EXFORGE HCT Amlodipine Besilate / Valsartan / Hydrochlorothiazide 5mg / 160mg / 25mg Film-Coated Tablet 1's

There is no experience of overdosage with Amlodipine/Valsartan/HCTZ (Exforge HCT). The major symptom of overdose with valsartan is possibly pronounced hypotension with dizziness. Overdosage with amlodipine may result in excessive peripheral vasodilatation and possibly reflex tachycardia. Marked and potentially prolonged systemic hypotension up to and including shock with fatal outcome have been reported.
Clinically significant hypotension due to amlodipine overdosage calls for active cardiovascular support including frequent monitoring of cardiac and respiratory function, elevation of extremities and attention to circulating fluid volume and urine output.
A vasoconstrictor may be helpful in restoring vascular tone and blood pressure, provided that there is no contraindication to its use. If the ingestion is recent, induction of vomiting or gastric lavage may be considered. Administration of activated charcoal to healthy volunteers immediately or up to two hours after ingestion of amlodipine has been shown to significantly decrease amlodipine absorption.
Intravenous calcium gluconate may be beneficial in reversing the effects of calcium channel blockade.
Both valsartan and amlodipine are unlikely to be removed by hemodialysis whereas clearance of HCTZ will be achieved by dialysis.

 

 

Pregnancy: Risk summary: As for any drug that acts directly on the RAAS, Amlodipine/Valsartan/HCTZ (Exforge HCT) must not be used during pregnancy (see CONTRAINDICATIONS). Due to the mechanism of action of angiotensin II antagonists, a risk to the foetus cannot be excluded. Administration of angiotensin converting enzyme (ACE) inhibitors (a specific class of drugs acting on the renin-angiotensin-aldosterone system, RAAS) to pregnant women during the second and third trimesters has been reported to cause injury and death to the developing foetus. In addition, in retrospective data, first trimester use of ACE inhibitors has been associated with a potential risk of birth defects. Hydrochlorothiazide crosses the placenta. There have been reports of spontaneous abortion, oligohydramnios and newborn renal dysfunction when pregnant women have inadvertently taken valsartan.
There are no adequate clinical data with amlodipine in pregnant women. Animal studies with amlodipine have shown reproductive toxicity at dose 8 times the maximum recommended human dose of 10 mg (see Animal data as follows). The potential risk to humans is unknown.
Intrauterine exposure to thiazide diuretics, including hydrochlorothiazide, is associated with fetal or neonatal jaundice or thrombocytopenia, and may be associated with other adverse reactions that have occurred in adults.
If pregnancy is detected during therapy, use should be discontinued as soon as possible (see Animal data as follows).
Clinical considerations: Disease-associated maternal and/or embryo/fetal risk: Hypertension in pregnancy increases the maternal risk for pre-eclampsia, gestational diabetes, premature delivery, and delivery complications (e.g., need for cesarean section, and post-partum hemorrhage). Hypertension increases the fetal risk for intrauterine growth restriction and intrauterine death.
Fetal/Neonatal Risk: Oligohydramnios in pregnant women who use drugs affecting the renin-angiotensin system in the second and third trimesters of pregnancy can result in the following: reduced fetal renal function leading to anuria and renal failure, fetal lung hypoplasia, skeletal deformations, including skull hypoplasia, hypotension and death.
In case of accidental exposure to ARB therapy, appropriate fetal monitoring should be considered. Infants whose mothers have taken ARB therapy should be closely observed for hypotension.
Animal data: Valsartan: In embryofetal development studies in mice, rats and rabbits, fetotoxicity was observed in association with maternal toxicity in rats at valsartan doses of 600 mg/kg/day approximately 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) and in rabbits at doses of 10 mg/kg/day approximately 0.6 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). There was no evidence of maternal toxicity or fetotoxicity in mice up to a dose level of 600 mg/kg/day approximately 9 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).
Hydrochlorothiazide: Hydrochlorothiazide was not teratogenic and had no effects on fertility and conception. No teratogenic potential was revealed in 3 animal species tested. There was no dose-related fetotoxicity at oral dose levels of 0, 100, 300 and 1000 mg/kg in rats. A decrease in weight gain in suckling rat pups was attributed to the high dose and diuretic effects of hydrochlorothiazide, with subsequent effects on milk production.
Amlodipine: No evidence of teratogenicity or embryo/fetal toxicity was found when pregnant rats and rabbits were treated orally with amlodipine maleate at doses up to 10 mg amlodipine/kg/day during their respective periods of major organogenesis. However, litter size was significantly decreased (by about 50%) and the number of intrauterine deaths was significantly increased (about 5-fold).
Amlodipine has been shown to prolong both the gestation period and the duration of labor in rats at this dose.
Valsartan and amlodipine: In an oral embryo-fetal development study in rats with dose levels of 5:80 mg/kg/day, amlodipine:valsartan, 10:160 mg/kg/day amlodipine:valsartan, and 20:320 mg/kg/day amlodipine:valsartan, treatment-related maternal and fetal effects (developmental delays and alterations noted in the presence of significant maternal toxicity) were noted with the high dose combination. The no-observed-adverse-effect level (NOAEL) for embryo-fetal effects was 10:160 mg/kg/day amlodipine:valsartan. These doses are, respectively, 4.3 and 2.7 times the systemic exposure in humans receiving the MRHD (10/320 mg/60 kg).
Lactation: It is not known whether valsartan is transferred into human milk. It is reported that amlodipine is transferred into human milk. The proportion of the maternal dose received by the infant has been estimated with an interquartile range of 3-7%, with a maximum of 15%. The effect of amlodipine on infants is unknown. Valsartan was transferred into the milk of lactating rats. Hydrochlorothiazide is transferred into human milk. It is therefore not advisable for women who are breast-feeding to use Amlodipine/Valsartan/HCTZ (Exforge HCT).
Female and males of reproductive potential: As for any drug that acts directly on the RAAS, Amlodipine/Valsartan/HCTZ (Exforge HCT) should not be used in women planning to become pregnant. Healthcare professionals prescribing any agents acting on the RAAS should counsel women of childbearing potential about the potential risk of these agents during pregnancy.
Infertility: There is no information on effects of amlodipine, valsartan or hydrochlorothiazide on human fertility. Studies in rats did not show any effects of amlodipine, valsartan or hydrochlorothiazide on fertility (see PHARMACOLOGY: TOXICOLOGY: NON-CLINICAL SAFETY DATA under ACTIONS).

 

INCOMPATIBILITIES: Not applicable.

Pharmacotherapeutic group: Angiotensin II antagonists, plain (valsartan) combinations with dihydropyridine derivatives (amlodipine) and thiazide diuretics (HCTZ). ATC code: C09DX01.
Pharmacology: Pharmacodynamics: Amlodipine/Valsartan/HCTZ (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 the combination 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 vasodilation 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). 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 PRECAUTIONS and ADVERSE REACTIONS).
CLINICAL STUDIES: Amlodipine/Valsartan/HCTZ (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 Amlodipine/Valsartan/HCTZ (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 Amlodipine/Valsartan/HCTZ (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. Statistically significant greater proportions of patients achieved BP control (<140/90 mmHg) (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 Amlodipine/Valsartan/HCTZ (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 per cent 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_1/2 β 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 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 the single pill combination 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. There is no apparent correlation between renal function (measured by GFR) and exposure (measured by AUC) to valsartan in patients with different degrees of renal impairment. Patients with mild to moderate renal impairment may therefore receive the usual initial dose (see DOSAGE & ADMINISTRATION and PRECAUTIONS).
In the presence of renal impairment, mean peak plasma levels and AUC values of hydrochlorothiazide are increased and the urinary excretion rate is reduced. In patients with mild to moderate renal impairment, the mean elimination half-life is almost doubled. The renal clearance of hydrochlorothiazide is also reduced to a great extent compared with the renal clearance of around 300 mL/min in patients with normal renal function. Therefore, use with caution in patients with severe renal impairment (GFR <30 mL/min) (see PRECAUTIONS).
Hepatic impairment: Patients with hepatic impairment have decreased clearance of amlodipine with resulting increase in AUC of approximately 40-60%. On average, in patients with mild to moderate chronic liver disease exposure (measured by AUC values) to valsartan is twice that found in healthy volunteers (matched by age, sex and weight). Hepatic disease does not significantly affect the pharmacokinetics of hydrochlorothiazide, and no dose reduction is considered necessary. However, it should be used with particular caution in patients with biliary obstructive disorders and severe hepatic impairment (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, there were no findings that would exclude the use of therapeutic doses 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: 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 ≥120/7.5 mg/kg/day. No such effects have been observed in female rats at dose ≥3/48 mg/kg/day or 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.