Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Angiotensin II antagonists + diuretics, ATC code: C09DA06.

Mechanism of action
Angiotensin II is the primary vasoactive hormone in the renin-angiotensin-aldosterone system and plays a role in the pathophysiology of hypertension and other cardiovascular diseases. It also plays a role in the pathogenesis behind organ hypertrophy and target organ damage. The main physiological effects of angiotensin II, such as vasoconstriction, aldosterone stimulation, regulation of salt and water homeostasis and stimulation of cell growth, are mediated via the type 1 receptor (AT1 receptor).

Pharmacodynamic effects
Candesartan cilexetil is a prodrug that rapidly converts to the active drug, candesartan, through esterhydrolysis during the absorption from the gastrointestinal tract. Candesartan is an AIIRA and binds selectively to AT 1 receptors. The binding is strong and dissociation from the receptor occurs slowly. Candesartan has no agonist activity.

Candesartan does not affect ACE or other enzyme systems commonly associated with the use of ACE inhibitors. As there is no effect on the breakdown of quinines or on the metabolism of other substances, such as substance P, it is unlikely that AIIRA would be associated with cough. In controlled clinical studies in which candesartan cilexetil was compared with ACE inhibitors, the incidence of cough was lower in patients who received candesartan cilexetil. Candesartan does not bind to or block other hormone receptors or ion channels known to be significant to cardiovascular regulation. The antagonistic effect on AT1 receptors leads to dose-related increases of the plasma levels of renin, angiotensin I and angiotensin II and a decrease of the plasma concentration of aldosterone.

Non-melanoma skin cancer:
Based on available data from epidemiological studies, a cumulative dose-dependent correlation has been observed between HCTZ and NMSC. A study including a population that consisted of 71,533 cases of BCC and 8,629 cases of SCC matched against 1,430,833 and 172,462 population controls, respectively. High use of HCTZ (≥ 50,000 mg cumulative) was associated with an adjusted odds ratio of 1.29 (95% CI: 1.23‐1.35) for BCC and 3.98 (95% CI: 3.68‐4.31) for SCC. A clear cumulative dose- response relationship was seen for both BCC and SCC. Another study showed a possible connection between lip cancer (SCC) and exposure to HCTZ: 633 cases of lip cancer were matched with 63,067 population controls, using a risk-set sampling strategy. A cumulative dose-response relationship was demonstrated with an adjusted odds ratio of 2.1 (95% CI: 1.7-2.6), increasing to an odds ratio of 3.9 (3.0-4.9) for high use (~25,000 mg) and an odds ratio of 7.7 (5.7-10.5) for the highest cumulative dose (~100,000 mg) (see also Section 4.4).
Clinical efficacy and safety
The effects of candesartan cilexetil 8-16 mg (mean dose 12 mg) once daily on cardiovascular morbidity and mortality was evaluated in a randomised clinical study involving 4,937 elderly patients (between 70-89 years of age, 21% were at least 80 years old) with mild to moderate hypertension, who were followed for an average of 3.7 years (Study on Cognition and Prognosis in the Elderly). The patients received candesartan or placebo with the addition of other antihypertensive treatment as needed.
The blood pressure was reduced from 166/90 to 145/80 mmHg in the candesartan group and from 167/90 to 149/82 mmHg in the control group. There was no statistically significant difference in the primary endpoint of major cardiovascular events (cardiovascular mortality, non-fatal stroke and non-fatal myocardial infarction). There were 26.7 events per 1,000 patient years in the candesartan group versus 30.0 events per 1,000 patient years in the control group (relative risk 0.89; 95% CI 0.75‐1.06; p=0.19).

Hydrochlorothiazide inhibits the active reabsorption of sodium, primarily in the distal renal tubules, and promotes the secretion of sodium, chloride and water. The renal secretion of potassium and magnesium increases in a dose-dependent manner, while calcium is reabsorbed to a greater extent. Hydrochlorothiazide reduces plasma volume and extracellular fluid and lowers cardiac output and blood pressure. During long-term treatment, a reduced peripheral resistance contributes to a lowering of blood pressure.

Large clinical studies have shown that long-term treatment with hydrochlorothiazide reduces the risk of cardiovascular morbidity and mortality.

Candesartan and hydrochlorothiazide have additive antihypertensive effects.

In hypertensive patients, Atacand Plus provides a dose-dependent and long-term decrease in arterial blood pressure without any reflex increase in heart rate. No signs of severe hypotension have been observed following the initial dose, or after discontinuation of treatment. The antihypertensive effect usually occurs within 2 hours after a single dose of candesartan cilexetil. With continuous treatment, the majority of the blood pressure decrease is achieved within four weeks and maintained during long- term treatment. Atacand Plus administered once daily provides an effective and consistent blood pressure decrease over 24 hours, and the difference between the highest and lowest effect during the dose interval is small. In a double-blind randomised study, Atacand Plus 16 mg/12.5 mg once daily lowered blood pressure significantly more, and maintained consistent blood pressure for significantly more patients than the combination of losartan/hydrochlorothiazide 50 mg/12.5 mg once daily.

In double-blind randomised studies, the incidence of adverse events, especially cough, was lower in treatment with Atacand Plus than in treatment with combinations of ACE inhibitors and hydrochlorothiazide.

In two clinical studies (randomised, double-blind, placebo-controlled, parallel-group studies) comprising 275 and 1,524 randomised patients, respectively, the candesartan cilexetil/hydrochlorothiazide combinations 32 mg/12.5 mg and 32 mg/25 mg provided blood pressure reductions of 22/15 mmHg and 21/14 mmHg, respectively, and were significantly more effective than the corresponding components in monotherapy.
In a randomised, double-blind clinical parallel group study comprising 1975 randomised patients, who could not be optimally controlled with 32 mg candesartan cilexetil once daily, the addition of 12.5 mg or 25 mg hydrochlorothiazide led to further blood pressure reductions. The combination candesartan cilexetil/hydrochlorothiazide 32 mg/25 mg was significantly more effective than the combination 32 mg/12.5 mg, and the overall mean blood pressure reductions were 16/10 mmHg and 13/9 mmHg, respectively.
Candesartan cilexetil/hydrochlorothiazide is equally effective in patients regardless of age and gender.
There is currently no data on the use of candesartan cilexetil/hydrochlorothiazide in patients with kidney disease/nephropathy, reduced left ventricular function/heart failure or in patients who have suffered a myocardial infarction.

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 investigated the combined use of an ACE inhibitor and an angiotensin II receptor blocker.

ONTARGET was a study conducted on patients with a history of cardiovascular and cerebrovascular disease, or type 2 diabetes mellitus accompanied by evidence of final organ damage. VA NEPHRON-D was a study involving patients suffering type 2 diabetes mellitus and diabetes nephropathy.
These studies have shown no significant benefit to renal and/or cardiovascular results and mortality, while an increased risk of hyperkalaemia, acute kidney damage and/or hypotension was observed, as compared with monotherapy. Since their pharmacodynamic properties are similar to each other, 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 benefits of adding aliskiren to a standard treatment with an ACE inhibitor or an angiotensin II receptor blocker in patients with type 2 diabetes mellitus and chronic kidney disease or cardiovascular disease, or both.
The study was terminated prematurely because there was an observed increased risk of unwanted outcomes. Both cardiovascular death and stroke were numerically more common in the aliskiren group than in the placebo group and adverse events and serious adverse events of interest (hyperkalaemia, hypotension and renal dysfunction) were reported with a higher frequency in the aliskiren group than in the placebo group.

Pharmacokinetic Properties

5.2 Pharmacokinetic properties

Concomitant administration of candesartan cilexetil and hydrochlorothiazide has no clinically significant effect on the pharmacokinetics of any of the substances.

Absorption and distribution

Candesartan cilexetil
Following oral administration, candesartan cilexetil is converted to the active substance candesartan. The absolute bioavailability of candesartan is approximately 40% for an oral solution of candesartan cilexetil. The relative bioavailability of a tablet formulation of candesartan cilexetil compared to the same oral solution is approximately 34% with very little variability. The mean value for the maximum concentration in serum (Cmax) is reached 3-4 hours after taking the tablet. Serum candesartan concentrations increase linearly with increasing doses within the therapeutic dose range. No gender-related differences in the pharmacokinetics of candesartan have been observed. The area below the curve for serum concentration as a function of the time (AUC) for candesartan is not significantly affected by food.

Candesartan binds to a high degree to plasma proteins (to more than 99%). The apparent volume of distribution for candesartan is 0.1 L/kg.

Hydrochlorothiazide
Hydrochlorothiazide is rapidly absorbed from the gastrointestinal tract with an absolute bioavailability of approximately 70%. Concomitant intake of food increases absorption by about 15%. The bioavailability may decrease in patients with heart failure and pronounced oedema.

The plasma protein binding for hydrochlorothiazide is approximately 60%. The apparent distribution volume is approximately 0.8 L/kg.

Metabolism and elimination

Candesartan cilexetil
Candesartan is mainly eliminated unchanged via urine and bile and is only eliminated to a lesser extent by metabolism in the liver (CYP2C9). Available interaction studies do not indicate any effect on CYP2C9 and CYP3A4. Based on in vitro data, no interaction is expected to occur in vivo with drugs whose metabolism is dependent on cytochrome P450 isoenzymes CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1 or CYP3A4. The terminal half-life (t½) for candesartan is approximately 9 hours. No accumulation after repeated dosing has been observed. The half-life of candesartan remains unchanged (approximately 9 hours) after administration of candesartan cilexetil in combination with hydrochlorothiazide. No further accumulation of candesartan occurs after repeated doses of the combination compared to monotherapy.

Total plasma clearance for candesartan is approximately 0.37 mL/min/kg, with a renal clearance of approximately 0.19 mL/min/kg. The renal elimination of candesartan occurs both through glomerular filtration and active tubular secretion. After an oral dose of 14C- labelled candesartan cilexetil, about 26% of the dose is excreted in the urine as candesartan and 7% as an inactive metabolite, while about 56% of the dose is found in faeces as candesartan and 10% as an inactive metabolite.

Hydrochlorothiazide
Hydrochlorothiazide is not metabolised and is almost completely excreted as an unchanged substance through glomerular filtration and active tubular secretion. The terminal half-life of hydrochlorothiazide is approximately 8 hours. Approximately 70% of an oral dose is eliminated in the urine within 48 hours. The half-life of hydrochlorothiazide remains unchanged (approximately 8 hours) after administration of hydrochlorothiazide in combination with candesartan cilexetil. No further accumulation of hydrochlorothiazide occurs after repeated doses of the combination compared with monotherapy.
Pharmacokinetics for special groups


Candesartan cilexetil
In elderly people (aged over 65 years), Cmax and AUC for candesartan are increased by approximately 50% and 80%, respectively, compared to young people. However, the blood pressure response and the incidence of adverse effects are comparable in young and elderly patients after a dose of Atacand Plus (see Section 4.2).


In patients with mild to moderate renal impairment, Cmax and AUC for candesartan increased with repeated doses by approximately 50% and 70%, respectively, but the terminal half-life did not change, compared to patients with normal renal function. The corresponding change in patients with severe renal impairment was approximately 50% and 110%, respectively. The terminal half-life of candesartan was approximately doubled in patients with severe renal impairment. The pharmacokinetics in patients treated with hemodialysis was comparable to that of patients with severe renal impairment.


In two studies, both of which included patients with mild to moderately impaired liver function, an increase in the mean AUC for candesartan of approximately 20% was observed in one study and 80% in the other study (see Section 4.2). There is no experience from patients with severe hepatic impairment.

Hydrochlorothiazide
The terminal half-life of hydrochlorothiazide is extended in patients with impaired renal function.