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Pharmacotherapeutic Group: Angiotensin II antagonists and calcium channel blockers. ATC Code: C09DB02.
Pharmacology: Pharmacodynamics: Normetec is a combination of an angiotensin II receptor antagonist, olmesartan medoxomil, and a calcium channel blocker, amlodipine besylate. The combination of these active ingredients has an additive antihypertensive effect, reducing blood pressure (BP) to a greater degree than either component alone.
Normetec: In an 8-week, double-blind, randomised, placebo-controlled factorial design study in 1940 patients (71% Caucasian and 29% non-Caucasian patients), treatment with each combination dose of Normetec resulted in significantly greater reductions in diastolic and systolic BP than the respective monotherapy components. The mean change in systolic/diastolic BP was dose-dependent: -24/-14 mmHg (5 mg/20 mg combination), -25/-16 mmHg (5 mg/40 mg combination) and -30/-19 mmHg (10 mg/40 mg combination).
Normetec 5 mg/40 mg reduced seated systolic/diastolic BP by an additional 2.5/1.7 mmHg over Normetec 5 mg/20 mg. Similarly, Normetec 10 mg/40 mg reduced seated systolic/diastolic BP by an additional 4.7/3.5 mmHg over Normetec 5 mg/40 mg. The proportions of patients reaching BP goal (<140/90 mmHg for nondiabetic patients and <130/80 mmHg for diabetic patients) were 42.5%, 51% and 49.1% for Normetec 5 mg/20 mg, 5 mg/40 mg and 10 mg/40 mg, respectively.
The majority of the antihypertensive effect of Normetec was generally achieved within the first 2 weeks of therapy.
A second, double-blind, randomised, placebo-controlled study evaluated the effectiveness of adding amlodipine to the treatment in Caucasian patients whose BP was inadequately controlled by 8 weeks of monotherapy with olmesartan medoxomil 20 mg.
In patients who continued to receive only olmesartan medoxomil 20 mg, systolic/diastolic BP was reduced by -10.6/-7.8 mmHg after a further 8 weeks. The addition of amlodipine 5 mg for 8 weeks resulted in a reduction in systolic/diastolic BP of -16.2/-10.6 mmHg (p=0.0006).
The proportion of patients reaching BP goal (<140/90 mmHg for nondiabetic patients and <130/80 mmHg for diabetic patients) was 44.5% for the 5 mg/20 mg combination compared to 28.5% for olmesartan medoxomil 20 mg.
A further study evaluated the addition of various doses of olmesartan medoxomil in Caucasian patients whose BP was not adequately controlled by 8 weeks of monotherapy with amlodipine 5 mg.
In patients who continued to receive only amlodipine 5 mg, systolic/diastolic BP was reduced by -9.9/-5.7 mmHg after a further 8 weeks. The addition of olmesartan medoxomil 20 mg resulted in a reduction in systolic/diastolic BP of -15.3/-9.3 mmHg and the addition of olmesartan medoxomil 40 mg resulted in a reduction in systolic/diastolic BP of -16.7/-9.5 mmHg (p<0.0001).
The proportions of patients reaching BP goal (<140/90 mmHg for nondiabetic patients and <130/80 mmHg for diabetic patients) was 29.9% for the group who continued to receive amlodipine 5 mg alone, 53.5% for Normetec 5 mg/20 mg and 50.5% for Normetec 5 mg/40 mg.
Randomised data in uncontrolled hypertensive patients, comparing the use of medium dose Normetec combination therapy versus escalation to top dose monotherapy of amlodipine or olmesartan, are not available.
The 3 studies performed confirmed that the BP lowering effect of Normetec once daily was maintained throughout the 24-hr dose interval, with trough-to-peak ratios of 71-82% for systolic and diastolic response and with 24-hr effectiveness being confirmed by ambulatory BP monitoring.
The antihypertensive effect of Normetec was similar irrespective of age and gender, and was similar in patients with and without diabetes.
In 2 open-label, non-randomised extension studies, sustained efficacy using Normetec 5 mg/40 mg was demonstrated at 1 year for 49-67% of patients.
Olmesartan Medoxomil: The olmesartan medoxomil component of Normetec is a selective angiotensin II type 1 (AT1) receptor antagonist. Olmesartan medoxomil is rapidly converted to the pharmacologically active metabolite, olmesartan. Angiotensin II is the primary vasoactive hormone of the renin-angiotensin-aldosterone system and plays a significant role in the pathophysiology of hypertension. The effects of angiotensin II include vasoconstriction, stimulation of the synthesis and release of aldosterone, cardiac stimulation and renal reabsorption of sodium. Olmesartan blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II by blocking its binding to the AT1 receptor in tissues including vascular smooth muscle and the adrenal gland. The action of olmesartan is independent of the source or route of synthesis of angiotensin II. The selective antagonism of the angiotensin II (AT1) receptors by olmesartan results in increases in plasma renin levels and angiotensin I and II concentrations, and some decrease in plasma aldosterone concentrations.
In hypertension, olmesartan medoxomil causes a dose-dependent, long-lasting reduction in arterial BP. There has been no evidence of 1st-dose hypotension of tachyphylaxis during long-term treatment, or of rebound hypertension after abrupt cessation of therapy.
Following once daily administration to patients with hypertension, olmesartan medoxomil produces an effective and smooth reduction in BP over the 24-hr dose interval. Once daily dosing produced similar decreases in BP as twice daily dosing at the same total daily dose. With continuous treatment, maximum reductions in BP are achieved by 8 weeks after the initiation of therapy, although a substantial proportion of the BP lowering effect is already observed after 2 weeks of treatment.
The effect of olmesartan medoxomil on mortality and morbidity is not yet known.
Amlodipine: The amlodipine component of Normetec is a calcium channel blocker that inhibits the transmembrane influx of calcium ions through the potential-dependent L-type channels into the heart and smooth muscle. Experimental data indicate that amlodipine binds to both dihydropyridine and non-dihydropyridine binding sites. Amlodipine is relatively vessel-selective, with a greater effect on vascular smooth muscle cells than on cardiac muscle cells. The antihypertensive effect of amlodipine derives from a direct relaxant effect on arterial smooth muscle, which leads to a lowering of peripheral resistance and hence of BP.
In hypertensive patients, amlodipine causes a dose-dependent, long-lasting reduction in arterial BP. There has been no evidence of 1st-dose hypotension of tachyphylaxis during long-term treatment, or of rebound hypertension after abrupt cessation of therapy.
Following administration of therapeutic doses to patients with hypertension, amlodipine produces an effective reduction in BP in the supine, sitting and standing positions. Chronic use of amlodipine is not associated with significant changes in heart rate or plasma catecholamine levels. In hypertensive patients with normal renal function, therapeutic doses of amlodipine reduce renal vascular resistance and increase glomerular filtration rate and effective renal plasma flow, without changing filtration fraction or proteinuria.
In haemodynamic studies in patients with heart failure and in clinical studies based on exercise tests in patients with NYHA class II-IV heart failure, amlodipine was found not to cause any clinical deterioration, as measured by exercise tolerance, left ventricular ejection fraction and clinical signs and symptoms.
In a placebo-controlled study (PRAISE) designed to evaluate patients with NYHA class III-IV heart failure treated with digoxin, diuretics and angiotensin-converting enzyme (ACE) inhibitors, amlodipine was shown not to cause any increase in the risk of death or in the combined risk of mortality and morbidity in patients with heart failure.
A follow-up study (PRAISE 2) showed that amlodipine did not have an effect on the total or cardiovascular mortality of decompensatio cordis class III-IV patients without ischemic origin. In this study, treatment with amlodipine was associated with an increase in pulmonary oedema, although this could not be related to an increase in symptoms.
Pharmacokinetics: Normetec: Following oral intake of Normetec, peak plasma concentrations of olmesartan and amlodipine are reached at 1.5-2 hrs and 6-8 hrs, respectively. The rate and extent of absorption of the 2 active substances from Normetec are equivalent to the rate and extent of absorption following intake of the 2 components as separate tablets. Food does not affect the bioavailability of olmesartan and amlodipine from Normetec.
Olmesartan Medoxomil: Absorption and Distribution: Olmesartan medoxomil is a prodrug. It is rapidly converted to the pharmacologically active metabolite, olmesartan, by esterases in the gut mucosa and in portal blood during absorption from the gastrointestinal tract (GIT). No intact olmesartan medoxomil or intact side chain medoxomil moiety have been detected in plasma or excreta. The mean absolute bioavailability of olmesartan from a tablet formulation was 25.6%.
The mean peak plasma concentration (Cmax) of olmesartan is reached within about 2 hrs after oral dosing with olmesartan medoxomil, and olmesartan plasma concentrations increase approximately linearly with increasing single oral doses up to about 80 mg.
Food had minimal effect on the bioavailability of olmesartan and therefore olmesartan medoxomil may be administered with or without food.
No clinically relevant gender-related differences in the pharmacokinetics of olmesartan have been observed.
Olmesartan is highly bound to plasma protein (99.7%), but the potential for clinically significant protein-binding displacement interactions between olmesartan and other highly bound co-administered active substances is low (as confirmed by the lack of a clinically significant interaction between olmesartan medoxomil and warfarin). The binding of olmesartan to blood cells is negligible. The mean volume of distribution after IV dosing is low (16-29 L).
Metabolism and Elimination: Total plasma clearance of olmesartan was typically 1.3 L/hr (CV, 19%) and was relatively slow compared to hepatic blood flow (ca 90 L/hr). Following a single oral dose of 14C-labelled olmesartan medoxomil, 10-16% of the administered radioactivity was excreted in the urine (the vast majority within 24 hrs of dose administration) and the remainder of the recovered radioactivity was excreted in the faeces. Based on the systemic availability of 25.6%, it can be calculated that absorbed olmesartan is cleared by both renal excretion (ca 40%) and hepatobiliary excretion (ca 60%). All recovered radioactivity was identified as olmesartan. No other significant metabolite was detected. Enterohepatic recycling of olmesartan is minimal. Since a large proportion of olmesartan is excreted via the biliary route, use in patients with biliary obstruction is contraindicated (see Contraindication).
The terminal elimination half-life (t½) of olmesartan is between 10 and 15 hrs after multiple oral dosing. Steady state is reached after the first few doses and no further accumulation is evident after 14 days of repeated dosing. Renal clearance is approximately 0.5-0.7 L/hr and is independent of dose.
Amlodipine: Absorption and Distribution: After oral administration of therapeutic doses, amlodipine is slowly absorbed from the GIT. The absorption of amlodipine is unaffected by the concomitant intake of food. The absolute bioavailability of the unchanged compound is estimated to be 64-80%. Peak plasma levels are reached 6-12 hrs post-dose. The volume of distribution is about 20 L/kg. The pKa of amlodipine is 8.6. Plasma protein-binding in vitro is approximately 98%.
Metabolism and Elimination: The plasma elimination t½ varies from 35-50 hrs. Steady-state plasma levels are reached after 7-8 consecutive days. Amlodipine is extensively metabolised to inactive metabolites. About 60% of the administered dose is excreted in the urine, about 10% of which in the form of unchanged amlodipine.
Olmesartan Medoxomil and Amlodipine: Special Populations: Paediatric Patients <18 years: No pharmacokinetic data in paediatric patients are available.
Elderly ≥65 years: In hypertensive patients, the olmesartan AUC at steady state is increased by ca 35% in elderly patients (65-75 years) and by ca 44% in very elderly patients (>75 years) compared with the younger age group (see Dosage & Administration). This may be at least in part related to a mean decrease in renal function in this group of patients. The recommended dosage regimen for elderly patients is, however, the same, although caution should be exercised when increasing the dosage.
Following oral intake of amlodipine, the time to peak plasma concentration is comparable in young and in elderly patients. In elderly patients, the clearance of amlodipine tends to decline, resulting in increases in AUC and in elimination t½.
Renal Impairment: In renally impaired patients, the olmesartan AUC at steady state increased by 62%, 82% and 179% in patients with mild, moderate and severe renal impairment, respectively, compared to healthy controls (see Dosage & Administration and Precautions).
Amlodipine is extensively metabolised to inactive metabolites. Ten percent (10%) of the substance is excreted unchanged in the urine. Changes in amlodipine plasma concentration are not correlated with the degree of renal impairment. In these patients, amlodipine may be administered at the normal dosage. Amlodipine is not dialysable.
Hepatic Impairment: After single oral administration, olmesartan AUC values are 6% and 65% higher in mildly and moderately hepatically impaired patients, respectively, than in their corresponding matched healthy controls. The unbound fraction of olmesartan at 2-hr post-dose in healthy subjects, in patients with mild hepatic impairment and in patients with moderate hepatic impairment is 0.26%, 0.34% and 0.41%, respectively. Following repeated dosing in patients with moderate hepatic impairment, olmesartan mean AUC is again about 65% higher than in matched healthy controls. Olmesartan mean Cmax values are similar in hepatically impaired and healthy subjects. Olmesartan medoxomil has not been evaluated in patients with severe hepatic impairment (see Dosage & Administration and Precautions).
The clearance of amlodipine is decreased and the t½ is prolonged in patients with impaired hepatic function, resulting in an increase in AUC of about 40-60% (see Dosage & Administration and Precautions).
Toxicology: Preclinical Safety Data: Based on the nonclinical toxicity profile of each substance, no exacerbation of toxicities for the combination is expected, because each substance has different targets ie, the kidneys for olmesartan medoxomil and the heart for amlodipine.
In a 3-month, repeat-dose toxicity study of orally administered olmesartan medoxomil/amlodipine in combination in rats the following alterations were observed: Decreases in red blood cell count-related parameters and kidney changes both of which might be induced by the olmesartan medoxomil component; alterations in the intestines (luminal dilatation and diffuse mucosal thickening of the ileum and colon), the adrenals (hypertrophy of the glomerular cortical cells and vacuolation of the fascicular cortical cells), and hypertrophy of the ducts in the mammary glands which might be induced by the amlodipine component. These alterations neither augmented any of the previously reported and existing toxicity of the individual agents nor induced any new toxicity, and no toxicologically synergistic effects were observed.
Olmesartan Medoxomil: In chronic toxicity studies in rats and dogs, olmesartan medoxomil showed similar effects to other AT1 receptor antagonists and ACE inhibitors: Raised blood urea (BUN) and creatinine; reduction in heart weight; reduction of red cell parameters (erythrocytes, haemoglobin, haematocrit); histological indications of renal damage (regenerative lesions of the renal epithelium, thickening of the basal membrane, dilatation of the tubules). These adverse effects caused by the pharmacological action of olmesartan medoxomil have also occurred in preclinical trials on other AT1 receptor antagonists and ACE inhibitors and can be reduced by simultaneous oral administration of sodium chloride. In both species, increased plasma renin activity and hypertrophy/hyperplasia of the juxtaglomerular cells of the kidney were observed. These changes, which are a typical effect of the class of ACE inhibitors and other AT1 receptor antagonists, would appear to have no clinical relevance.
Like other AT1 receptor antagonists olmesartan medoxomil was found to increase the incidence of chromosome breaks in cell cultures in vitro. No relevant effects were observed in several in vivo studies using olmesartan medoxomil at very high oral doses of up to 2000 mg/kg. The overall data of a comprehensive genotoxicity testing programme suggest that olmesartan is very unlikely to exert genotoxic effects under conditions of clinical use.
Olmesartan medoxomil was not carcinogenic, in a 2-year study in rats nor in two 6-month carcinogenicity studies in transgenic mice.
In reproductive studies in rats, olmesartan medoxomil did not affect fertility and there was no evidence of a teratogenic effect. In common with other angiotensin II antagonists, survival of offspring was reduced following exposure to olmesartan medoxomil and pelvic dilatation of the kidney was seen after exposure of the dams in late pregnancy and lactation. In common with other antihypertensive agents, olmesartan medoxomil was shown to be more toxic to pregnant rabbits than to pregnant rats, however, there was no indication of a fetotoxic effect.
Amlodipine: Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated-dose toxicity, genotoxicity and carcinogenic potential. In animal studies with respect to the reproduction in rats at high doses delayed parturition, difficult labour and impaired fetal and pup survival were seen.
