Source: European Medicines Agency (EU) Revision Year: 2023 Publisher: Takeda Pharma A/S, Delta Park 45, 2665 Vallensbaek Strand, Denmark
Pharmacotherapeutic group: Agents acting on the renin-angiotensin system, angiotensin II antagonists, plain
ATC Code: C09CA09
Azilsartan medoxomil is an orally active prodrug that is rapidly converted to the active moiety, azilsartan, which selectively antagonises the effects of angiotensin II by blocking its binding to the ATi receptor in multiple tissues (see section 5.2). Angiotensin II is the principal pressor agent of the RAAS, with effects that include vasoconstriction, stimulation of synthesis and release of aldosterone, cardiac stimulation, and renal reabsorption of sodium.
Blockade of the AT1 receptor inhibits the negative regulatory feedback of angiotensin II on renin secretion, but the resulting increases in plasma renin activity and angiotensin II circulating levels do not overcome the antihypertensive effect of azilsartan.
In seven double blind controlled studies, a total of 5,941 patients (3,672 given Edarbi, 801 given placebo, and 1,468 given active comparator) were evaluated. Overall, 51% of patients were male and 26% were 65 years or older (5% ≥75 years); 67% were white and 19% were black.
Edarbi was compared with placebo and active comparators in two 6 week randomised, double blind studies. Blood pressure reductions compared with placebo based on 24 hour mean blood pressure by ambulatory blood pressure monitoring (ABPM) and clinic blood pressure measurements at trough are shown in the table below for both studies. Additionally, Edarbi 80 mg resulted in significantly greater reductions in SBP than the highest approved doses of olmesartan medoxomil and valsartan.
| Placebo | Edarbi 20 mg | Edarbi 40 mg# | Edarbi 80 mg# | OLM-M 40 mg# | Valsartan 320 mg# | |
|---|---|---|---|---|---|---|
| Primary end point: 24 Hour Mean SBP: LS Mean Change from Baseline (BL) to Week 6 (mmHg) | ||||||
| Study 1 | ||||||
| Change from BL | -1.4 | -12.2* | -13.5 * | -14.6*† | -12.6 | - |
| Study 2 | ||||||
| Change from BL | -0.3 | - | -13.4* | -14.5*† | -12.0 | -10.2 |
| Key Secondary End Point: Clinic SBP: LS Mean Change from Baseline (BL) to Week 6 (mmHg) (LOCF) | ||||||
| Study 1 | ||||||
| Change from BL | -2.1 | -14.3* | -14.5* | -17.6* | -14.9 | - |
| Study 2 | ||||||
| Change from BL | -1.8 | - | -16.4*† | -16.7*† | -13.2 | -11.3 |
OLM-M = olmesartan medoxomil, LS = least squares, LOCF = last observation carried forward
* Significant difference vs. Placebo at 0.05 level within the framework of the step-wise analysis
† Significant difference vs. Comparator(s) at 0.05 level within the framework of the step-wise analysis
# Maximum dose achieved in study 2. Doses were force-titrated at Week 2 from 20 to 40 mg and 40 to 80 mg for Edarbi, and 20 to 40 mg and 160 to 320 mg, respectively, for olmesartan medoxomil and valsartan
In these two studies, clinically important and most common adverse events included dizziness, headache and dyslipidemia. For Edarbi, olmesartan medoxomil and valsartan, respectively dizziness was observed at an incidence of 3.0%, 3.3% and 1.8%; headache at 4.8%, 5.5% and 7.6% and dyslipidemia at 3.5%, 2.4% and 1.1%.
In active-comparator studies with either valsartan or ramipril, the blood-pressure-lowering effect with Edarbi was sustained during long-term treatment. Edarbi had a lower incidence of cough (1.2%) compared with ramipril (8.2%).
The antihypertensive effect of azilsartan medoxomil occurred within the first 2 weeks of dosing with the full effect achieved by 4 weeks. The blood pressure lowering effect of azilsartan medoxomil was also maintained throughout the 24 hour dosing interval. The placebo-corrected trough-to-peak ratios for SBP and DBP were approximately 80% or higher.
Rebound hypertension was not observed following abrupt cessation of Edarbi therapy after 6 months of treatment.
No overall differences in safety and effectiveness were observed between elderly patients and younger patients, but greater sensitivity to blood pressure lowering effects in some elderly individuals cannot be ruled out (see section 4.2). As with other angiotensin II receptor antagonists and angiotensin converting enzyme inhibitors the antihypertensive effect was lower in black patients (usually a low-renin population).
Coadministration of Edarbi 40 and 80 mg with a calcium channel blocker (amlodipine) or a thiazide-type diuretic (chlortalidone) resulted in additional blood pressure reductions compared with the other antihypertensive alone. Dose dependent adverse events including dizziness, hypotension and serum creatinine elevations were more frequent with diuretic coadministration compared with Edarbi alone, while hypokalemia was less frequent compared with diuretic alone.
Beneficial effects of Edarbi on mortality and cardiovascular morbidity and target organ damage are currently unknown.
A thorough QT/QTc study was conducted to assess the potential of azilsartan medoxomil to prolong the QT/QTc interval in healthy subjects. There was no evidence of QT/QTc prolongation at a dose of 320 mg of azilsartan medoxomil.
Two large randomised, controlled trials (ONTARGET (ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial) and VA NEPHRON-D (The Veterans Affairs Nephropathy in Diabetes)) have examined the use of the combination of an ACE-inhibitor with an angiotensin II receptor blocker.
ONTARGET was a study conducted in patients with a history of cardiovascular or cerebrovascular disease, or type 2 diabetes mellitus accompanied by evidence of end-organ damage. VA NEPHRON-D was a study in patients with type 2 diabetes mellitus and diabetic nephropathy.
These studies have shown no significant beneficial effect on renal and/or cardiovascular outcomes and mortality, while an increased risk of hyperkalaemia, acute kidney injury and/or hypotension as compared to monotherapy was observed. Given their similar pharmacodynamic properties, these results are also relevant for other ACE-inhibitors and angiotensin II receptor blockers.
ACE inhibitors and angiotensin II receptor blockers should therefore not be used concomitantly in patients with diabetic nephropathy.
ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints) was a study designed to test the benefit of adding aliskiren to a standard therapy of an ACE inhibitor or an angiotensin II receptor blocker in patients with type 2 diabetes mellitus and chronic kidney disease, cardiovascular disease, or both. The study was terminated early because of an increased risk of adverse outcomes. Cardiovascular death and stroke were both numerically more frequent in the aliskiren group than in the placebo group and adverse events and serious adverse events of interest (hyperkalaemia, hypotension and renal dysfunction) were more frequently reported in the aliskiren group than in the placebo group.
The antihypertensive effects of azilsartan medoxomil were evaluated in a Phase 3 randomised, double-blind study in children or adolescents 6 to <18 years of age with primary or secondary hypertension. This study involved a 6-week, double-blind, randomised treatment phase (DB Phase), followed by a 2-week, double-blind, randomised placebo-controlled withdrawal phase (WD Phase). In the DB Phase, subjects were randomised (1:1:1:1) to the following groups: azilsartan medoxomil 10 mg, 20 mg, and 40 mg/80 mg (based on subject body weight), or losartan. All patients started at the 10 mg treatment for 2 weeks; subsequently, patients either continued at 10 mg or were up-titrated to 20, 40, or 80 mg. In the WD Phase, subjects were randomised (1:1) to continue taking their previously assigned active treatment or were switched to placebo. This study also included a 44-week, open-label extension (OL Phase), in which all subjects received azilsartan medoxomil or azilsartan medoxomil and other antihypertensive medications as needed in a titrate-to-target blood pressure dosing algorithm, starting at 10 mg azilsartan medoxomil.
In the 6-week DB Phase, 162 subjects were exposed to azilsartan medoxomil. In the 2-week WD Phase, 77 subjects were exposed to azilsartan medoxomil and 103 subjects were exposed to placebo. In the 44-week OL Phase, 156 subjects were exposed to azilsartan medoxomil alone and 41 subjects were exposed to azilsartan medoxomil and other antihypertensives.
In the 2-week withdrawal period, there was a loss of blood pressure control in subjects randomised to placebo, while subjects who remained on azilsartan medoxomil treatment had stable blood pressure control. The difference in mean seated diastolic blood pressure change from Week 6 to Week 8 in the subjects treated with azilsartan medoxomil versus placebo was -5.42 mmHg (95% CI, -7.29 to -3.55 mmHg; p<0.001). Percentage of subjects who achieved target blood pressure (defined as <90th percentile for age, gender, and height) at Week 8 (week 2 of the withdrawal period) was significantly higher with azilsartan medoxomil treatment compared with placebo. Subjects who were treated with azilsartan medoxomil (all doses pooled) had a statistically significantly greater change in mean seated DBP from baseline to Week 6 compared with losartan-treated subjects. The effect of azilsartan medoxomil remained consistent over time during the open-label phase.
Following oral administration, azilsartan medoxomil is rapidly hydrolyzed to the active moiety azilsartan in the gastrointestinal tract and/or during absorption. Based on in vitro studies, carboxymethylenebutenolidase is involved in the hydrolysis in the intestine and liver. In addition, plasma esterases are involved in the hydrolysis of azilsartan medoxomil to azilsartan.
The estimated absolute oral bioavailability of azilsartan medoxomil based on plasma levels of azilsartan is approximately 60%. After oral administration of azilsartan medoxomil, peak plasma concentrations (Cmax) of azilsartan are reached within 1.5 to 3 hours. Food does not affect the bioavailability of azilsartan (see section 4.2).
The volume of distribution of azilsartan is approximately 16 litres. Azilsartan is highly bound to plasma proteins (>99%), mainly serum albumin. Protein binding is constant at azilsartan plasma concentrations well above the range achieved with recommended doses.
Azilsartan is metabolised to two primary metabolites. The major metabolite in plasma is formed by O-dealkylation, referred to as metabolite M-II, and the minor metabolite is formed by decarboxylation, referred to as metabolite M-I. Systemic exposures to the major and minor metabolites in humans were approximately 50% and less than 1% that of azilsartan, respectively. M-I and M-II do not contribute to the pharmacologic activity of azilsartan medoxomil. The major enzyme responsible for azilsartan metabolism is CYP2C9.
Following an oral dose of 14C-labelled azilsartan medoxomil, approximately 55% of radioactivity was recovered in faeces and approximately 42% in urine, with 15% of the dose excreted in urine as azilsartan. The elimination half-life of azilsartan is approximately 11 hours and renal clearance is approximately 2.3 ml/min. Steady-state levels of azilsartan are achieved within 5 days and no accumulation in plasma occurs with repeated once-daily dosing.
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 population pharmacokinetics of azilsartan following oral doses of azilsartan medoxomil were evaluated in hypertensive children aged 6 to <18 years in a single dose study as well as in a multiple dose study of 10 mg to a maximum of 80 mg for 6 weeks. Generally, a dose proportional increase of the maximum concentration (Cmax,ss) and exposure (AUCss) of azilsartan was observed. Exposure of azilsartan was dependent on body weight, generally a higher exposure was observed for paediatric patients weighing ≤50 kg compared to those weighing >50 kg. The azilsartan exposure was similar between children and adults when allometric scaling was applied.
Pharmacokinetics of azilsartan do not differ significantly between young (age range 18-45 years) and elderly (age range 65-85 years) patients.
In patients with mild, moderate, and severe renal impairment azilsartan total exposure (AUC) was +30%, +25% and +95% increased. No increase (+5%) was observed in end-stage renal disease patients who were dialysed. However, there is no clinical experience in patients with severe renal impairment or end stage renal disease (see section 4.2). Hemodialysis does not remove azilsartan from the systemic circulation.
Administration of Edarbi for up to 5 days in subjects with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment resulted in slight increase in azilsartan exposure (AUC increased by 1.3 to 1.6 fold, see section 4.2). Edarbi has not been studied in patients with severe hepatic impairment.
Pharmacokinetics of azilsartan do not differ significantly between males and females. No dose adjustment is necessary based on gender.
Pharmacokinetics of azilsartan do not differ significantly between black and white populations. No dose adjustment is necessary based on race.
In preclinical safety studies, azilsartan medoxomil and M-II, the major human metabolite, were examined for repeated-dose toxicity, reproduction toxicity, mutagenicity and carcinogenicity.
In the repeated-dose toxicity studies, doses producing exposure comparable to that in the clinical therapeutic range caused reduced red cell parameters, changes in the kidney and renal haemodynamics, as well as increased serum potassium in normotensive animals. These effects, which were prevented by oral saline supplementation, do not have clinical significance in treatment of hypertension.
In rats and dogs, increased plasma renin activity and hypertrophy/hyperplasia of the renal juxtaglomerular cells were observed. These changes, also a class effect of angiotensin converting enzyme inhibitors and other angiotensin II receptor antagonists, do not appear to have clinical significance.
Azilsartan and M-II crossed the placenta and were found in the fetuses of pregnant rats and were excreted into the milk of lactating rats. In the reproduction toxicity studies, there were no effects on male or female fertility. There is no evidence of a teratogenic effect, but animal studies indicated some hazardous potential to the postnatal development of the offspring such as lower body weight, a slight delay in physical development (delayed incisor eruption, pinna detachment, eye opening), and higher mortality.
Azilsartan and M-II showed no evidence of mutagenicity and relevant clastogenic activity in in vitro studies and no evidence of carcinogenicity in rats and mice.
Juvenile oral toxicity studies up to 3 months in duration in rats (2 or 3 weeks old) with azilsartan medoxomil, alone or in combination with M-II, showed that juvenile rats may be more susceptible to angiotensin-related altered renal morphology and function when exposed from postnatal week 2, corresponding with the period of growth and maturation of the renal system. The growth and maturation stage of the human renal system extends to about 2 years of age.
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