CO-DIOVAN Film-coated tablet Ref.[50869] Active ingredients: Hydrochlorothiazide Valsartan

Mechanism of action

The active hormone of the renin-angiotensin-aldosterone system (RAAS) is angiotensin II, which is formed from angiotensin I through angiotensin converting enzyme (ACE). Angiotensin II binds to specific receptors located in the cell membranes of various tissues. It has a wide variety of physiological effects, including in particular both direct and indirect involvement in the regulation of blood pressure. As a potent vasoconstrictor, angiotensin II exerts a direct pressor response. In addition, it promotes sodium retention and stimulation of aldosterone secretion.

Valsartan is an orally active, potent and specific angiotensin II (Ang II) receptor antagonist. It acts selectively on the AT1 receptor subtype, which is responsible for the known actions of angiotensin II. The AT2 receptor subtype has not been definitely shown to be associated with cardiovascular homeostasis. The increased plasma levels of Ang II following AT1 receptor blockade with valsartan may stimulate the unblocked AT2 receptor. This may counteract the effect of blocking the AT1 receptor. Valsartan does not exhibit any partial agonist activity at the AT1 receptor and about a 20,000-fold greater affinity for the AT1 receptor than for the AT2 receptor.

Valsartan does not inhibit ACE, also known as kininase II, which converts Ang I to Ang II and degrades bradykinin. Since there is no effect on ACE and no potentiation of bradykinin or substance P, angiotensin II antagonists are unlikely to be associated with cough. In clinical trials where valsartan was compared with an ACE inhibitor, the incidence of dry cough was significantly (P < 0.05) less in patients treated with valsartan than in those treated with an ACE inhibitor (2.4% versus 7.9% respectively). In a clinical trial of patients with a history of dry cough during ACE inhibitor therapy, 19.5% of trial subjects receiving valsartan and 19.0% of those receiving a thiazide diuretic experienced cough, compared to 68.9% of those treated with an ACE inhibitor (P < 0.05). Valsartan does not bind to or block other hormone receptors or ion channels known to be important in cardiovascular regulation.

Administration of valsartan to patients with hypertension results in reduction of blood pressure without affecting pulse rate.

In most patients, after administration of a single oral dose, onset of antihypertensive activity occurs within 2 hours, and the peak reduction of blood pressure is achieved within 4-6 hours. The antihypertensive effect persists over 24 hours after administration. During repeated administration, the maximum reduction in blood pressure with any dose is generally attained within 2-4 weeks and is sustained during long-term therapy. When valsartan is combined with hydrochlorothiazide, a significant additional reduction in blood pressure is achieved.

Abrupt withdrawal of Diovan has not been associated with rebound hypertension or other adverse clinical events.

In multiple dose studies in hypertensive patients valsartan had no notable effects on total cholesterol, fasting triglycerides, or fasting serum glucose. Valsartan has no uricosuric effect.

The site of action of thiazide diuretics is primarily in the renal distal convoluted tubule. It has been shown that there is a high affinity receptor in the renal cortex with the primary binding site for the thiazide diuretic action and inhibition of Na Cl transport in the distal convoluted tubule. The mode of action of thiazides is through inhibition of the Na+Clsymporter, which affects mechanisms of electrolyte reabsorption. Inhibition of the Na+Clsymporter directly increases excretion of sodium and chloride in approximately equivalent amounts. It also indirectly reduces plasma volume, with consequent increases in plasma renin activity, aldosterone secretion and urinary potassium loss, and decreases in serum potassium. The renin-aldosterone link is mediated by angiotensin II, so coadministration of an angiotensin II receptor antagonist tends to reverse the potassium loss associated with these diuretics.

Clinical trials

The combination of valsartan and hydrochlorothiazide in once daily doses ranging from 80/12.5 mg to 160/25 mg was studied in three controlled studies (19, 301 and 201) and two uncontrolled studies (11E and 31E) in patients with hypertension.

Study 19 evaluated the effect of valsartan monotherapy (80 mg and 160 mg) and valsartan 80 mg in combination with 12.5 mg or 25 mg hydrochlorothiazide. A total of 708 patients whose hypertension remained inadequately controlled after 4 weeks of treatment with valsartan 80 mg were randomised to one of four treatments for an 8-week period. Valsartan 80 mg combined with either 12.5 mg or 25 mg hydrochlorothiazide produced a greater blood pressure lowering effect than increasing the dose of valsartan to 160 mg. The additional diastolic blood pressure reduction with valsartan 80 mg/hydrochlorothiazide 12.5 mg was a statistically (p=0.002) and clinically (3.2mmHg) significant improvement over 80 mg valsartan.

Study 301 was a placebo controlled, randomised, double-blind study to evaluate the efficacy, safety and tolerability of once daily dosing of 25 mg or 12.5 mg hydrochlorothiazide in combination with valsartan 80 mg or 160 mg in hypertensive patients. In this study, 871 patients were randomised into one of nine treatment groups for an 8-week period. The primary efficacy variable was the mean change from baseline in trough sitting diastolic blood pressure (MSDBP). Secondary efficacy variables were mean change from baseline in trough sitting systolic blood pressure (MSSBP) and response rates, defined as the proportion of patients with SDBP <90 mmHg at endpoint or a drop ≥10 mmHg from base line.

The decrease in blood pressure with the combination of valsartan 160 mg with either 12.5 or 25 mg hydrochlorothiazide was clinically and statistically significantly greater than placebo or monotherapy with valsartan 160 mg or the corresponding does of hydrochlorothiazide alone. A positive dose response in MSDBP, and in MSSBP was observed when either hydrochlorothiazide dose was combined with valsartan 80 mg or 160 mg. The following table summarises the additional blood pressure reduction seen with Co-Diovan compared to monotherapy and placebo.

Table 1. Study 301 Additional blood pressure reduction (MSSBP / MSDBP, mmHg) with Co-Diovan compared to valsartan and hydrochlorothiazide monotherapy and placebo:

Study 201 was an active controlled, randomised, double-blind study to compare the combination of valsartan 160 mg plus hydrochlorothiazide at doses of 12.5 mg and 25 mg with valsartan 160 mg monotherapy in patients whose hypertension was inadequately controlled (i.e. 95 mmHg < MSDBP < 110 mmHg) after 4 weeks on valsartan 160 mg monotherapy. In this study, 2002 patients were randomized into three treatment arms for a duration of 8-weeks.

The addition of 12.5 mg hydrochlorothiazide to valsartan 160 mg resulted in additional lowering of systolic BP of 3.74 mmHg and diastolic BP of 1.65 mmHg compared to valsartan alone. The addition of 25 mg hydrochlorothiazide to valsartan 160 mg resulted in an additional lowering of 5.92 mmHg systolic BP and 3.16 mmHg diastolic BP compared to valsartan alone.

The main objective for the extension studies 11E and 31E was to obtain long-term tolerability, safety and efficacy data in adult patients with hypertension treated with valsartan and hydrochlorothiazide. Patients whose blood pressure was inadequately controlled in the extension phase of these studies could have hydrochlorothiazide 12.5 or 25 mg in addition to valsartan therapy. More than 350 patients were treated with hydrochlorothiazide in combination with valsartan for a period of one to three years.

These studies demonstrated that long-term treatment with valsartan in combination with hydrochlorothiazide was efficacious in lowering blood pressure and maintained significant antihypertensive effect in patients with hypertension, with no evidence of development of tolerance. These studies also demonstrated that long-term combination treatment was safe and well tolerated.

The combination of valsartan and hydrochlorothiazide in once daily doses of 320/12.5 mg and 320/25 mg has been shown to be efficacious in the treatment of patients with essential hypertension in a large placebo-controlled study C2301; and in the treatment of patients with essential hypertension not adequately controlled with valsartan 320 mg monotherapy in an activecontrolled study C2302.

Study C2301 was a multicenter, double-blind, randomized, placebo-controlled, multifactorial, 8-arm parallel design study comparing the efficacy and safety of the combination therapy of valsartan/hydrochlorothiazide (320/12.5 mg, 320/25 mg, 160/12.5 mg) to their respective monotherapies, valsartan (160 mg, 320 mg), hydrochlorothiazide (12.5 mg, 25 mg) or to placebo once daily for 8 weeks in patients with essential hypertension (MSDBP ≥ 95 mmHg and < 110 mmHg). The first week post-randomization was a forced titration period for patients randomized to the valsartan/hydrochlorothiazide 320/12.5 and 320/25 mg treatment groups. During this period, patients randomized to the valsartan/hydrochlorothiazide 320/12.5 and 320/25 mg treatment groups received valsartan/hydrochlorothiazidE 160/12.5 mg, while patients randomized to the remaining six treatment groups received their respective final doses. From the second postrandomization week through the end of the study (week 8), all treatment groups received their final dose giving a minimum of 7 weeks on each of the final doses. A total of 1652 patients were enrolled into the single-blind period of the study and 1346 patients were randomized into the double-blind treatment phase. A total of 1329 patients were included in the primary efficacy population (ITT) and 1161 patients completed the study.

In patients with essential hypertension, global assessment of MSDBP and MSSBP reductions at endpoint shows that both monotherapy treatments contribute to the overall effect of the combination treatment on blood pressure reduction (p < 0.0001 for both valsartan and hydrochlorothiazide).

Statistically significant greater reductions in both MSDBP and MSSBP were observed for both valsartan/hydrochlorothiazide 320/12.5 mg and valsartan/hydrochlorothiazide 320/25 mg compared with placebo and each of the respective monotherapy doses (p < 0.0001 for all comparisons).

These results with both valsartan 320 mg/hydrochlorothiazidE combinations were clinically relevant with minimum differences in MSDBP of at least 8.0 mmHg compared to placebo and at least 3.6 mmHg compared to their respective monotherapies. Similarly, the results in MSSBP were clinically relevant with minimum differences of at least 15.8 mmHg compared to placebo and at least 8.0 mmHg compared to their respective monotherapies. These results were valid across age, race and gender subgroups.

Dose-dependent hypokalaemia occurred in controlled clinical studies with valsartan + hydrochlorothiazide. Hypokalaemia occurred more frequently in patients given 25 mg hydrochlorothiazide than in those given 12.5 mg hydrochlorothiazide.

Dose-dependent orthostatic reactions were reported in < 1 % of patients given a combination of valsartan + hydrochlorothiazide. A dose-dependent increase in the frequency of “dizziness” was reported in patients treated with doses ranging from valsartan 80 mg + hydrochlorothiazide 12.5 mg to valsartan 160 mg + hydrochlorothiazide 25 mg. In a non-controlled study in which Co-Diovan 160 mg/25 mg was given for 4 weeks to patients who had not been adequately treated with valsartan 160 mg and hydrochlorothiazide 12.5 mg, total cholesterol rose from 209 to 220 mg/dl.

Beneficial effects of valsartan in combination with hydrochlorothiazide on cardiovascular mortality and morbidity are currently unknown.

Table 2. Study C2301 Additional blood pressure reduction (MSSBP / MSDBP, mmHg) with Co-Diovan compared to valsartan and hydrochlorothiazide monotherapy and placebo at endpoint (ITT population):

^* no significant difference observed between 320/12.5 vs. 160/12.5

Study C2302 was a multicenter, double-blind, randomized, active-controlled, parallel design study comparing the efficacy and safety of the combination therapy of valsartan/hydrochlorothiazide (320/12.5 mg, 320/25 mg) to the valsartan 320 mg monotherapy once daily for 8 weeks in patients with essential hypertension (MSDBP ≥ 90 mmHg and < 110 mmHg) not adequately controlled with valsartan 320 mg monotherapy. After a 1 to 4 week washout phase, patients started the 4-week valsartan 320 mg run-in phase. Patients responding to treatment were discontinued from the study, while patients not adequately controlled (MSDBP ≥ 90 mmHg and < 110 mmHg) entered the 8-week double-blind phase and were randomized to one of three treatment groups: valsartan 320 mg, valsartan/hydrochlorothiazide 320/12.5 mg or valsartan/hydrochlorothiazide 320/25 mg. In total, 3805 patients were enrolled into the single-blind period of the study and 2702 patients were randomized into the double-blind treatment phase. A total of 2675 patients were included in the primary efficacy population (ITT) and 2579 patients completed the study.

In patients whose blood pressure was not adequately controlled with valsartan monotherapy, all treatments produced reductions in MSDBP and MSSBP from baseline to endpoint. The reduction in MSDBP and MSSBP at endpoint was statistically significantly greater for the valsartan/hydrochlorothiazide 320/12.5 mg and 320/25 mg combinations than for valsartan 320 mg monotherapy (p < 0.0001).

The reductions in BP at endpoint with both valsartan/hydrochlorothiazide combinations were clinically relevant compared to valsartan monotherapy with minimum differences in MSDBP of at least 3.9 mmHg and minimum differences in MSSBP of at least 7.5 mmHg. These results were valid across age and gender subgroups.

Diastolic response rates were 74.9% in the valsartan/hydrochlorothiazide 320/25 mg and 68.8% in the valsartan/hydrochlorothiazide 320/12.5 mg groups. Both combination doses show clinically and statistically greater diastolic response rates than the valsartan monotherapy (52.7%). Similarly, diastolic control rates were significantly greater with valsartan/hydrochlorothiazide 320/25 mg and 320/12.5 mg than with valsartan monotherapy (70.6%, 65.3% and 49.8%, respectively).

These efficacy results demonstrate that patients not adequately controlled with valsartan 320 mg benefit from clinically relevant additional BP reductions when treated with the valsartan/hydrochlorothiazide combinations.

No specific studies were performed to assess the efficacy of Co-Diovan in patients inadequately controlled on hydrochlorothiazide alone, or to determine in direct comparison the difference between Co-Diovan 160/25 mg and 320/25 mg.

Non-melanoma skin cancer

Based on available data from epidemiological studies, cumulative dose-dependent association between hydrochlorothiazide and non-melanoma skin cancer has been observed. One study included a population comprised of 71,553 cases of BCC and of 8,629 cases of SCC matched to 1,430,883 and 172,462 population controls, respectively. High hydrochlorothiazide use (≥50,000 mg cumulative) was associated with an adjusted OR 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 observed for both BCC and SCC. Another study showed a possible association between lip cancer (SCC) and exposure to hydrochlorothiazide: 633 cases of lip-cancer were matched with 63,067 population controls, using a risk-set sampling strategy. A clear cumulative dose-response relationship was demonstrated with an adjusted OR 2.1 (95% CI: 1.7-2.6) increasing to OR 3.9 (3.0-4.9) for high use (~25,000 mg) and OR 7.7 (5.7-10.5) for the highest cumulative dose (~100,000 mg). For example: A 100,000 mg cumulative dose corresponds to more than 10 years' daily use with a defined daily dose of 25 mg (see Section 4.4 Special warnings and precautions for use and Section 4.8 Adverse effects (undesirable effects)).