although the underlying basis was considered pharmacologic.
Severe toxicity, including mortality, occurred in dogs with high oral doses of azilsartan medoxomil (≥200 mg/kg/day) or azilsartan (≥100 mg/kg/day) and were considered a consequence of uremia. Deaths occurred in mice treated with azilsartan medoxomil 2,000 mg/kg/day in a 4-week gavage study and with doses ≥200 mg/kg/day in a 13-week gavage study. The cause of death in mice was not explained. No deaths occurred in mice when azilsartan was administered in the diet with doses up to 3,000 mg/kg/day for 13 weeks. Moreover, no deaths were reported in rats when azilsartan medoxomil was administered at doses up to 2,000 mg/kg/day by gavage for a maximum of 26 weeks,or with azilsartan administered by gavage at doses up to 3,000 mg/kg/day for 13 weeks, or up to 1,000 mg/kg/day for 26 weeks.
In the repeat-dose toxicity studies with azilsartan medoxomil or azilsartan, the reported no observed adverse effect level (NOAEL) typically was based on toxicologically significant findings in the kidneys, although these changes were considered to reflect extensions of the pharmacologic effects of azilsartan. Other pharmacologically-mediated toxicity observed in studies conducted with azilsartan medoxomil or azilsartan included changes in erythroid parameters, direct and indirect effects of reduction in blood pressure with associated changes in clinical chemistry parameters, decreases in heart and thymus weights, erosion and ulceration in the stomach, kidney changes, atrophy of the adrenal zona glomerulosa, and gastric erosions/ulcers. The reported effects of azilsartan in rats on heart weight and haematological parameters, as well as the pathological changes seen in the kidneys and stomach were secondary to AT1 receptor blockade and were eliminated or diminished as a result of saline supplementation in rats. A narrow therapeutic index was obtained for the renal tubular changes, erosion of the glandular stomach and adrenal zona glomerulosa atrophy findings. However, the renal tubular changes and gastric lesions are commonly observed in non-clinical studies with agents that affect the renin-angiotensin system (RAS). The low incidence of gastrointestinal side effects observed with RAS agents in therapeutic use suggest that ulcerogenicity observed in normotensive animals does not translate into an increased risk in hypertensive patients. Furthermore, renal tubular changes were seen in mice, but not in the other species at a similar drug exposure to azilsartan medoxomil or azilsartan. With regard to the adrenal zona glomerulosa atrophy, this effect, albeit not deemed a class effect, was also reported in animal studies for other RAS agents that have been on the market for many years and are known to have an acceptable safety profile in patients with mild to moderate essential hypertension. Hence, the findings pertaining to the renal tubular changes, glandular stomach erosion and adrenal zona glomerulosa atrophy did not represent major issues that preclude the market authorization of Edarbi. Nevertheless, as a precautionary measure, the Product Monograph recommends appropriate assessments of renal function for patients treated with Edarbi and information regarding these effects has been included in the toxicology section of the Product Monograph.
Genotoxicity
In the genotoxicity studies, azilsartan medoxomil, azilsartan, and M-II (the main metabolite in humans) were positive for structural aberrations in the in vitro Chinese Hamster Lung Cytogenetic Assay. Azilsartan medoxomil, azilsartan, and M-II were devoid of genotoxic potential in the bacterial (Ames) mutagenicity assays; azilsartan was negative in the in vitro Chinese Hamster Ovary Cell forward mutation and mouse lymphoma tk locus gene mutation assays; and azilsartan medoxomil and azilsartan were negative in unscheduled deoxyribonucleic acid (DNA) synthesis tests in rats, and in vivo mouse and/or rat bone marrow micronucleus assays.
Overall, from a weight of evidence perspective, the genotoxicity risk from azilsartan medoxomil and its metabolites is considered low.
Carcinogenicity
Azilsartan medoxomil was not carcinogenic when assessed in 26-week transgenic mouse (highest dose tested 450 mg/kg/day) and 2-year rat (highest dose tested 600 mg/kg/day) studies, with systemic exposures to azilsartan 7 and 17 (male and female mice), and 25 and 28 (male and female rats) times the average exposure to azilsartan in humans given the MRHD (80 mg/day).
No carcinogenic effects were also observed for the metabolite M-II in 26-week transgenic mouse and 24-month oral rat studies (highest dose tested 3,000 mg/kg/day).
Reproductive and Developmental Toxicity
In reproductive and developmental toxicity studies, azilsartan medoxomil had no effects on fertility or early embryonic development in rats at oral doses up to 1,000 mg/kg/day with systemic exposure to azilsartan 30-times that found in healthy humans at the MRHD (80 mg/day).
Azilsartan medoxomil was not teratogenic in rats at oral doses up to 1,000 mg/kg/day or in rabbits at oral doses up to 50 mg/kg/day. However, azilsartan medoxomil administered during the period of organogenesis, produced embryo-foetal toxicity at doses of 1,000 mg/kg/day in rats (dilated renal pelvis and short supernumerary ribs) and 50 mg/kg/day in rabbits (increased post-implantation loss, embryo-foetal deaths, and decreased number of live fetuses). Azilsartan systemic exposure (AUC) at NOAELs (100 and 30 mg/kg/day, respectively) was estimated at 20 and 9.2 times that at the MRHD (80 mg/day). Azilsartan was also found to induce embryo-foetal toxicity in rats (delayed ossification in the caudal vertebrae at doses ≥30mg/kg and lower body weight of male foetuses at 100 mg/kg) and in rabbits (increased post-implantation at 500 mg/kg) with systemic exposure at NOAELs (10 and 100 mg/kg, respectively) approximately 1.2-times that with the MRHD (80 mg/day).
In pre- and post-natal studies conducted in rats, the maternal dose of azilsartan medoxomil 10 mg/kg/day was found to induce maternal toxicity (decreased body weight gain and food consumption) and effects on the first filial generation [(F1), decreased live birth and viability indices; decreased body weight during lactation and growth; delayed incisor eruption; and renal pelvis dilatation and hydronephrosis]. The NOAEL for azilsartan medoxomil was 1 mg/kg/day, which corresponds to exposure approximately 0.1-times that of the MRHD (80 mg/day), when doses are expressed in terms of body surface area. Similarly, azilsartan induced maternal toxicity, including mortality, (at doses ≥ 1 mg/kg/day) and effects on F1 offspring (dilatation of the renal pelvis/ureter; lower body weight and survival; increased incidence of rough kidney surface; and F1 reproductive effects, at doses ≥ 0.3 mg/kg) in rats, at doses that provide a narrow therapeutic index. Based on the findings of embryo-foetal toxicity and effects on offspring at doses and exposures that were associated with low or no safety margin relative to humans, Edarbi should not be taken by women before or during pregnancy. This is consistent with other drugs of its class.
3.2.4 Summary and Conclusion
The non-clinical pharmacology studies demonstrated that azilsartan, the active form of azilsartan medoxomil (Edarbi), is a long-lasting, competitive, reversible and selective antagonist at the angiotensin II receptor AT1. Azilsartan medoxomil and azilsartan dose-dependently reduced blood pressure in animal models of normo- and supra-renin hypertension. Azilsartan had little effect on a variety of physiological systems, except for those that would be expected based on its pharmacological activity. In the non-clinical toxicology programme there was no evidence of findings to preclude the proposed therapeutic administration of Edarbi in patients. The toxicity findings were predictable, are well-known for this class of drugs, and can be monitored for clinically.
3.3 Clinical basis for decision
Under the provisions of the Draft Guidance Document: The Use of Foreign Reviews by Health Canada, the Canadian regulatory decision on the clinical pharmacology, efficacy, and safety of Edarbi was based on a critical assessment of the Canadian data package, with the use of foreign reviews completed by the FDA and EMA as an additional reference.
3.3.1 Pharmacodynamics
It is well known that angiotensin II AT1 receptor blockers (ARBs) exhibit anti-hypertensive effects by inhibiting the renin-angiotensin-aldosterone system (RAAS) at the angiotensin II receptor level. A Phase I, double-blind, placebo-controlled, ascending multiple-dose study with single oral doses of 0.3 to 20 mg of azilsartan showed a non-linear, dose-related inhibition of pressor response to exogenous angiotensin II. When RAAS is blocked, a negative feedback system will be in function, resulting in increased levels of renin, angiotensin I and angiotensin II and decreases in aldosterone. In a Phase 1, randomized, double-blind, placebo-controlled, sequential-panel, escalating single oral dose study similar information was found regarding the compensatory hormonal profile.
- Plasma renin activity increased after the administration of azilsartan medoxomil compared with placebo. Increases in plasma renin activity were generally observed within 24 hours of azilsartan treatment. Day 10 values compared with Day 1 showed there was a cumulative effect of multiple dosing on plasma renin activity. The Day 10 results also showed there was a dose effect. The plasma renin activity increased with increasing doses of azilsartan medoxomil.
- Plasma concentrations of angiotensin I increased within 24 hours after administration of azilsartan medoxomil compared with placebo. Day 10 values compared with Day 1 showed there was a cumulative effect of multiple dosing on the concentrations of angiotensin I. There was also a trend of a dose effect with concentrations of angiotensin I. As the doses of azilsartan medoxomil increased, the concentrations of angiotensin I increased.
- Aldosterone concentrations decreased within 24 hours after administration of azilsartan medoxomil compared with placebo. Decreases of aldosterone persisted at Day 10. There was evidence of an inverse dose-effect particularly at Day 10. Aldosterone concentrations decreased with increasing doses of azilsartan medoxomil.
A randomized, double-blind, placebo, and positive-controlled, crossover study evaluated the effect of azilsartan medoxomil on the QTc interval in 58 healthy adult subjects. Azilsartan medoxomil was administered as a single 320 mg dose. No clinically or statistically significant effects on the QTc interval were observed.
3.3.2 Pharmacokinetics
Absorption
Azilsartan medoxomil was rapidly hydrolyzed to azilsartan in the gastrointestinal tract during absorption. Dose proportionality in exposure was established for azilsartan in the azilsartan medoxomil dose range of 20 mg to 320 mg after single or multiple dosing. The estimated absolute bioavailability of azilsartan medoxomil was approximately 60%, based on levels of azilsartan. After oral administration of azilsartan medoxomil, peak plasma concentrations (Cmax) of azilsartan were reached within 1.5 to 3 hours. Food does not affect the bioavailability of azilsartan.
In order to support the proposed dosing recommendations that Edarbi can be taken with or without food, the sponsor provided a single dose, three-way crossover bioavailability study comparing the proposed commercial Edarbi 80 mg tablets administered under fasting conditions to the proposed commercial Edarbi 80 mg tablets administered following a high fat, high calorie meal. The study met the applicable bioequivalence standards for azilsartan medoxomil on log transformed parameters calculated from measured data, and data corrected for measured drug content.
Distribution
The volume of distribution of azilsartan was approximately 16 L.
Azilsartan was highly bound to human plasma proteins (>99%), mainly serum albumin.
Metabolism
Azilsartan was metabolized to two primary metabolites. The major metabolite in plasma was formed by O-dealkylation, referred to as metabolite M-II, and the minor metabolite was formed by decarboxylation, referred to as metabolite M-I. Neither of them was identified to have pharmacologic activity. The major enzyme responsible for azilsartan metabolism was CYP2C9.
Excretion
Following an oral dose of radiolabelled azilsartan medoxomil, approximately 55% of the radioactivity was recovered in the faeces and approximately 42% in the urine, with 15% of the dose excreted in the urine as azilsartan. The elimination half-life of azilsartan was approximately 11 hours and renal clearance was approximately 2.3 mL/min.
Special Populations
Hepatic Impairment
The pharmacokinetics of azilsartan medoxomil was not studied in patients with severe hepatic impairment and therefore its use is not recommended in this patient group. Total exposure (AUC) was increased by 64% in moderate and by 28% in mild hepatic impaired patients.
Renal Impairment
Total exposure to azilsartan, after a single dose of azilsartan medoxomil, was increased by 30%, 25%, and 96%, in patients with mild, moderate, and severe renal impairment, respectively. Caution should be exercised in hypertensive patients with severe renal impairment and end stage renal disease as there is no experience of use of Edarbi in these patients.
3.3.3 Clinical Efficacy
Two Phase III, 6-week randomized, double-blind, placebo-controlled studies (Study 1 and Study 2) evaluated the efficacy and safety of Edarbi (40 mg and 80 mg) compared to placebo in patients with essential hypertension. The primary endpoint was the change from Baseline to Week 6 in 24-hour mean systolic blood pressure (SBP) assessed by ambulatory blood pressure monitoring (ABPM). Both studies provided convincing evidence for clinical efficacy in reducing blood pressure in patients with uncomplicated mild to moderate essential hypertension.
In Study 1, the changes from Baseline to Week 6 in 24-hour mean SBP by ABPM were: -0.25 mm Hg with placebo; -13.42 mm Hg with Edarbi 40 mg; and -14.53 mm Hg with Edarbi 80 mg. Relative to placebo, the reductions in 24-hour mean SBP, were: -13.16 mm Hg with Edarbi 40 mg; and -14.27 mm Hg with Edarbi 80 mg. The 24-hour mean SBP measured by ABPM were validated by the traditional "gold standard" clinic diastolic blood pressure (DBP) measurement. The changes of DBP at trough were: -0.76 mm Hg with placebo; -6.97 mm Hg with Edarbi 40 mg; and -8.27 mm Hg with Edarbi 80 mg. The effects on blood pressure reduction were similar in Study 2. Edarbi demonstrated a significantly greater decrease of mean SBP for all the Edarbi treatment groups: -12.15 mm Hg; -13.48 mm Hg; and -14.62 mm Hg in the 20, 40, and 80 mg groups, respectively; compared with -1.40 mm Hg in the placebo group.
Another study evaluated the clinical efficacy in Black patients who tend to have low renin levels. The blood pressure reduction by the treatment of Edarbi 40 mg and 80 mg was statistically significant compared to placebo. The changes in 24-hour mean SBP by ABPM from Baseline to Week 6 in Black patients were: -7.70 mm Hg and -10.48 mm Hg in the Edarbi 40 mg and 80 mg treatment groups, respectively, compared to -2.70 mm Hg in the placebo treatment group.
Two long-term efficacy and safety pivotal studies examined the effects of Edarbi on reducing blood pressure over six months. The results from the two long-term pivotal studies were consistent with those demonstrated in the short-term studies.
In addition, two studies showed clinical efficacy in blood pressure reduction with concomitant use with chlorthalidone and amlodipine. Edarbi 40 and 80 mg co-administered with a calcium channel blocker (amlodipine, 5 mg) or a thiazide-type diuretic (chlorthalidone, 25 mg) resulted in additional blood pressure reductions.
3.3.4 Clinical Safety
A total of 4,814 patients were evaluated for safety when treated with Edarbi in the clinical studies. This included 1,704 patients treated for at least 6 months, of these, 588 were treated for at least 1 year. In the two pivotal short-term studies, Study 1 and Study 2, there were over 1,400 patients treated with Edarbi at different doses. Compared with placebo, Edarbi had an acceptable rate of adverse events.
In Study 1, the most common treatment-emergent adverse events observed in the Edarbi-treated groups were headache, dizziness, nasopharyngitis, urinary tract infection, fatigue, peripheral oedema, increased levels of plasminogen activator inhibitor (PAI), diarrhoea, increased levels of blood creatine phosphokinase (CPK), dyslipidemia, upper respiratory tract infection, nausea, increased levels of C-reactive protein, hypertriglyceridemia, and myalgia. No deaths were reported in this study. One gastrointestinal haemorrhage in the Edarbi 80 mg group was considered possibly related to the study drug. Markedly abnormal alanine aminotransferase (ALT) values were reported for 3 patients, 1 in each of the placebo, Edarbi 40 mg, and Edarbi 80 mg groups. Edarbi was shown to cause increased levels of serum creatinine. Increased levels of blood uric acid were reported with Edarbi 80 mg.
In Study 2, the overall frequency of adverse events (35.9% to 41.2%) was similar across all treatment groups. The most commonly reported adverse events were headache, dyslipidemia, and dizziness. Discontinuations due to adverse events were reported more frequently in the placebo (4.2%) and Edarbi 20 mg (3.9%) groups than other groups. Serious adverse events (SAEs) were low across all treatment groups, with the highest frequency in the Edarbi 20 mg (2.8%) and placebo groups (2.1%), and SAEs were reported in <1% of patients in the remaining groups. A single death due to SAEs of gastrointestinal haemorrhage and shock in the Edarbi 20 mg group was reported. This case was complicated with multiple medical issues and may not be related the study drug.
Overall, Edarbi showed an acceptable safety profile in Study 1 and Study 2 for the treatment of subjects with essential hypertension. Edarbi was well-tolerated without adverse events/reactions that were remarkable in the short-term studies.
Edarbi showed no significant safety concerns in two long-term studies that evaluated the safety of Edarbi after 6-months of treatment, as well as two other studies that treated patients for 8-12 months. The long-term use of Edarbi had a reasonable frequency of adverse events, and there were no outstanding safety issues.
Eight deaths were reported during all of the clinical studies; however, none of the deaths were confirmed as being associated with Edarbi. Serious adverse events associated with Edarbi were comparable with placebo and/or the positive controls in the studies. Edarbi had similar adverse drug reactions with other ARBs on the Canadian market, which are captured in the Edarbi Product Monograph. The safety profile of Edarbi 40 mg and 80 mg was considered acceptable.
3.4 Benefit/Risk Assessment and Recommendation
3.4.1 Benefit/Risk Assessment
The efficacy of Edarbi was established in clinical studies with more than 1,400 patients with mild to moderate essential hypertension treated with mono-therapy or with the concomitant use of other antihypertensive drugs. Two short-term 6 week pivotal studies demonstrated a treatment benefit for Edarbi for the reduction of blood pressure, measured as ABPM in comparison to placebo, at the dose 40 mg and 80 mg per day. The beneficial effect of Edarbi was also validated by the clinic DBP measurements.
Edarbi shares the general risk of ARBs, including but not limited to diarrhoea, fatigue, oedema, myalgia, headache, dizziness, and upper respiratory tract infection. The drug showed an acceptable safety profile with no unusual or unexpected adverse events. Overall, Edarbi is considered as having a favourable risk/benefit ratio.
The review of a Risk Management Plan (RMP) for Edarbi was completed on February 8, 2012. Based on the information submitted in the RMP, the adverse event profile appears to be similar to the well-known safety profiles of other ARBs. It was recommended that additional pharmacovigilance activities would be beneficial to clarify possible differences in the renal safety profile of this drug in comparison to other ARBs.
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 Edarbi is favourable in the treatment of mild to moderate essential hypertension. 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: Edarbi
| Submission Milestone | Date |
|---|---|
| Pre-submission meeting: | 2011-01-13 |
| Submission filed: | 2011-03-28 |
| Screening | |
| Screening Acceptance Letter issued: | 2011-05-13 |
| Review | |
| Biopharmaceutics Evaluation complete: | 2011-11-08 |
| Quality Evaluation complete: | 2012-03-07 |
| Clinical Evaluation complete: | 2012-03-07 |
| Labelling Review complete: | 2012-03-01 |
| Notice of Compliance issued by Director General: | 2012-03-01 |
Related Drug Products
| Product name | DIN | Company name | Active ingredient(s) & strength |
|---|---|---|---|
| EDARBI | 02381397 | BAUSCH HEALTH, CANADA INC. | AZILSARTAN MEDOXOMIL (AZILSARTAN MEDOXOMIL POTASSIUM) 80 MG |
| EDARBI | 02381389 | BAUSCH HEALTH, CANADA INC. | AZILSARTAN MEDOXOMIL (AZILSARTAN MEDOXOMIL POTASSIUM) 40 MG |