Treatment of hypertension in adults.
Ezeact PLUS is a fixed-dose combination indicated in adults whose blood pressure is not adequately
controlled by azilsartan medoxomil monotherapy.

Posology
Adults
The recommended starting dose is 40 mg/12.5 mg once daily in patients whose blood pressure is not
adequately controlled with current antihypertensive monotherapy such as Ezeact 40 mg or Ezeact 80 mg.
If needed the dose may be increased to a maximum of 40 mg/25 mg once daily.
Near-maximal antihypertensive effect is usually evident within 1-2 weeks of dosing, with maximal effects
attained by 4 weeks.
Special populations
Older people (65 years and over)
No initial dose adjustment with Ezeact PLUS is necessary in elderly patients; caution should be exercised and
close medical monitoring is recommended in the very elderly (≥ 75 years), who may be at increased risk of
adverse events (see section 5.2).
Renal impairment
Chlortalidone, a component drug of Ezeact PLUS, should not be used in patients with severe renal
impairment (GFR <30 mL/min/1.73m2) and anuria (see section 4.3). There is no experience regarding the
administration of Ezeact PLUS in patients with recent kidney transplantation. No dose adjustment is
required in patients with mild or moderate renal impairment (GFR ≥30-<90 mL/min/1.73m2).
Hepatic impairment
Chlortalidone, a component drug of Ezeact PLUS, should not be used in patients with severe hepatic impairment (see section 4.3). There is limited experience of use of Ezeact PLUS in patients with mild to
moderate hepatic impairment; however, no initial dose adjustment of Ezeact PLUS is necessary in patients
with mild to moderate hepatic impairment.
Thiazides should be used with caution in patients with impaired hepatic function (see sections 4.3 and 4.4).
Minor changes in the fluid and electrolyte balance due to thiazide diuretics may precipitate hepatic coma.
Close monitoring is recommended (see section 5.2).
Intravascular volume depletion
For patients with depletion of intravascular volume or salt (e.g. patients with vomiting, diarrhoea or taking
high doses of diuretics), Ezeact PLUS should be initiated under close medical supervision only after
correct volume has been obtained (see section 4.4).
A transient hypotensive response due to volume depletion does not preclude patients from further treatment,
which usually can be continued without difficulty once the blood pressure and volume status have stabilized.
Heart failure
Caution should be exercised in hypertensive patients with congestive heart failure as there is no experience
of use of Ezeact PLUS in these patients (see section 4.4).
Black population
No dose adjustment is required in the black population, who are commonly characterised as “low renin”
hypertensives with an attenuated response to Renin-Angiotensin-Aldosterone System (RAAS) blockers. The
blood pressure effect and safety profile of Ezeact PLUS in black patients are similar to those in the non-black
population.
Paediatric population
The safety and efficacy of Ezeact PLUS in children and adolescents aged 0 to <18 years have not
been established. No data are available.
Method of administration
Ezeact PLUS is for oral use and may be taken with or without food (see section 5.2).

- Hypersensitivity to the active substance or to any of the excipients. - Pregnancy (see sections 4.4 and 4.6). - Severe hepatic impairment. - Severe renal impairment (GFR <30 mL/min/1.73m2). - Anuria. - Refractory hyponatraemia (see sections 4.4 and 4.8). - Hypercalcaemia (see sections 4.4). - Symptomatic hyperuricaemia (see sections 4.4 and 4.8). - Concomitant use of Ezeact PLUS with aliskiren-containing products is contraindicated in patients with diabetes mellitus or renal impairment (GFR <60 mL/min/1.73m2) (see sections 4.5 and 5.1).

Dual blockade of the Renin-Angiotensin-Aldosterone System (RAAS)
There is evidence that the concomitant use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren
increases the risk of hypotension, hyperkalaemia and decreased renal function (including acute renal failure).
Dual blockade of RAAS through the combined use of ACE-inhibitors, angiotensin II receptor blockers or
aliskiren is therefore not recommended (see sections 4.5 and 5.1).
If dual blockade therapy is considered absolutely necessary, this should only occur under specialist
supervision and subject to frequent close monitoring of renal function, electrolytes and blood pressure.
ACE-inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with
diabetic nephropathy.
Activated renin-angiotensin-aldosterone system
In patients whose vascular tone and renal function depend predominantly on the activity of the reninangiotensin-
aldosterone system (e.g. patients with congestive heart failure, or underlying renal disease,
including bilateral renal artery stenosis ), treatment with medicinal products that affect this system, such as
ACE-inhibitors and angiotensin II receptor blockers, has been associated with acute hypotension, azotaemia,
oliguria or, rarely, acute renal failure. The possibility of similar effects cannot be excluded with Ezeact
PLUS.
Evaluation of hypertensive patients with activated RAAS should include periodic assessment of renal
function and electrolyte levels.
Excessive blood pressure decreases in patients with ischaemic cardiomyopathy or ischaemic cerebrovascular
disease could result in a myocardial infarction or stroke.
Renal impairment
Chlortalidone, a component drug of Ezeact PLUS, should not be used in severe renal impairment (GFR
<30 mL/min/1.73m2) (see section 4.3). No dose adjustment is required in patients with mild or moderate
renal impairment.
Observe for worsening renal function in patients with renal impairment by periodic monitoring of serum
creatinine and electrolyte levels. Patients with renal impairment are more likely to report abnormally high
serum creatinine values. In these patients, Ezeact PLUS should be carefully titrated with monitoring of
blood pressure and renal function parameters. Renal function may worsen in patients with renal artery
stenosis.

Chlortalidone should be used with caution in patients with renal impairment, since chlortalidone may
precipitate azotaemia. If progressive renal impairment becomes evident consider withholding or
discontinuing diuretic therapy.
Kidney transplantation
There is currently no experience on the use of Ezeact PLUS in patients who have recently undergone kidney
transplantation.
Hepatic impairment
Chlortalidone, a component drug of Ezeact PLUS, should not be used in severe hepatic impairment (see
section
4.3).
There is limited experience of use of Ezeact PLUS in patients with mild to moderate hepatic impairment,
however, based on PK data, no initial dose adjustment of Ezeact PLUS is necessary in patients with mild
to moderate hepatic impairment. Minor changes in the fluid and electrolyte balance due to thiazide
diuretics may precipitate hepatic coma. Close monitoring is therefore recommended (see section 5.2).

For patients with possible depletion of intravascular volume or salt depletion (e.g. patients with vomiting,
diarrhoea, or patients taking high doses of diuretics), Ezeact PLUS should be initiated under close medical
supervision (see section 4.2). Volume- and/or salt- depletion should be corrected before initiating Ezeact
PLUS treatment.
Primary hyperaldosteronism
Patients with primary hyperaldosteronism generally will not respond to antihypertensive medicinal products
acting through inhibition of the renin-angiotensin system. Therefore, the use of Ezeact PLUS is not
recommended in these patients.
Electrolyte imbalance
As for any patient receiving diuretic therapy, determination of serum electrolytes should be performed
periodically.
Thiazides can cause fluid or electrolyte imbalance (including hypokalaemia, hypercalcaemia, hyponatraemia,
and hypochloraemic alkalosis). Warning signs of fluid or electrolyte imbalance are dryness of mouth, thirst,
asthenia, lethargy, drowsiness, restlessness, muscle pain or cramps, muscular fatigue, hypotension, oliguria,
tachycardia, and gastrointestinal disturbances such as nausea or vomiting (see section 4.8). Fluid and
electrolyte imbalance should be corrected prior to initiating treatment with Ezeact PLUS.
Hypokalaemia
Hypokalaemia is a dose-dependent adverse reaction that may develop with chlortalidone monotherapy.
Concurrent therapy with azilsartan medoxomil has been shown to reduce chlortalidone-associated
hypokalaemia. Coadministration of digitalis may exacerbate the adverse effects of hypokalaemia.
Hypokalaemia should be corrected prior to initiating treatment with Ezeact PLUS.
Hyperkalaemia
Due to the antagonism of the angiotensin II receptors by the azilsartan medoxomil component of Ezeact
PLUS, hyperkalaemia may occur. Although clinically significant hyperkalaemia has not been documented
with Ezeact PLUS, risk factors for developing hyperkalaemia include renal impairment and/or heart
failure, and diabetes mellitus. Potassium-sparing diuretics, potassium supplements or potassium-containing
salt substitutes should be co-administered cautiously with Ezeact PLUS (see section 4.5).
Hyponatraemia and hypochloraemic alkalosis

Thiazides have been shown to induce hyponatraemia. Ezeact PLUS should not be used in patients with
refractory hyponatraemia (see section 4.3). Chloride deficit is generally mild and usually does not require
treatment.
Hypercalcaemia
Thiazides may decrease urinary calcium excretion and cause an intermittent and slight elevation of serum
calcium in the absence of known disorders of calcium metabolism. Marked hypercalcaemia may be evidence
of hidden hyperparathyroidism. Thiazides should be discontinued before carrying out tests for parathyroid
function. Ezeact PLUS should not be used in patients with hypercalcaemia (see section 4.3).
Hypomagnesaemia
Thiazides have been shown to increase the urinary excretion of magnesium, which may result in
hypomagnesaemia (see section 4.5).
Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy
As with other agents causing vasodilation or volume depletion special caution is indicated in patients
suffering from aortic or mitral valve stenosis, or hypertrophic obstructive cardiomyopathy (HOCM).
Metabolic and endocrine effects
Thiazide therapy may impair glucose tolerance, so a dose adjustment of insulin or antidiabetic therapy may
be required. Latent diabetes mellitus may become manifest during thiazide therapy. An increase in
cholesterol and triglyceride levels has been associated with thiazide diuretic therapy.

Hyperuricaemia
Hyperuricaemia may occur or frank gout may be precipitated in certain patients receiving chlortalidone or
other thiazide diuretics. Ezeact PLUS should not be used in patients with symptomatic hyperuricaemia (see
section 4.3).
Pregnancy
Ezeact PLUS should not be used in pregnancy (see section 4.3).
Angiotensin II receptor blockers should not be initiated during pregnancy. Unless continued angiotensin II
receptor blocker therapy is essential, patients planning pregnancy should be changed to alternative
antihypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy
is diagnosed, treatment with angiotensin II receptor blockers should be stopped immediately, and, if
appropriate, alternative therapy should be started (see sections 4.3 and 4.6).
Diuretics should not be used for the management of oedema or hypertension in pregnancy (see section 4.6).
Lithium
As with other angiotensin II receptor blockers, the combination of lithium and Ezeact PLUS is not
recommended
(see section 4.5).
Paediatric population
The safety and efficacy of Ezeact PLUS in children and adolescents aged 0 to <18 years have not
been established. No data are available.

Concomitant use not recommended
Lithium
Reversible increases in serum lithium concentrations and toxicity have been reported during concurrent use
of lithium and angiotensin-converting enzyme inhibitors. A similar effect may occur with angiotensin II
receptor blockers. Lithium renal clearance is reduced by diuretics, such as chlortalidone, increasing the risk
of lithium toxicity.
Due to the lack of experience with concomitant use of Ezeact PLUS and lithium, this combination is not
recommended. If the combination proves necessary, consider monitoring of serum lithium levels when using
Ezeact PLUS.
Caution required with concomitant use
Non-steroidal anti-inflammatory drugs (NSAIDs), including selective COX-2 inhibitors, acetylsalicylic acid
> 3 g/day), and non-selective NSAIDs
When angiotensin II receptor blockers are administered simultaneously with NSAIDs (i.e. selective
COX-2 inhibitors, acetylsalicylic acid (> 3 g/day) and non-selective NSAIDs), attenuation of the
antihypertensive effect may occur. Furthermore, in patients who are elderly, volume-depleted (including
those on diuretic therapy), or who have compromised renal function concomitant use of angiotensin II
receptor blockers and NSAIDs may lead to an increased risk of worsening of renal function (including
possible acute renal failure) and an increase in serum potassium. Therefore, adequate hydration and
monitoring of renal function at the beginning of the treatment are recommended.
Potassium supplements, salt substitutes containing potassium and other substances that may increase
potassium levels
Based on experience with the use of other medicinal products that affect the RAAS, use of Ezeact PLUS
with potassium supplements, salt substitutes containing potassium, or other medicinal products that may
increase potassium levels (e.g. heparin) may lead to increases in serum potassium in hypertensive patients
(see
section 4.4).

Digitalis
Coadministration of digitalis may exacerbate the adverse effects of hypokalemia (see section 4.4).
Additional information
Ezeact PLUS
Clinical trial data has shown that dual blockade of the renin-angiotensin-aldosterone-system (RAAS) through
the combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is associated with a higher
frequency of adverse events such as hypotension, hyperkalaemia and decreased renal function (including
acute renal failure) compared to the use of a single RAAS-acting agent (see sections 4.3, 4.4 and 5.1).
The pharmacokinetics of azilsartan medoxomil and chlortalidone is not altered when the drugs are
co-administered.
No drug interaction studies have been conducted with other drugs and Ezeact PLUS, although studies have
been conducted with azilsartan medoxomil and chlortalidone.
Azilsartan medoxomil
No clinically significant interactions have been reported in studies of azilsartan medoxomil or azilsartan
given with amlodipine, antacids, chlortalidone, digoxin, fluconazole, glyburide, ketoconazole, metformin,
and warfarin.
Azilsartan medoxomil is a prodrug, which is rapidly hydrolysed to the active moiety azilsartan by esterases
in the gastrointestinal tract and/or during drug absorption (see section 5.2). In vitro studies indicated that interactions based on esterase inhibition are unlikely.
Chlortalidone
Diuretics potentiate the action of curare derivatives and antihypertensive agents (e.g. guanethidine,
metyldopa, beta-blockers, vasodilators, calcium antagonists, ACE-inhibitors and ARBs).
The hypokalaemic effect of chlortalidone may be potentiated by corticosteroids, ACTH, β2-agonists,
amphotericin and carbenoloxone.
Allopurinol
Coadministration of chlortalidone may increase the incidence of hypersensitivity reactions to allopurinol.
Amantadine
Chlortalidone may increase the risk of adverse effects caused by amantadine.
Anticholinergic agents (e.g. atropine, biperiden) may increase the bioavailability of chlortalidone by
decreasing gastrointestinal motility and stomach emptying rate.
Antidiabetic medicinal products (oral agents and insulin)
Dosage adjustment of the antidiabetic medicinal products may be required.
Calcium salts
The pharmacological effects of both calcium salts and vitamin D may be increased to clinically significant
levels if administered together with chlortalidone.
Ciclosporin
Concomitant treatment with ciclosporin may increase the risk of hyperuricaemia and gout-type
complications.

Colestyramine
Absorption of chlortalidone is impaired in the presence of anionic exchange resins. A decrease in the
pharmacological effect may be expected.
Cytotoxic agents
Concurrent administration may reduce renal excretion of cytotoxic medicinal products (e.g.
cyclophosphamide, metothrexate) and potentiate their myelosuppressive effects.
Diazoxide
The hyperglycaemic effect of diazoxide may be enhanced by chlortalidone.

Pregnancy
Ezeact PLUS should not be used in pregnancy (see section 4.3 and 4.4).
The use of angiotensin II receptor blockers is not recommended during the first trimester of pregnancy
(see section 4.4).
The use of angiotensin II receptor blockers is contraindicated during the second and third trimester of
pregnancy (see sections 4.3 and 4.4).
Thiazides are contraindicated in pregnancy (see section 4.3 and 4.4).
There are no clinical data from the use of Ezeact PLUS in pregnant women. Studies in animals have
shown reproductive toxicity (see section 5.3).
Azilsartan medoxomil
Epidemiological evidence regarding the risk of teratogenicity following exposure to angiotensin converting
enzyme inhibitors during the first trimester of pregnancy has not been conclusive; however, a small increase
in risk cannot be excluded. Whilst there are no controlled epidemiological data on the risk with angiotensin
II receptor blockers, similar risks may exist for this class of medicinal products. Unless continued
angiotensin II receptor blocker therapy is considered essential, patients planning pregnancy should be
changed to alternative anti-hypertensive treatments which have an established safety profile for use in
pregnancy. When pregnancy is diagnosed, treatment with angiotensin II receptor blockers should be stopped
immediately and, if appropriate, alternative therapy should be started.
Exposure to angiotensin II receptor blocker therapy during the second and third trimesters is known to
induce human fetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and
neonatal toxicity (renal failure, hypotension, hyperkalaemia) (see section 5.3).
Should exposure to angiotensin II receptor blockers have occurred from the second trimester of pregnancy,
ultrasound check of renal function and skull is recommended.
Infants whose mothers have taken Angiotensin II receptor blockers should be closely observed for
hypotension (see sections 4.3 and 4.4).

Chlortalidone
Diuretics should not be used for the management of oedema or hypertension in pregnancy as their use may
be associated with hypovolaemia, increased blood viscosity and reduced placental perfusion. Diuretics such
as chlortalidone have been shown to cross the placental barrier and appear in cord blood. There have been
reports of fetal bone marrow depression, thrombocytopenia, and fetal and neonatal jaundice associated with
the use of thiazide-like diuretics.
Breastfeeding
No information is available regarding the use of Ezeact PLUS or azilsartan medoxomil during breastfeeding.
However, chlortalidone passes into breast milk and Ezeact PLUS is therefore not recommended during
breastfeeding. Alternative treatments with better established safety profiles during breastfeeding are
preferable, especially while nursing a newborn or preterm infant.
Fertility
No data are available on the effect of Ezeact PLUS on human fertility. Nonclinical studies demonstrated
that azilsartan medoxomil did not appear to affect male or female fertility in the rat (see section 5.3).

Based on its pharmacodynamic properties, it is expected that Ezeact PLUS would have negligible
influence on the ability to drive and use machines. However, when taking any antihypertensive it should
be taken into account that dizziness or tiredness may occur.

Summary of the safety profile
Ezeact PLUS has been evaluated for safety in clinical studies in patients treated for up to 52 weeks. In
these clinical studies, adverse reactions associated with treatment with Ezeact PLUS were mostly mild or
moderate. The most common adverse reaction was blood creatinine increased. The increases in blood
creatinine were
dose-related and mostly transient or nonprogressive while on treatment, and reversible following cessation of
treatment. The incidence of adverse reactions with Ezeact PLUS was not affected by gender, age, or race.
Clinical Investigation
In the short term studies, the safety profile was comparable to active comparators and showed no clinically
important differences across diverse subgroups including age, gender, or race. When Ezeact PLUS was
administered to patients not adequately controlled on azilsartan medoxomil 40 mg, the overall safety profile
of Ezeact PLUS 40 mg/12.5 mg was similar to the safety profile of azilsartan medoxomil 40 mg. Ezeact
PLUS 40 mg/25 mg was also safe and well tolerated, although elevated blood creatinine, headache and
dizziness occurred more frequently in conjunction with greater blood pressure reduction. In the long term
safety study in patients with moderate renal impairment, the adverse events observed were similar for Ezeact
PLUS compared with olmesartan medoxomil/hydrochlorothiazide.
Cardiovascular outcome studies have shown that long-term treatment with chlortalidone reduces the risk of
cardiovascular mortality and morbidity.
Tabulated list of adverse reactions
Adverse reactions based on pooled data from all Phase 3 clinical trials are listed below according to system
organ class and preferred terms. These are ranked by frequency, using the following convention: very
common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1,000, < 1/100); rare (≥ 1/10,000, < 1/1,000);
very rare (< 1/10,000), including isolated reports. Within each frequency grouping, adverse reactions are
presented in order of decreasing seriousness.

Blood and lymphatic system
disorders
Uncommon Anaemia

Metabolism and nutrition
disorders
Common:Blood uric acid increased, hyperuricaemia
Uncommon:Hypokalaemia, blood potassium increased,
hyponatraemia, blood sodium decreased, gout

Nervous system disorders

Common:Dizziness, dizziness postural
Uncommon:Syncope, paraesthesia

Vascular disorders

Common Hypotension
Gastrointestinal disorders

Common Diarrhoea, nausea

Uncommon Vomiting

 

Skin and subcutaneous tissue
disorders
Uncommon Rash, pruritus

Musculoskeletal and
connective tissue disorders
Common Muscle spasms

General disorders and
administration site conditions
Common Fatigue

Investigations

Very common: Blood creatinine increased
Common:Blood urea increased
Uncommon:Blood glucose increased

Additional information on individual components
Adverse reactions known to occur with each component given singly but not seen in the clinical studies may
occur during treatment with Ezeact PLUS.
Azilsartan medoxomil
In addition to the adverse reactions noted above for Ezeact PLUS, the following adverse reactions have
been reported for azilsartan medoxomil:
Peripheral oedema, migraine, and increased blood creatine phosphokinase were reported as uncommon
adverse reactions
Renal impairment was reported rarely during the clinical trials. Serious angioedema may occur rarely (≥
1/10,000 to <1/1,000).
Chlortalidone
In addition to the adverse reactions noted above for Ezeact PLUS, the following adverse reactions have
been reported for chlortalidone:

Blood and lymphatic system
disorders
Rare Thrombocytopenia, leucopenia
agranulocytosis, eosinophilia
Metabolism and nutrition
disorders
Very common Rise in blood lipids
Common Hypomagnesaemia
Rare Hypercalcaemia, glycosuria, worsening of
diabetic metabolic state
Very rare Hypochloraemic alkalosis

Nervous system disorders Rare Headache
Cardiac disorders Common Postural hypotension
Rare Cardiac arrhythmias

Respiratory, thoracic and
mediastinal disorders
Rare Idiosyncratic pulmonary oedema

Gastrointestinal disorders Common Loss of appetite, minor gastrointestinal distress
Rare Constipation, gastric pain
Very rare Pancreatitis

Hepatobiliary disorders Rare Intrahepatic cholestasis or jaundice
Skin and subcutaneous tissue
disorders
Common Urticaria
Rare Photosensitisation, cutaneous vasculitis

Renal and urinary disorders Rare Allergic interstitial nephritis
Reproductive system and breast disorders
Common Impotence
 

Description of selected adverse reactions
Renal impairment and renal failure were reported uncommonly in conjunction with blood creatinine
increased; the majority was reversible either on treatment or after discontinuation of Ezeact PLUS and
none required dialysis.
As with other ARBs, serious angioedema may occur rarely (≥1/10,000 to <1/1,000).
Investigations
Serum creatinine
Increased blood creatinine is a known pharmacologic effect of RAAS blockers, such as ARBs and ACEinhibitors,
and is related to the magnitude of blood pressure reduction. Treatment with Ezeact PLUS
resulted in a greater incidence of blood creatinine increases, compared with azilsartan medoxomil and
chlortalidone. Elevations were transient or non-progressive and reversible, and associated with large blood
pressure reductions.
Uric acid
Ezeact PLUS was associated with increases in serum uric acid consistent with the known pharmacological
effects of diuretics. The uric acid elevations are dose dependent increasing with the chlortalidone dose
although reports of gout were infrequent across treatment groups, even in long-term studies.
Hemoglobin and hematocrit
Ezeact PLUS was associated with small decreases in hematocrit, hemoglobin levels, and red blood cell
count, consistent with the known pharmacological effects of inhibitors of the renin-angiotensin-aldosterone
system.
Post-marketing experience
A rare incidence of angioedema has been reported in conjunction with use of Ezeact PLUS. No other
adverse reactions have been identified in post-marketing spontaneous reports.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked
to report any suspected adverse reactions via national pharmacovigilance and drug safety centre (NPC)
To report any side effect(s):
 Saudi Arabia:
The National Pharmacovigilance and Drug Safety Centre (NPC)
Fax: +966-11-205-7662
Call NPC at +966-11-2038222
Exts: 2317-2356-2353-2354-2334-2340.
Toll free phone: 8002490000
E-mail: npc.drug@sfda.gov.sa
Website: www.sfda.gov.sa/npc

There is limited information available related to overdosage of Ezeact PLUS in humans.
Azilsartan medoxomil
Based on pharmacological effects, the main manifestation of an overdose of azilsartan medoxomil is likely to
be symptomatic hypotension and dizziness. During controlled clinical studies in healthy subjects, once daily
doses up to 320 mg of Ezeact were administered for 7 days and were well tolerated.
If symptomatic hypotension should occur, supportive treatment should be instituted and vital signs
monitored. Azilsartan is not removed by dialysis.
Chlortalidone
Symptoms of chlortalidone overdose include nausea, weakness, dizziness, and disturbances of electrolyte
balance. There is no specific antidote, but gastric lavage is recommended, followed by supportive treatment.
Blood pressure and fluid and electrolyte balance should be monitored and appropriate corrective measures
taken. Intravenous fluid and electrolyte replacement may be indicated.

Pharmacotherapeutic group: Angiotensin II antagonists and diuretics, ATC code: C09DA09.
Ezeact PLUS is a combination of two antihypertensive agents with complementary mechanisms to control
blood pressure: the prodrug of an angiotensin II AT1 receptor antagonist, azilsartan medoxomil, and a
thiazide-like diuretic, chlortalidone.
Mechanism of action and pharmacodynamic effect
Azilsartan medoxomil is an orally administered prodrug that is rapidly converted by esterases in the
gastrointestinal tract and/or during absorption to the active moiety, azilsartan, which selectively antagonises
the effects of angiotensin II by blocking its binding to the AT1 receptor in multiple tissues (see section 5.2).
Angiotensin II is the principal pressor agent of the renin-angiotensin system, 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.
Chlortalidone produces diuresis with increased excretion of sodium and chloride. The site of action appears
to be the early convoluted part of the distal renal tubule in the nephron. The diuretic effect of chlortalidone is
due to inhibition of sodium reabsorption inhibiting Na+Cl- reabsorption by antagonising the Na+Clcotransporter
at that site which leads to increased sodium and water excretion
Clinical efficacy and safety
Clinical efficacy
Nearly additive reduction of blood pressure provided by the individual components was observed across the
therapeutic dose range that persists for 24 hours.

In an 8-week, multicenter, randomized, double-blind, active-controlled, parallel group factorial study,
1714 patients with moderate to severe essential hypertension were randomized to one of the 11 active
treatment arms that compared the relative effect on blood pressure of Ezeact PLUS with the respective
monotherapy components without titration. Ezeact PLUS treatment combinations resulted in significantly
greater reduction in systolic and diastolic blood pressure compared with the respective individual
monotherapies as determined by clinic blood pressure measurements (see Table 1). Ambulatory blood
pressure monitoring (ABPM) of trough blood pressure (22-24 hours post-dose) had similar results.
 

In a multicenter, randomized, double-blind, active-controlled, parallel group study of patients with grade 2 or
3 hypertension, not controlled adequately on azilsartan medoxomil 40 mg, target clinic systolic blood
pressure (<140 mm Hg for the general population and <130 mm Hg for those with diabetes or CKD) was
achieved in 63% of patients treated with azilsartan medoxomil and chlortalidone 40 mg/12.5 mg and 78% of
patients treated with azilsartan medoxomil and chlortalidone 40 mg/25 mg, compared to 35% of patients
remaining on azilsartan medoxomil 40 mg. Following an initial 4-week treatment with Ezeact 40 mg,
treatment with Ezeact PLUS of those subjects whose blood pressure remained equal to or higher than 140
mm Hg resulted in a reduction in systolic/diastolic blood pressure of 15.8/7.7 mm Hg (40 mg/12.5 mg) and
21.1/10.3 mm Hg (40 mg/25 mg) compared to patients who remained on azilsartan medoxomil 40 mg of
6.4/3.2 mm Hg.
In two randomized, double-blind titration studies, azilsartan medoxomil and chlortalidone produced greater
reduction in systolic and diastolic blood pressure compared to olmesartan medoxomil/hydrochlorothiazide
in patients with moderate to severe hypertension.
Ezeact PLUS’s blood pressure lowering effects are maintained throughout the 24-hour period, with most
of the antihypertensive effect of Ezeact PLUS occurring within 1-2 weeks of dosing and being maintained
for up to 12 months of evaluation.
Ezeact PLUS led to robust reductions in all blood pressure parameters across diverse subgroups including
age, gender, or race. In black patients in particular, treatment with Ezeact PLUS resulted in blood pressure
reductions that were generally similar to the overall population, despite a known attenuated response to
RAAS blockade in this population.
Effect on cardiac repolarisation
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 azilsartan medoxomil.

Paediatric population
The European Medicines Agency has waived the obligation to submit the results of studies with Ezeact
PLUS (azilsartan medoxomil/chlortalidone) in all subsets of the paediatric population in hypertension as
per Paediatric Investigation Plan (PIP) decision (EMA/PDCO/430493/2012), in the granted indication
(see section 4.2 for information on paediatric use).
Additional information
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 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.

Concomitant administration of azilsartan 80 mg and chlortalidone 25 mg once daily for 7 days does not
affect the PK of either substance in healthy subjects.
Following oral administration of the fixed dose tablet, the peak plasma concentration (Cmax) of chlortalidone
is 45% higher compared to administration of chlortalidone and azilsartan as separate tablets. The extent of
absorption as defined by the area under the curve (AUC) of both azilsartan and chlortalidone following
administration of Ezeact PLUS is similar to that when azilsartan and chlortalidone are administered as
separate tablets.
Ezeact PLUS may be administered with or without food.
The following section outlines the pharmacokinetic properties of the individual components of Ezeact PLUS
(azilsartan medoxomil/chlortalidone) as reported in their respective Summary of Product Characteristics.
Absorption
Azilsartan medoxomil
Following oral administration, azilsartan medoxomil is rapidly hydrolyzed to azilsartan, the active
metabolite, in the gastrointestinal tract during absorption. Azilsartan medoxomil is not detected in plasma
after oral administration. 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, the time to maximal concentration
(Tmax) of azilsartan is reached within 1.5 to 3 hours. Food does not affect the bioavailability of azilsartan (see
section 4.2).
Chlortalidone
The estimated bioavailability of chlortalidone is approximately 64%, after 8 to 12 hours post dose. On
repeated daily doses of 50 mg, mean steady state blood concentration of 7.2 μg/ml (21.2 μmo/L), measured
at the end of the 24 hour dosage interval, is reached after 1 to 2 weeks.
Distribution

Azilsartan medoxomil
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.
Chlortalidone
In whole blood, chlortalidone is predominantly bound to erythrocyte carbonic anhydrase. In vitro, plasma
protein binding of chlortalidone is approximately 76%, with the major binding protein being albumin.
Chlortalidone crosses the placental barrier and passes into the breast milk. In mothers treated with 50 mg
chlortalidone daily before and after delivery, chlortalidone levels in fetal whole blood were about 15% of
those found in maternal blood. Chlortalidone concentrations in amniotic fluid and in the maternal milk are
approximately 4% of the corresponding maternal blood level.
Biotransformation
Azilsartan medoxomil
Azilsartan is metabolised to two primary metabolites. The major metabolite in plasma is formed by Odealkylation,
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 Ezeact PLUS. The major enzyme responsible for azilsartan metabolism is CYP2C9.

Chlortalidone
Metabolism and hepatic excretion into bile constitute a minor pathway of elimination. Within 120 hours,
about 70% of the dose is excreted in the urine and the faeces, mainly in unchanged form.
Elimination
Azilsartan medoxomil
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.
Chlortalidone
Chlortalidone is eliminated from whole blood and plasma with an elimination half-life averaging 50 hours.
The elimination half-life is unaltered after chronic administration. The major part of an absorbed dose of
chlortalidone is excreted by the kidneys, with a mean renal clearance of 60 ml/min.
Linearity/non-linearity
Azilsartan medoxomil
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.
Chlortalidone
For doses of 25 mg and 50 mg, Cmax values average 1.5 μg/ml (4.4 μmol/L) and 3.2 μg/ml (9.4 μmol/L)
respectively. For doses up to 100 mg there is a proportional increase in AUC.
Special populations
Paediatric population
The pharmacokinetics of azilsartan has been studied in paediatric subjects with hypertension, between the
ages of 4 to 16 years. However, safety and efficacy in paediatric patients has not been established.
The pharmacokinetics of chlortalidone is not available in children under 18 years of age.

Older population
Pharmacokinetics of azilsartan does not differ significantly between young (age range 18-45 years) and
elderly (age range 65-85 years) patients.
In elderly patients, the elimination of chlortalidone is slower than in healthy young adults, although
absorption is the same. Therefore, caution is recommended when treating the very elderly (≥75 years) with
Ezeact PLUS (see section 4.2).
Renal impairment
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
(GFR <30 mL/min/1.73m2) or end stage renal disease (see section 4.2). Haemodialysis does not remove
azilsartan from the systemic circulation.
The major part of an absorbed dose of chlortalidone is excreted by the kidneys; however renal dysfunction
does not alter the pharmacokinetics of chlortalidone. The rate-limiting factor in the elimination of
chlortalidone from blood or plasma is most probably the affinity of the drug to the carbonic anhydrase of
erythrocytes. As a result, no dosage adjustment is needed for Ezeact PLUS in patients with mild and
moderately impaired renal function (GFR ≥30-< 90 mL/min/1.73 m2).

Hepatic impairment
Administration of azilsartan medoxomil for up to 5 days in subjects with mild (Child-Pugh A) or moderate
(Child-Pugh B) hepatic impairment resulted in a slight increase in azilsartan exposure (AUC increased by
1.3 to 1.6 fold). Azilsartan has not been studied in patients with severe hepatic impairment. Chlortalidone has
not been studied in patients with hepatic impairment.
Ezeact PLUS is contraindicated in patients with severely impaired hepatic function (see section
4.2). Gender
Pharmacokinetics of azilsartan does not differ significantly between males and females. In a population
pharmacokinetic analysis of patients with hypertension receiving Ezeact PLUS, male subjects had a
lower exposure (Cmax and AUC) than female subjects (≤30%). The differences in pharmacokinetics are
not considered clinically relevant.
No dose adjustment is necessary based on gender.
Race
Pharmacokinetics of azilsartan does not differ significantly between black and white populations. In a
population pharmacokinetic analysis of patients with hypertension receiving Ezeact PLUS, there was no
effect of race on the pharmacokinetics of azilsartan or chlortalidone.
No dose adjustment is necessary based on race.

Azilsartan medoxomil/chlortalidone
No mutagenicity, carcinogenicity or fertility studies have been conducted with the combination of azilsartan
medoxomil and chlortalidone.
The decreased plasma potassium levels and renal corticomedullary mineralization attributed to chlortalidone
treatment were not observed after treatment with chlortalidone, azilsartan medoxomil and M-II in
combination. There were no unexpected or unique toxicities associated with dosing of the combination.
In an embryo-fetal developmental study in rats, there was no teratogenicity or increase in fetal mortality in
the litters of dams receiving azilsartan medoxomil, M-II and chlortalidone concomitantly during the period
of organogenesis at maternally toxic doses.
Azilsartan medoxomil
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 blockers, 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 reproductive and developmental toxicity studies, there were no effects
on male or female fertility and no evidence of a teratogenic effect in rats or rabbits. However, in peri- and
post-natal animal studies, in which dosing of pregnant animals was continued through lactation, some
hazardous potential to the postnatal development of the offspring was seen, such as lower body weight, a
slight delay in physical development (delayed incisor eruption, pinna detachment, eye opening), and higher
rates of mortality. Azilsartan and M-II showed no evidence of mutagenicity or relevant clastogenic activity
in in vitro or in vivo studies and no evidence of carcinogenicity in rats or mice.
Chlortalidone
Reports in the literature indicate that treatment with chlortalidone does not produce reproductive toxicity in
dams or cause embryo-fetal mortality or teratogenicity in pregnant mice, rats, hamsters or rabbits.
Chlortalidone has been demonstrated to be a safe and effective prophylactic treatment for toxemia in gravid
women at least 30 weeks pregnant and at high risk for developing the condition.
Environmental Risk Assessment
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to
dispose of medicines no longer required. These measures will help to protect the environment.

Mannitol (E 421)
Fumaric acid (E 297) (for pH adjustment)
Sodium hydroxide (for pH adjustment)
Hydroxypropylcellulose (E 463)
Crospovidone (Type A)
Cellulose, microcrystalline (E 460)
Magnesium stearate (E 572)
Titanium dioxide (E171)
Iron oxide, red (E172)
Hypromellose 2910
Talc
Macrogol 8000
Printing ink grey F1:
Shellac
Iron oxide, black (E172)

Not applicable.

3 years.

Store in the original package in order to protect from moisture.
Do not store above 30 °C.

Cartons containing desiccated or non-desiccated aluminum/aluminum blister packs (contains PE and PVC).
Pack sizes:
One blister pack contains 14 tablets.
14, 28 or 56 tablets.
Not all pack sizes may be marketed.

No special requirements.
Any unused product or waste material should be disposed of in accordance with local requirements.