Candesartan Cilexetil plus Hydrochlorothiazide Combination

The combination of candesartan cilexetil [an angiotensin II type 1 (AT₁) receptor antagonist] plus hydrochlorothiazide (a thiazide diuretic), has been used in the treatment of patients with hypertension. The blood pressure (BP) lowering effect of various doses of this combination, administered orally once a day for 4 to 52 weeks, has been demonstrated in clinical trials. These studies showed that combinations of candesartan cilexetil 4 to 16mg with hydrochlorothiazide 12.5 or 25mg induced significant reductions in systolic (S) BP and diastolic (D) BP from baseline in patients with mild to severe hypertension.

Data from clinical trials indicated that reductions in BP induced by candesartan cilexetil 4 to 32mg/hydrochlorothiazide 12.5mg combinations were significantly greater than those observed after monotherapy with either drug. Treatment for 8 weeks with candesartan cilexetil 16mg/hydrochlorothiazide 12.5mg or candesartan cilexetil 16mg induced SBP/DBP reductions of 12.0/7.5mm Hg and 7.5/5.5mm Hg, respectively (p < 0.05 both comparisons). Moreover, data from a randomised, double-blind, placebo-controlled, dose-finding study in 1038 patients with mild to moderate hypertension showed that the greatest reductions in SBP/DBP were achieved by candesartan cilexetil 16mg/hydrochlorothiazide 12.5mg. Significant differences in BP reduction in favour of the combination were observed when hypertensive patients were given candesartan cilexetil 4 or 8mg/hydrochlorothiazide 12.5mg or hydrochlorothiazide monotherapy for 8 weeks. Additionally, greater efficacy of the combination compared to monotherapy with either drug was demonstrated by response rates to treatment. Moreover, a fixed combination of candesartan cilexetil 16mg/hydrochlorothiazide 12.5mg demonstrated a greater antihypertensive effect than losartan 50mg/hydrochlorothiazide 12.5mg in two clinical trials. Candesartan cilexetil 8mg/hydrochlorothiazide 12.5mg showed a similar antihypertensive effect compared with that of combined lisinopril 10mg/hydrochlorothiazide 12.5mg.

Candesartan cilexetil/hydrochlorothiazide combination therapy was well tolerated in patients with hypertension. Combined data from placebo-controlled trials showed that most adverse events were uncommon and not serious. Patients receiving combination therapy exhibited, among other adverse events, headache (3.2 vs 5.5% for candesartan cilexetil/hydrochlorothiazide and placebo, respectively), back pain (3.0 vs 2.4%), dizziness (2.6 vs 1.2%) and respiratory infection (2.5 vs 1.4%). Moreover, 3.3 and 2.7% of patients receiving candesartan cilexetil/hydrochlorothiazide or placebo, respectively, discontinued treatment because of adverse events.

Conclusion: The combination of candesartan cilexetil and hydrochlorothiazide (AT₁ receptor antagonist and thiazide diuretic, respectively) is an effective treatment for patients with hypertension. Data from randomised, double-blind, placebo-controlled clinical trials showed that this combination is significantly more efficacious than either agent alone. Moreover, the combination of these two agents showed an excellent adverse event profile. Current data support the use of this combination as an alternative when monotherapy with either agent is not effective, and there are no compelling or specific indications for other drugs. However, data from large clinical trials, evaluating morbidity and mortality outcomes, are needed to determine the precise role of candesartan cilexetil/hydrochlorothiazide combination in the treatment of patients with hypertension.

The pharmacodynamic properties of candesartan cilexetil and hydrochlorothiazide have been studied extensively.

Candesartan cilexetil is rapidly and completely converted to candesartan, the active compound, during absorption in the upper gastrointestinal tract. Candesartan is a nonpeptide angiotensin II receptor antagonist that binds to angiotensin subtype 1 (AT₁) receptors without interacting with AT₂ receptors. Data from animal studies showed that candesartan binding to AT₁ receptors is tight, highly specific and insurmountable, while dissociation from AT₁ receptors is slow. Human studies in healthy volunteers and patients with hypertension showed that candesartan dose-dependently and significantly (p < 0.05 vs placebo) increased plasma renin activity and plasma angiotensin II levels. This action of candesartan was present 24 hours after administration and increased after repeated doses. Also, in vivo inhibition of angiotensin II activity by candesartan (per mg of active drug) was stronger than that shown by losartan, irbesartan, telmisartan or valsartan. The dose required to induce a 2-fold rightward shift in the angiotensin II dose-response curve was 6mg for candesartan cilexetil, 54mg for telmisartan, 123mg for irbesartan and 93.5mg for valsartan. A study reported similar blockade of AT₁ receptors after administration of a single dose of candesartan cilexetil 32mg (a dosage approved only in the US) or losartan 150mg (supratherapeutic dose of losartan) to healthy volunteers. However, the inhibitory action of candesartan cilexetil appeared to be of longer duration than that of losartan (72 vs 62% blockade of AT₁ receptors, 24 hours after administration).

In patients with hypertension, candesartan cilexetil 8 or 16mg daily reduced plasma endothelin-1 levels from baseline (2.49 ±1.32 ng/L) after 2 (1.61 ±0.88 ng/L, p < 0.05) and 12 months (0.72 ±0.53 ng/L) of treatment. Also, candesartan cilexetil treatment improved vasoconstriction induced by a nitric oxide antagonist.

Candesartan cilexetil 2 to 12mg once daily for up to 24 weeks reduced left ventricular (LV) mass by up to 9.3% in 18 Japanese patients with mild to moderate hypertension. Beneficial effects of candesartan cilexetil therapy on LV hypertrophy, diastolic time, peak velocity filling and forearm vascular resistance have also been suggested by recent studies.

Candesartan cilexetil improves/preserves renal function and reduces proteinuria in hypertensive patients with concomitant type 2 diabetes mellitus and/or renal impairment without affecting urinary sodium, potassium or uric acid excretion. In hypertensive patients receiving candesartan cilexetil 16 mg/day for 6 weeks or 4 to 8 mg/day for 2 weeks, glomerular filtration rate was unchanged. Candesartan cilexetil decreased urinary albumin excretion and proteinuria in hypertensive patients with concurrent type 2 diabetes mellitus or renal impairment. The CALM (Candesartan and Lisinopril Microalbuminuria) study (n = 199) indicated that candesartan cilexetil 16mg once a day in hypertensive patients with type 2 diabetes mellitus reduced urinary albumin to creatinine ratio from baseline by 15 to 42% (p < 0.001) and 0 to 43% (p = 0.05) after 12 or 24 weeks of treatment, respectively.

Thiazides act within the distal tubule of the nephron blocking the transmembrane-coupled Na-Cl transport system. However, despite their wide use and proven efficacy in patients with hypertension, their mechanism of BP reduction is not fully understood. Hydrochlorothiazide treatment significantly reduces mean arterial pressure and the reductions are observed from the first week of therapy. Decreases in cardiac output and stroke volume are detected in the first weeks of treatment but after 24 weeks these parameters return to baseline levels. More importantly, it appears that there are substantial differences between patients who respond to hydrochlorothiazide therapy and those who do not. After up to 36 weeks of treatment only nonresponders showed reductions in cardiac output (≈13%) and heart rate (10%), and increases in total peripheral resistance (≈10 to 12%), whereas responders showed significant reductions in total peripheral resistance (≈12 to 20%, p < 0.05).

Data from human studies suggest that hydrochlorothiazide reduces LV mass and size in patients with hypertension. Hydrochlorothiazide 25 to 50mg daily for 6 months significantly reduced septum thickness, posterior wall thickness, left atrium size, LV diastolic dimension and LV mass index compared with baseline values. Reductions in LV mass and left atrial size have been confirmed by a large (n = 1105), long-term (1 to 2 years), randomised, double-blind clinical trial, but not by other studies.

Candesartan cilexetil is rapidly and completely converted to the active compound candesartan during absorption from the gastrointestinal tract. Candesartan peak plasma concentrations (C_max) are reached after =3 to 5 hours (t_max) of administration and increase dose-dependently. Accumulation of the drug is not observed after repeated administration of candesartan cilexetil and its bioavailability (administered as an oral solution) is 42% that of intravenous administration and is not affected by food intake.

Candesartan is mainly eliminated unchanged, through the urine (33%) and faeces (67%), although a small amount is metabolised to its inactive metabolite, CV 15959. The total plasma clearance of candesartan in hypertensive patients receiving candesartan cilexetil 2 to 16 mg/day for 28 days was calculated to be 14.07 L/h. In healthy volunteers, values of 0.25 and 0.20 L/h/kg on day 1 and day 8, respectively, were calculated after oral administration of candesartan cilexetil 1 to 8 mg/day. The elimination half-life (t½ ) of the drug was 9 to 13 hours and was independent of the dose.

Compared with Cmax in 19-to 40-year old patients with hypertension, Cmax increases of up to ≈ 50% were observed in elderly patients. The t½ was slightly longer among elderly volunteers but accumulation of the drug was not observed after repeated administration.

Hypertensive patients with renal impairment showed substantial (≥40%) increases of C_max, area under the plasma concentration-time curve (AUC) and t½ compared with patients with normal kidney functions. These increases were almost 2-fold in those with severe renal impairment (creatinine clearance <1.8 L/h/1.73m²). The t½ was significantly higher in patients with severe renal impairment, after single (12 vs 6.7 hours, p < 0.05) and multiple dose administration (15.7 vs 7.1 hours, p < 0.01) than in with patients normal, or mildly impaired renal function.

No significant changes in the pharmacokinetic properties of candesartan were observed after single or repeated administration of candesartan cilexetil 12 mg/day to hypertensive patients with mild to moderate liver impairment. However, compared with healthy volunteers, patients with moderate to severe liver impairment showed increases of AUC and C_max of 78 and 64%, respectively, after receiving a single dose of candesartan cilexetil 16mg.

Significant interactions of candesartan with other drugs were not observed. Candesartan is only metabolised to a limited extent by the cytochrome P450 system and inhibitors or inducers of this system are unlikely to interact with candesartan.

Hydrochlorothiazide is not metabolised and is rapidly eliminated by the kidney (≥61% of the dose within 24 hours) in the urine (≥95%) as the unchanged drug. After oral administration, C_max is observed within 1 to 5 hours, and concentrations of hydrochlorothiazide are greater in whole blood than in plasma. After a 24-hour observation period, plasma t½ ranged from 6 to 15 hours. Food intake reduces Cmax (by 20%) and bioavailability (by 10%), and increases t_max (by 1.6 to 2.9 hours). Renal impairment prolongs hydrochlorothiazide t½ and increases C_max.

Hydrochlorothiazide may interact with alcohol and other agents including barbiturates, narcotics, antidiabetic drugs, cholestyramine and colestipol resins and corticosteroids. Hydrochlorothiazide should not be administered with lithium, since it may cause lithium toxicity.

Data from well designed studies that included patients with mild to severe hypertension have shown that combination of candesartan cilexetil 4 to 16mg with hydrochlorothiazide 12.5 to 25mg administered once daily effectively reduces BP in most patients. Moreover, patients treated with this combination showed significantly greater reductions of BP than those receiving either drug as monotherapy.

In a randomised, double-blind, placebo-controlled, dose-finding study including 1038 hypertensive patients, reductions in systolic (SBP)/diastolic (DBP) blood pressure ranged from 12.9 to 23.0mm Hg/7.2 to 16.6mm Hg after candesartan cilexetil 4, 8 or 16mg/hydrochlorothiazide 12.5 or 25mg administration. Patients receiving candesartan cilexetil 16mg/hydrochlorothiazide 12.5mg showed the greatest reductions in DBP and SBP. Moreover, the percentage of patients who responded to therapy (i.e. sitting DBP was <90mm Hg or was reduced by ≥10mm Hg after treatment) was greater in the combination therapy group (47 to 85%) than in the placebo group (30%; p < 0.05).

Candesartan cilexetil 16mg/hydrochlorothiazide 12.5mg demonstrated BP lowering effects superior to those of candesartan cilexetil 16mg monotherapy. Reductions in SBP/DBP and response rates were greater among patients receiving the combination treatment although the proportion of patients who had controlled their BP (DBP <90mm Hg) at treatment endpoint did not differ significantly between treatment groups. Similar superiority of the combination over candesartan cilexetil monotherapy was also observed with the use of candesartan cilexetil 32mg/hydrochlorothiazide 12.5mg or candesartan cilexetil 4mg/hydrochlorothiazide 6.25mg, daily. Moreover, statistically significant differences between combination and monotherapy in SBP/DBP reductions and response rates showed superiority of candesartan cilexetil 4 to 32mg/hydrochlorothiazide 12.5mg treatment over hydrochlorothiazide 12.5mg monotherapy. Add-on candesartan cilexetil 8 or 16mg in patients with severe hypertension, who did not respond to 1 week of hydrochlorothiazide 12.5mg, was also significantly more efficacious than add-on placebo, and this superiority of the combination was confirmed in a subset of Black patients.

The antihypertensive effect of candesartan cilexetil/hydrochlorothiazide combination has been compared with that of losartan/hydrochlorothiazide and lisinopril/hydrochlorothiazide. Data from randomised, double blind studies in patients with mild to severe hypertension showed that the antihypertensive effect of candesartan cilexetil/hydrochlorothiazide was greater than that of losartan/hydrochlorothiazide and similar to that of lisinopril/hydrochlorothiazide. These studies used single, fixed, submaximal doses of the combinations tested; it is not clear if the tested doses are therapeutically equivalent dosages.

Combined data from five randomised, double-blind, placebo-controlled clinical trials during preregistration phase, in patients with mild to moderate hypertension receiving candesartan cilexetil/hydrochlorothiazide (up to 16mg/25mg once daily) indicated that adverse events are uncommon and include few of serious nature. Among patients receiving combination therapy (n = 1025) or placebo (n = 526) the incidence of serious adverse events was 1.6 and 2.1%, respectively, and only 3.3 and 2.7% of patients discontinued treatment. The most commonly reported adverse events (cumulative 8-week incidence) were headache (3.2 vs 5.5% for candesartan cilexetil/hydrochlorothiazide and placebo, respectively), back pain (3.0 vs 2.4%), dizziness (2.6 vs 1.2%) and respiratory infection (2.5 vs 1.4%). Clinically important changes in laboratory parameters were seldom associated with combination therapy.

Combined tolerability data from placebo-controlled studies, mainly performed in the US, included patients (n = 1089) receiving various candesartan cilexetil/hydrochlorothiazide combinations (2 to 32mg/6.25 to 25mg daily, respectively). Adverse events, regardless of attribution to treatment, reported among combination and placebo recipients, respectively, included respiratory tract infection (3.6 vs 3.0%), back pain (3.3 vs 2.4%), influenza-like symptoms (2.5 vs 1.9%), dizziness (2.9 vs 1.2%) and headache (2.9 vs 5.2%). Hypokalaemia was observed in at least 0.5% of patients worldwide.

Candesartan cilexetil 16mg/hydrochlorothiazide 12.5mg is the most commonly recommended dosage of the fixed combination in the US and Europe. In the US and Europe, a combination tablet of candesartan cilexetil 16mg/hydrochlorothiazide 12.5mg is available for patients in whom adequate BP control is not achieved with candesartan cilexetil 16 mg/day, and in the US a candesartan cilexetil 32mg/hydrochlorothiazide 12.5mg combination tablet is recommended in patients whose BP is not controlled by candesartan cilexetil 32 mg/day. Candesartan cilexetil 8mg/hydrochlorothiazide 12.5mg is available in some European countries.

Use of the combination in patients with severe renal impairment is not recommended and is contraindicated in pregnant women. Hypertensive patients with hepatic function deficiency should be monitored during candesartan cilexetil/hydrochlorothiazide treatment.