Exforge HCT Mechanism of Action

Pharmacotherapeutic Group: Angiotensin II antagonists combinations plain (valsartan) with dihydropyridine derivatives (amlodipine) and thiazide diuretics (HCTZ).
Pharmacology: Pharmacodynamics: Exforge HCT combines three antihypertensive compounds with complementary mechanisms to control blood pressure in patients with essential hypertension: amlodipine belongs to the calcium antagonist class, valsartan to the angiotensin II (Ang II) antagonist class and hydrochlorothiazide belongs to the thiazide diuretics class of medicines. The combination of these ingredients has an additive antihypertensive effect, reducing blood pressure to a greater degree than either component alone.
Amlodipine: The amlodipine component of Exforge HCT inhibits the transmembrane entry of calcium ions into cardiac and vascular smooth muscle. The mechanism of the antihypertensive action of amlodipine is due to a direct relaxant effect on vascular smooth muscle, causing reductions in peripheral vascular resistance and blood pressure. Experimental data suggest that amlodipine binds to both dihydropyridine and nondihydropyridine binding sites. The contractile processes of cardiac muscle and vascular smooth muscle are dependent upon the movement of extracellular calcium ions into these cells through specific ion channels.
Following administration of therapeutic doses to patients with hypertension, amlodipine produces vasodilatation resulting in a reduction of supine and standing blood pressures. These decreases in blood pressure are not accompanied by a significant change in heart rate or plasma catecholamine levels with chronic dosing.
Plasma concentrations correlate with effect in both young and elderly patients.
In hypertensive patients with normal renal function, therapeutic doses of amlodipine resulted in a decrease in renal vascular resistance and an increase in glomerular filtration rate and effective renal plasma flow without change in filtration fraction or proteinuria.
As with other calcium channel blockers, hemodynamic measurements of cardiac function at rest and during exercise (or pacing) in patients with normal ventricular function treated with amlodipine have generally demonstrated a small increase in cardiac index without significant influence on dP/dt or on left ventricular end diastolic pressure or volume. In hemodynamic studies, amlodipine has not been associated with a negative inotropic effect when administered in the therapeutic dose range to intact animals and humans, even when co-administered with beta blockers to humans.
Amlodipine does not change sinoatrial nodal function or atrioventricular conduction in intact animals or humans. In clinical studies in which amlodipine was administered in combination with beta-blockers to patients with either hypertension or angina, no adverse experiences on electrocardiographic parameters were observed.
Amlodipine has demonstrated beneficial clinical effects in patients with chronic stable angina, vasospastic angina and angiographically documented coronary artery disease.
Valsartan: Valsartan is an orally active, potent, and specific angiotensin II receptor antagonist. It acts selectively on the AT1 receptor subtype, which is responsible for the known actions of angiotensin II. The increased plasma levels of angiotensin II following AT1 receptor blockade with valsartan may stimulate the unblocked AT2 receptor, which appears to counterbalance the effect of the AT1 receptor. Valsartan does not exhibit any partial agonist activity at the AT1 receptor and has much (about 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 angiotensin I to angiotensin 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) lower in patients treated with valsartan than in those treated with an ACE inhibitor (2.6% 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 68.5% 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. Abrupt withdrawal of valsartan has not been associated with rebound hypertension or other adverse clinical events.
Valsartan has been demonstrated to significantly reduce hospitalizations in patients with chronic heart failure (NYHA class II-IV). The benefits were greatest in patients not receiving either an ACE inhibitor or a beta blocker. Valsartan has also been shown to reduce cardiovascular mortality in clinically stable patients with left ventricular failure or left ventricular dysfunction following myocardial infarction.
Hydrochlorothiazide: 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 as the primary binding site for the thiazide diuretic action and inhibition of NaCl transport in the distal convoluted tubule. The mode of action of thiazides is through inhibition of the Na+Cl- symporter perhaps by competing for the Cl- site, thereby affecting electrolyte reabsorption mechanisms: directly increasing sodium and chloride excretion to an approximately equal extent, and indirectly by this diuretic action reducing plasma volume, with consequent increases in plasma renin activity, aldosterone secretion and urinary potassium loss, and a decrease in serum potassium.
Non-melanoma skin cancer: Based on available data from epidemiological studies, cumulative dose-dependent association between HCTZ and NMSC has been observed. One study included a population comprised of 71,533 cases of BCC and of 8,629 cases of SCC matched to 1,430,833 and 172,462 population controls, respectively. High HCTZ 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 HCTZ: 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).
Clinical Studies: Exforge HCT was studied in a double-blind, active controlled study in hypertensive patients. A total of 2271 patients with moderate to severe hypertension (mean baseline systolic/diastolic blood pressure was 170/107 mmHg) received treatments of amlodipine/valsartan/HCTZ 10/320/25 mg, valsartan/HCTZ 320/25 mg, amlodipine/valsartan 10/320 mg, or HCTZ/amlodipine 25/10 mg. At study initiation patients were assigned lower doses of their treatment combination and were titrated to their full treatment dose by week 2. A total of 55% of patients were male, 14% were 65 years or older, 72% were Caucasian and 17% were Black.
At week 8, the mean reductions in systolic/diastolic blood pressure were 39.7/24.7 mmHg with Exforge HCT (n=571), 32.0/19.7 mmHg with valsartan/HCTZ (n=553), 33.5/21.5 mmHg with amlodipine/valsartan (n=558) and 31.5/19.5 with amlodipine/HCTZ (n=554). The triple combination therapy was statistically superior to each of the three dual combination treatments in reduction of diastolic and systolic blood pressures. The reductions in systolic/diastolic blood pressure with Exforge HCT were 7.6/5.0 mmHg greater than with valsartan/HCTZ, 6.2/3.3 mmHg greater than with amlodipine/valsartan, and 8.2/5.3 mmHg greater than with amlodipine/HCTZ. The full blood pressure lowering effect was achieved 2 weeks after being on their maximal dose of Exforge HCT. Statistically significant greater proportions of patients achieved BP control (<140/90 mmHg) with Exforge HCT (71%) compared to each of the three dual combination therapies (45-54%).
A subgroup of 268 patients was studied with ambulatory blood pressure monitoring. Clinically and statistically superior reductions in 24-hour systolic and diastolic blood pressures with the triple combination compared to valsartan/HCTZ, valsartan/amlodipine, and HCTZ/amlodipine were observed.
In controlled double-blind studies, age, gender, and race did not significantly influence the response to Exforge HCT.
EXCITE (EXperienCe of amlodIpine and valsarTan in hypErtension) Study: In an open, uncontrolled study, 9,794 hypertensive patients across 13 countries in the Middle East and Asia were treated according to routine clinical practice and prospectively observed for 26 weeks. A total of 8,603 were prescribed amlodipine/valsartan and 1,191 prescribed amlodipine/valsartan/hydrochlorothiazide. Among these, 15.5% were elderly, 32.5% were obese, 31.3% had diabetes, and 9.8% had isolated systolic hypertension. Both amlodipine/valsartan and amlodipine/valsartan/hydrochlorothiazide single-pill combinations, respectively, were associated with clinically relevant and significant mean sitting systolic/diastolic BP reductions in the overall population (-31.0/-16.6 mmHg and -36.6/-17.8 mmHg, respectively. These results were consistent regardless of age, body mass index, and diabetic status. Similarly, clinically relevant and significant systolic BP reductions were observed in patients with isolated systolic hypertension (-25.5 mmHg and -30.2 mmHg, respectively).
Pharmacokinetics: Linearity: Amlodipine, valsartan and HCTZ exhibit linear pharmacokinetics.
Amlodipine: Absorption: After oral administration of therapeutic doses of amlodipine alone, peak plasma concentrations of amlodipine are reached in 6-12 hours. Absolute bioavailability has been calculated as between 64% and 80%. Amlodipine bioavailability is unaffected by food ingestion.
Distribution: Volume of distribution is approximately 21 L/kg. In vitro studies with amlodipine have shown that approximately 97.5% of circulating drug is bound to plasma proteins. Amlodipine crosses the placenta and is excreted into breast milk.
Biotransformation/Metabolism: Amlodipine is extensively (approximately 90%) metabolized in the liver to inactive metabolites.
Elimination: Amlodipine elimination from plasma is biphasic with a terminal elimination half-life of approximately 30 to 50 hours. Steady-state plasma levels are reached after continuous administration for 7-8 days. Ten percent of original amlodipine and 60% of amlodipine metabolites are excreted in urine.
Valsartan: Absorption: Following oral administration of valsartan alone, peak plasma concentrations of valsartan are reached in 2-4 hours. Mean absolute bioavailability is 23%. Food decreases the exposure (as measured by AUC) to valsartan by about 40% and peak plasma concentration (C_max) by about 50%, although from about 8 h post dosing plasma valsartan concentrations are similar for the fed and fasted group. This reduction in AUC, however, is not accompanied by a clinically significant reduction in the therapeutic effect, and valsartan can therefore be given either with or without food.
Distribution: The steady-state volume of distribution of valsartan after intravenous administration is about 17 litres indicating that valsartan is not distributed into tissues extensively. Valsartan is highly bound to serum proteins (94-97%), mainly serum albumin.
Biotransformation/Metabolism: Valsartan is not transformed to a high extent as only about 20% of dose is recovered as metabolites. A hydroxy metabolite has been identified in plasma at low concentrations (less than 10 % of the valsartan AUC). This metabolite is pharmacologically inactive.
Elimination: Valsartan shows multiexponential decay kinetics (t_1/2α <1h and t_1/2β about 9 h). Valsartan is primarily eliminated in faeces (about 83% of dose) and urine (about 13% of dose) mainly as unchanged drug. Following intravenous administration, plasma clearance of valsartan is about 2 L/h and its renal clearance is 0.62 L/h (about 30% of total clearance). The half-life of valsartan is 6 hours.
Hydrochlorothiazide: Absorption: The absorption of hydrochlorothiazide, after an oral dose, is rapid (T_max about 2 h). The increase in mean AUC is linear and dose proportional in the therapeutic range. Concomitant administration with food has been reported to both increase and decrease the systemic availability of hydrochlorothiazide compared with the fasted state. The magnitude of these effects is small and has little clinical importance. Absolute bioavailability of hydrochlorothiazide is 70 % after oral administration.
Distribution: The distribution and elimination kinetics have generally been described as a bi-exponential decay function. The apparent volume of distribution is 4-8 L/kg. Circulating hydrochlorothiazide is bound to serum proteins (40-70%), mainly serum albumin. Hydrochlorothiazide also accumulates in erythrocytes at approximately 3 times the level in plasma.
Biotransformation/Metabolism: Hydrochlorothiazide is eliminated predominantly as unchanged drug.
Elimination: Hydrochlorothiazide is eliminated from plasma with a half-life averaging 6 to 15 hours in the terminal elimination phase. There is no change in the kinetics of hydrochlorothiazide on repeated dosing, and accumulation is minimal when dosed once daily. More than 95 % of the absorbed dose is excreted as unchanged compound in the urine.
Amlodipine/Valsartan/Hydrochlorothiazide: Following oral administration of Exforge HCT in normal healthy adults, peak plasma concentrations of amlodipine, valsartan and HCTZ are reached in 6-8 hours, 3 hours, and 2 hours, respectively. The rate and extent of absorption of amlodipine, valsartan and HCTZ from Exforge HCT are the same as when administered as individual dosage forms.
Special Populations: Geriatric patients: The time to reach peak plasma concentrations of amlodipine is similar in elderly and younger subjects. Amlodipine clearance tends to be decreased with resulting increases in AUC and elimination half-life in elderly patients.
Systemic exposure to valsartan is slightly elevated in the elderly as compared to the young, but this has not been shown to have any clinical significance.
Limited data suggest that the systemic clearance of hydrochlorothiazide is reduced in both healthy and hypertensive elderly subjects compared to young healthy volunteers.
Renal impairment: The pharmacokinetics of amlodipine is not significantly influenced by renal impairment.
As expected for a compound where renal clearance accounts for only 30% of total plasma clearance, there is no apparent correlation between renal function (measured by creatinine clearance) and systemic exposure to valsartan (measured by AUC) in patients with different degrees of renal failure. A trial in 5 normotensive patients undergoing haemodialysis demonstrated that complete loss of renal function does not lead to a gross increase in the exposure to valsartan and does not have a major impact on the kinetics of valsartan. This study also confirmed that valsartan is not removed from the plasma by haemodialysis.
Renal clearance of hydrochlorothiazide is composed of passive filtration and active secretion into the renal tubule. As expected for a compound which is cleared almost exclusively via the kidneys, renal function has a marked effect on the kinetics of hydrochlorothiazide (see CONTRAINDICATIONS and PRECAUTIONS).
Hepatic impairment: Patients with hepatic insufficiency have decreased clearance of amlodipine with resulting increase in AUC of approximately 40-60% in AUC. In a small number of patients with mild to moderate hepatic impairment given single doses of 5 mg, amlodipine half-life has been prolonged. Worsening of liver function test values may occur.
About 70% of the absorbed valsartan dose is excreted in the bile, mainly as unchanged compound. The AUC with valsartan has been observed to approximately double in patients with mild or moderate hepatic impairment including patients with biliary obstructive disorders (see Patients with hepatic impairment under PRECAUTIONS). There are no data available on the use of valsartan in patients with severe hepatic dysfunction (see CONTRAINDICATIONS).
Hepatic disease does not significantly affect the pharmacokinetics of hydrochlorothiazide. Care should be exercised in patients with liver disease (see PRECAUTIONS).
Toxicology: Non-Clinical Safety Data: Amlodipine:Valsartan:Hydrochlorothiazide: In a variety of preclinical safety studies conducted in several animal species with amlodipine/valsartan/hydrochlorothiazide (Exforge HCT), there were no findings that would exclude the use of therapeutic doses of Exforge HCT in humans. Preclinical safety studies with amlodipine/valsartan/ hydrochlorothiazide were conducted in rats up to 13-weeks duration and a no observable adverse effect level (NOAEL) was determined to be 0.5/8/1.25 mg/kg/day. Higher doses of this combination (≥2/32/5 mg/kg/day) resulted in expected reduction of red blood cell mass (erythrocytes, hemoglobin, hematocrit, and reticulocytes), increase in serum urea, increase in serum creatinine, increase in serum potassium, juxtaglomerular (JG) hyperplasia in the kidney and focal erosions in the glandular stomach in rats. All these changes were reversible after a 4-week recovery period and were considered to be exaggerated pharmacological effects.
The amlodipine/valsartan/hydrochlorothiazide combination was not tested for mutagenicity, clastogenicity, reproductive performance or carcinogenicity as there was no evidence of any interaction between these drugs, which have been on the market for a long time.
Amlodipine: Safety data for amlodipine are well established both clinically and non-clinically. No relevant findings were observed in carcinogenicity studies, mutagenicity studies.
There was no effect on the fertility of rats treated with amlodipine (males for 64 days and females 14 days prior to mating) at doses up to 10 mg/kg/day (8 times the maximum recommended human dose of 10 mg on a mg/m² basis, based on patient weight of 50 kg). Amlodipine has been tested individually for mutagenicity, clastogenicity, reproductive performance and carcinogenicity with negative results.
Valsartan: Preclinical data revealed no special hazard for humans based on conventional studies of safety pharmacology, genotoxicity, carcinogenic potential and effects on fertility.
Safety pharmacology and Long term toxicity: In a variety of preclinical safety studies conducted in several animal species, there were no findings that would exclude the use of therapeutic doses of valsartan in humans. In preclinical safety studies, high doses of valsartan (200 to 600 mg/kg/day body weight) caused in rats a reduction of red blood cell parameters (erythrocytes, hemoglobin, hematocrit) and evidence of changes in renal hemodynamics (slightly raised blood urea nitrogen, and renal tubular hyperplasia and basophilia in males).
These doses in rats (200 and 600 mg/kg/day) are approximately 6 and 18 times the maximum recommended human dose on a mg/m² basis (calculations assume an oral dose of 320 mg/day and a 60-kg patient). In marmosets at comparable doses, the changes were similar though more severe, particularly in the kidney where the changes developed to a nephropathy which included raised blood urea nitrogen and creatinine. Hypertrophy of the renal juxtaglomerular cells was also seen in both species. All changes were considered to be caused by the pharmacological action of valsartan which produces prolonged hypotension, particularly in marmosets. For therapeutic doses of valsartan in humans, the hypertrophy of the renal juxtaglomerular cells does not seem to have any relevance.
Reproductive toxicity: In a rat fertility study, valsartan had no adverse effects on the reproductive performance of male or female rats at oral doses up to 200 mg/kg/day, approximately 6 times the maximum recommended human dose on a mg/m² basis (calculations assume an oral dose of 320 mg/day and a 60-kg patient).
Mutagenicity: Valsartan was devoid of mutagenic potential at either the gene or chromosome level when investigated in various standard in vitro and in vivo genotoxicity studies.
Carcinogenicity: There was no evidence of carcinogenicity when valsartan was administered in the diet to mice and rats for 2 years at doses up to 160 and 200 mg/kg/day, respectively.
Hydrochlorothiazide: Hydrochlorothiazide has been tested individually for mutagenicity, clastogenicity, reproductive performance and carcinogenicity with negative results.
According to the experimental data available, hydrochlorothiazide did not reveal evidence of carcinogenic activity in rats and mice (hepatocellular tumors in mice were only seen in the high-dosed males; the incidence did not exceed those levels historically found in controls). The mutagenic potential was assessed in a series of in vitro and in vivo test systems. While some positive results were obtained in vitro, all in vivo studies provided negative results. Hydrochlorothiazide enhanced the UVA-induced formation of pyrimidine dimers in vitro and in the skin of mice following oral treatment. It is therefore concluded that there is no relevant mutagenic potential in vivo, although hydrochlorothiazide could enhance the genotoxic effects of UVA light.
Valsartan:Hydrochlorothiazide: In a variety of preclinical safety studies conducted in several animal species, there were no findings that would exclude the use of therapeutic doses of valsartan:hydrochlorothiazide in humans. High doses of valsartan:hydrochlorothiazide (100:31.25 to 600:187.5 mg/kg body weight) caused, in rats, a reduction of red blood cell parameters (erythrocytes, hemoglobin, hematocrit) and evidence of changes in renal hemodynamics (moderate to severe raised plasma urea, increases in plasma potassium and magnesium and mild increases in urinary volume and electrolytes, minimal to slight tubular basophilia, and afferent arteriolar hypertrophy at the highest dose level). In marmosets (30:9.375 to 400:125 mg/kg), the changes were fairly similar though more severe, particularly at the higher dose levels and in the kidney, where the changes developed to a nephropathy, which included raised urea and creatinine. Marmoset also had gastrointestinal mucosal changes at 30: 9.373 to 400: 125 mg/kg. Hypertrophy of the renal juxtaglomerular cells was also seen in rats and marmosets. All changes were considered to be caused by the pharmacological action of valsartan:hydrochlorothiazide which is synergistic (potentiation is about tenfold compared to valsartan alone) rather than additive, producing prolonged hypotension particularly in marmosets. For therapeutic doses of valsartan:hydrochlorothiazide in humans, the hypertrophy of the renal juxtaglomerular cells does not seem to have any relevance. The main preclinical safety findings are attributed to the pharmacological action of the compounds which appear to act synergistically with no evidence of any interaction between the two compounds. In the clinic, the actions of the two compounds are additive, and the preclinical findings have not been demonstrated to have any clinical significance. The combination valsartan:hydrochlorothiazide was not tested for mutagenicity, clastogenicity or carcinogenicity as there was no evidence for any interaction between the two compounds.
Amlodipine:Valsartan: In a variety of preclinical safety studies conducted in several animal species with amlodipine:valsartan, there were no findings that would exclude the use of therapeutic doses of amlodipine:valsartan in humans. Animal studies lasting 13 weeks have been conducted with amlodipine:valsartan combination in rats and marmosets, as well as studies in rats to investigate embryofetal development toxicity.
In a 13-week oral toxicity study in rats, amlodipine/valsartan-related inflammation of the glandular stomach was observed in males at doses ≥3/48 mg/kg/day and in females at doses ≥7.5/120 mg/kg/day. No such effects have been observed in the 13-week marmoset study at any dose, although inflammation of the large intestine was observed in the high-dose marmosets only (no effects at dose ≤5/80 mg/kg/day). The gastrointestinal adverse effects observed in clinical trials with Exforge were no more frequent with the combination than with the respective monotherapies. The combination amlodipine:valsartan was not tested for mutagenicity, clastogenicity, reproductive performance or carcinogenicity as there was no evidence for any interaction between the two compounds.