Normetec

Amlodipine, olmesartan medoxomil.

Each 5 mg/20 mg, 5 mg/40 mg and 10 mg/40 mg tablets contains amlodipine (as amlodipine besylate) 5 mg, 5 mg and 10 mg, respectively, and olmesartan medoxomil 20 mg, 40 mg and 40 mg, respectively.
Excipients/Inactive Ingredients: Tablet Core: Pregelatinized maize starch, silicified microcrystalline cellulose (microcrystalline cellulose with colloidal silicon dioxide), croscarmellose sodium and magnesium stearate. Tablet Coat: Polyvinyl alcohol, macrogol 3350, talc, titanium dioxide (E171), yellow iron (III) oxide (E172) (Normetec 5 mg/40 mg and 10 mg/40 mg), and red iron (III) oxide (E172) (Normetec 10 mg/40 mg).

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 (C_max) 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 (t_½) 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 t_½ 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 t_½.
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 C_max 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 t_½ 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.

Treatment of essential hypertension.
Normetec is indicated in patients whose blood pressure (BP) is not adequately controlled on olmesartan medoxomil or amlodipine monotherapy (see Pharmacology: Pharmacodynamics under Actions and Dosage & Administration).

Dosage: Adults: Recommended Dose: 1 tab/day.
Normetec 5 mg/20 mg may be administered in patients whose BP is not adequately controlled by 5 mg amlodipine alone or 20 mg olmesartan medoxomil. Normetec 5 mg/40 mg may be administered in patients whose BP is not adequately controlled by Normetec 5 mg/20 mg. Normetec 10 mg/40 mg may be administered in patients whose BP is not adequately controlled by Normetec 5 mg/40 mg.
A step-wise titration of the dosage of the individual components is recommended before changing to the fixed combination. When clinically appropriate, direct change from monotherapy to the fixed combination may be considered.
For convenience, patients receiving olmesartan medoxomil and amlodipine from separate tablets may be switched to Normetec tablets containing the same component doses.
Elderly ≥65 years: No adjustment of the recommended dose is generally required for elderly patients (see Pharmacokinetics under Actions). If up-titration to the maximum dose of olmesartan medoxomil 40 mg daily is required, BP should be closely monitored.
Children and Adolescents: Normetec is not recommended for use in children and adolescents <18 years due to a lack of data on safety and efficacy (see Pharmacokinetics under Actions).
Renal Impairment: The maximum dose of olmesartan medoxomil in patients with mild to moderate renal impairment [creatinine clearance (CrCl) of 20-60 mL/min] is olmesartan medoxomil 20 mg once daily, owing to limited experience of higher dosages in this patient group. The use of Normetec in patients with severe renal impairment (CrCl <20 mL/min) is not recommended (see Pharmacokinetics under Actions and Precautions).
Monitoring of potassium levels and creatinine is advised in patients with moderate renal impairment.
Hepatic Impairment: Normetec should be used with caution in patients with mild to moderate hepatic impairment (see Pharmacokinetics under Actions and Precautions). In patients with moderate hepatic impairment, an initial dose of olmesartan medoxomil 10 mg once daily is recommended and the maximum dose should not exceed 20 mg once daily. Close monitoring of BP and renal function is advised in hepatically-impaired patients who are already receiving diuretics and/or other antihypertensive agents. There is no experience of olmesartan medoxomil in patients with severe hepatic impairment. As with all calcium antagonists, amlodipine t_½ is prolonged in patients with impaired liver function and dosage recommendations have not been established. Normetec should therefore be administered with caution in these patients.
Administration: The tablet should be swallowed with a sufficient amount of fluid (eg, 1 glass of water). The tablet should not be chewed and should be taken at the same time each day. Normetec can be taken with or without food.

Symptoms: There is no experience of overdose with Normetec. The most likely effects of olmesartan medoxomil overdosage are hypotension and tachycardia; bradycardia could be encountered if parasympathetic (vagal) stimulation occurred. Amlodipine overdosage can be expected to lead to excessive peripheral vasodilatation with marked hypotension and possibly a reflex tachycardia. Marked and potentially prolonged systemic hypotension up to and including shock with fatal outcome has been reported.
Treatment: If intake is recent, gastric lavage may be considered. In healthy subjects, the administration of activated charcoal immediately or up to 2 hrs after ingestion of amlodipine has been shown to reduce substantially the absorption of amlodipine.
Clinically significant hypotension due to an overdose of Normetec requires active support of the cardiovascular system, including close monitoring of heart and lung function, elevation of the 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. IV calcium gluconate may be beneficial in reversing the effects of calcium channel blockade.
Since amlodipine is highly protein bound, dialysis is not likely to be of benefit. The dialysability of olmesartan is unknown.

Hypersensitivity to amlodipine and olmesartan medoxomil, to dihydropyridine derivatives or to any of the excipients of Normetec (see Description).
Due to the component amlodipine, Normetec is also contraindicated in patients with cardiogenic shock, acute myocardial infarction (within the first 4 weeks), unstable angina pectoris.
Severe hepatic insufficiency and biliary obstruction (see Pharmacokinetics under Actions).
Use in Pregnancy: There are no data about the use of Normetec in pregnant patients. Animal reproductive toxicity studies with Normetec have not been performed.
Olmesartan Medoxomil: The use of angiotensin II antagonists is not recommended during the 1st trimester of pregnancy (see Pregnancy under Precautions). The use of angiotensin II antagonists is contraindicated during the 2nd and 3rd trimester of pregnancy.
Epidemiological evidence regarding the risk of teratogenicity following exposure to ACE inhibitors during the 1st trimester of pregnancy has not been conclusive; however a small increase in risk cannot be excluded.
While there is no controlled epidemiological data on the risk with angiotensin II antagonists, similar risks may exist for this class of drugs. Unless continued angiotensin receptor blocker therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with angiotensin II antagonists should be stopped immediately and, if appropriate, alternative therapy should be started.
Angiotensin II antagonists therapy exposure during the 2nd and 3rd trimesters is known to induce human fetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia). (See Toxicology: Preclinical Safety Data under Actions.)
Should exposure to angiotensin II antagonists have occurred from the 2nd trimester on, ultrasound examinations of the renal function and of the skull are recommended. Newborns exposed to angiotensin II antagonists in utero must be closely monitored for the occurrence of hypotension, oliguria and hyperkalaemia.
Amlodipine: Data on a limited number of exposed pregnancies do not indicate that amlodipine or other calcium receptor antagonists have a harmful effect on the health of the fetus. However, there may be a risk of prolonged delivery. As a consequence, Normetec is not recommended during the 1st trimester of pregnancy and is contraindicated during the 2nd and 3rd trimesters of pregnancy (see Contraindications).
Use in Lactation: Olmesartan is excreted into the milk of lactating rats. However, it is not known whether olmesartan passes into human milk. It is not known whether amlodipine is excreted in breast milk. Similar calcium channel blockers of the dihydropyridine type are excreted in breast milk. The risks to newborn infants of exposure to Normetec in breast milk are unknown. Therefore, as a precaution, the use of Normetec during lactation is contraindicated. A decision should be made whether to discontinue breastfeeding or discontinue Normetec, taking into account the importance of Normetec to the mother.

Patients with Hypovolaemia or Sodium Depletion: Symptomatic hypotension may occur in patients who are volume- and/or sodium depleted by vigorous diuretic therapy, dietary salt restriction, diarrhea or vomiting, especially after the 1st dose. Correction of this condition prior to administration of Normetec or close medical supervision at the start of the treatment is recommended.
Other Conditions with Stimulation of the Renin-Angiotensin-Aldosterone System: In patients whose vascular tone and renal function depend predominantly on the activity of the renin-angiotensin-aldosterone system (eg, patients with severe congestive heart failure or underlying renal disease, including renal artery stenosis), treatment with other medicinal products that affect this system eg, angiotensin II receptor antagonists, has been associated with acute hypotension, azotaemia, oliguria or, rarely, acute renal failure.
Renovascular Hypertension: There is an increased risk of severe hypotension and renal insufficiency when patients with bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney are treated with medicinal products that affect the renin-angiotensin-aldosterone system.
Renal Impairment and Kidney Transplantation: When Normetec is used in patients with impaired renal function, periodic monitoring of serum potassium and creatinine levels is recommended. Use of Normetec is not recommended in patients with severe renal impairment (CrCl <20 mL/min) (see Pharmacokinetics under Actions and Dosage & Administration). There is no experience of the administration of Normetec in patients with a recent kidney transplant or in patients with end-stage renal impairment (ie, CrCl <12 mL/min).
Hepatic Impairment: Exposure to amlodipine and olmesartan medoxomil is increased in patients with hepatic impairment (see Pharmacokinetics under Actions). Care should be taken when Normetec is administered in patients with mild to moderate hepatic impairment. In moderately impaired patients, the dose of olmesartan medoxomil should not exceed 20 mg (see Dosage & Administration). Use of Normetec in patients with severe hepatic impairment is contraindicated (see Contraindications).
Hyperkalaemia: As with other angiotensin II antagonists and ACE inhibitors, hyperkalaemia may occur during treatment, especially in the presence of renal impairment and/or heart failure (see Interactions). Close monitoring of serum potassium levels in patients at risk is recommended.
Concomitant use with potassium supplements, potassium-sparing diuretics, salt substitutes containing potassium or other medicinal products that may increase potassium levels (heparin, etc) should be undertaken with caution and with frequent monitoring of potassium levels.
Lithium: As with other angiotensin II receptor antagonists, the concomitant use of Normetec and lithium is not recommended (see Interactions).
Aortic or Mitral Valve Stenosis, Obstructive Hypertrophic Cardiomyopathy: Due to the amlodipine component of Normetec, as with all other vasodilators, special caution is indicated in patients suffering from aortic or mitral valve stenosis, or obstructive hypertrophic cardiomyopathy.
Primary Aldosteronism: Patients with primary aldosteronism generally will not respond to antihypertensive medicinal products acting through inhibition of the renin-angiotensin system. Therefore, the use of Normetec is not recommended in such patients.
Heart Failure: As a consequence of the inhibition of the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in susceptible individuals. In patients with severe heart failure whose renal function may depend on the activity of the renin-angiotensin-aldosterone system, treatment with ACE inhibitors and angiotensin receptor antagonists has been associated with oliguria and/or progressive azotaemia and (rarely) with acute renal failure and/or death.
In a long-term, placebo controlled study (PRAISE-2) of amlodipine in patients with NYHA III and IV heart failure of nonischaemic aetiology, amlodipine was associated with increased reports of pulmonary oedema despite no significant difference in the incidence of worsening heart failure as compared to placebo (see Pharmacology: Pharmacodynamics under Actions).
Ethnic Differences: As with all other angiotensin II antagonists, the BP lowering effect of Normetec can be somewhat less in Black patients than in non-Black patients, possibly because of a higher prevalence of low-renin status in the Black hypertensive population.
Pregnancy: Angiotensin II antagonists should not be initiated during pregnancy. Unless continued angiotensin II antagonist therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with angiotensin II antagonists should be stopped immediately, and, if appropriate, alternative therapy should be started (see Use in pregnancy under Contraindications).
Other: As with any antihypertensive agent, excessive BP decrease in patients with ischaemic heart disease or ischaemic cerebrovascular disease could result in a myocardial infarction or stroke.
Effects on the Ability to Drive or Operate Machinery: No studies on the effects on the ability to drive and use machines have been performed. However, it should be borne in mind that dizziness or fatigue may occasionally occur in patients taking antihypertensive therapy.

Use in Pregnancy: There are no data about the use of Normetec in pregnant patients. Animal reproductive toxicity studies with Normetec have not been performed.
Olmesartan Medoxomil: The use of angiotensin II antagonists is not recommended during the 1st trimester of pregnancy (see Pregnancy under Precautions). The use of angiotensin II antagonists is contraindicated during the 2nd and 3rd trimester of pregnancy.
Epidemiological evidence regarding the risk of teratogenicity following exposure to ACE inhibitors during the 1st trimester of pregnancy has not been conclusive; however a small increase in risk cannot be excluded.
While there is no controlled epidemiological data on the risk with angiotensin II antagonists, similar risks may exist for this class of drugs. Unless continued angiotensin receptor blocker therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with angiotensin II antagonists should be stopped immediately and, if appropriate, alternative therapy should be started.
Angiotensin II antagonists therapy exposure during the 2nd and 3rd trimesters is known to induce human fetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia). (See Toxicology: Preclinical Safety Data under Actions.)
Should exposure to angiotensin II antagonists have occurred from the 2nd trimester on, ultrasound examinations of the renal function and of the skull are recommended. Newborns exposed to angiotensin II antagonists in utero must be closely monitored for the occurrence of hypotension, oliguria and hyperkalaemia.
Amlodipine: Data on a limited number of exposed pregnancies do not indicate that amlodipine or other calcium receptor antagonists have a harmful effect on the health of the fetus. However, there may be a risk of prolonged delivery. As a consequence, Normetec is not recommended during the 1st trimester of pregnancy and is contraindicated during the 2nd and 3rd trimesters of pregnancy (see Contraindications).
Use in Lactation: Olmesartan is excreted into the milk of lactating rats. However, it is not known whether olmesartan passes into human milk. It is not known whether amlodipine is excreted in breast milk. Similar calcium channel blockers of the dihydropyridine type are excreted in breast milk. The risks to newborn infants of exposure to Normetec in breast milk are unknown. Therefore, as a precaution, the use of Normetec during lactation is contraindicated. A decision should be made whether to discontinue breastfeeding or discontinue Normetec, taking into account the importance of Normetec to the mother.

The safety of Normetec was investigated in controlled clinical trials in 2892 patients receiving olmesartan medoxomil in combination with amlodipine.
The following terminologies arranged by system organ class have been used in order to classify the occurrence of undesirable effects: Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1000 to <1/100); rare (≥1/10,000 to <1/1000); very rare (<1/10,000); not known (cannot be estimated from the available data).
Immune System Disorders: Rare: Drug hypersensitivity.
Metabolism and Nutrition Disorders: Uncommon: Hyperkalaemia.
Psychiatric Disorders: Uncommon: Decreased libido.
Nervous System Disorders: Common: Dizziness, headache. Uncommon: Postural dizziness, lethargy, paraesthesia, hypoaesthesia. Rare: Syncope.
Ear and Labyrinth Disorders: Uncommon: Vertigo.
Cardiac Disorders: Uncommon: Palpitations, tachycardia.
Vascular Disorders: Uncommon: Hypotension, orthostatic hypotension.
Respiratory, Thoracic and Mediastinal Disorders: Uncommon: Dyspnoea, cough.
Gastrointestinal Disorders: Uncommon: Nausea, vomiting, dyspepsia, diarrhoea, constipation, dry mouth, upper abdominal pain.
Skin and Subcutaneous Tissue Disorders: Uncommon: Rash. Rare: Urticaria.
Musculoskeletal and Connective Tissue Disorders: Uncommon: Muscle spasm, pain in extremity, back pain.
Renal and Urinary Disorders: Uncommon: Pollakiuria.
Reproductive System and Breast Disorders: Uncommon: Erectile dysfunction.
General Disorders and Administration Site Conditions: Common: Oedema; peripheral and pitting oedema; fatigue. Uncommon: Asthenia. Rare: Face oedema.
Investigations: Uncommon: Decreased blood potassium; increased blood creatinine, blood uric acid and γ-glutamyl transferase.
Additional Information on the Individual Components: Adverse reactions previously reported with 1 of the individual components may be potential adverse reactions with Normetec, even if not observed in clinical trials with Normetec.
Olmesartan Medoxomil: Further adverse events reported in clinical studies with olmesartan medoxomil monotherapy in hypertension were as follows: Angina pectoris, bronchitis, pharyngitis, rhinitis, abdominal pain, gastroenteritis, arthritis, skeletal pain, haematuria, urinary tract infection, chest pain, influenza-like symptoms, pain.
Further laboratory adverse events reported in clinical studies with olmesartan medoxomil monotherapy (irrespective of causality) were: Increased creatine phosphokinase, hypertriglyceridaemia, liver enzyme elevations.
In post-marketing experience with olmesartan medoxomil, additional adverse reactions reported, all at very rare frequency, were as follows: Thrombocytopenia, pruritus, exanthema, angioneurotic oedema, face oedema, allergic dermatitis, myalgia, acute renal failure, renal insufficiency, increased blood urea, malaise.
Single cases of rhabdomyolysis have been reported in temporal association with the intake of angiotensin II receptor blockers. A causal relationship, however, has not been established.
Additional Information on Special Populations: In elderly patients the frequency of hypotension is slightly increased from rare to uncommon.
Amlodipine: Further adverse reactions reported with amlodipine monotherapy were as follows: Common additional adverse reactions are facial flushing and abdominal pain. Less common adverse reactions include: Leukocytopenia, thrombocytopenia, gynaecomastia, hyperglycaemia, sleep disorder, irritability, depression, confusion, mood changes including anxiety, malaise, tremor, increased sweating, taste changes, peripheral neuropathy, visual disturbances, tinnitus, chest pain, aggravation of angina pectoris, vasculitis, rhinitis, gingival hyperplasia, gastritis, elevated liver enzymes, jaundice, hepatitis, pancreatitis, increased micturition frequency, impotency, exanthema, pruritus, alopecia, skin discolouration, purpura, isolated cases of allergic reactions (pruritus, rash, angio-oedema, erythema exsudativum multiforme, exfoliative dermatitis, Stevens-Johnson syndrome, Quincke oedema), myalgia, arthralgia, increase or decrease in weight. Isolated cases of myocardial infarction and arrhythmias (including extrasystole, ventricular tachycardia, bradycardia and atrial arrhythmias) and angina pectoris have been reported in patients with coronary artery disease, but a clear association with amlodipine has not been established.

Potential Interactions Related to the Normetec Combination: To be taken into account with concomitant use of other antihypertensive agents: The blood pressure lowering effect of Normetec can be increased by concomitant use of other antihypertensive medicinal products (eg, α-blockers, diuretics).
Potential Interactions Related to the Olmesartan Medoxomil Component of Normetec: Concomitant use not recommended.
Medicinal Products Affecting Potassium Levels: Concomitant use of potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium or other medicinal products that may increase serum potassium levels (eg, heparin, ACE inhibitors) may lead to increases in serum potassium (see Precautions). If medicinal products which affect potassium levels are to be prescribed in combination with Normetec, monitoring of serum potassium levels is recommended.
Lithium: Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with ACE inhibitors and, rarely, with angiotensin II antagonists. Therefore concomitant use of Normetec and lithium is not recommended (see Precautions). If concomitant use of Normetec and lithium proves necessary, careful monitoring of serum lithium levels is recommended.
Concomitant Use Requiring Caution: Nonsteroidal anti-inflammatory medicinal products (NSAIDs) including selective COX-2 inhibitors, acetylsalicylic acid (>3 g/day) and nonselective NSAIDs: When angiotensin II antagonists are administered simultaneously with NSAIDs, attenuation of the antihypertensive effect may occur. Furthermore, concomitant use of angiotensin II antagonists and NSAIDs may increase the risk of worsening of renal function and may lead to an increase in serum potassium. Therefore, monitoring of renal function at the beginning of such concomitant therapy is recommended, as well as adequate hydration of the patient.
Additional Information: After treatment with antacid (aluminium magnesium hydroxide), a modest reduction in bioavailability of olmesartan was observed.
Olmesartan medoxomil had no significant effect on the pharmacokinetics or pharmacodynamics of warfarin or the pharmacokinetics of digoxin. Co-administration of olmesartan medoxomil with pravastatin had no clinically relevant effects on the pharmacokinetics of either component in healthy subjects.
Olmesartan had no clinically relevant inhibitory effects on human CYP450 enzymes 1A1/2, 2A6, 2C8/9, 2C19, 2D6, 2E1 and 3A4 in vitro, and had no or minimal inducing effects on rat CYP450 activities. No clinically relevant interactions between olmesartan and medicinal products metabolised by the previously mentioned CYP450 enzymes are expected.
Potential Interactions Related to the Amlodipine Component of Normetec: Concomitant use requiring caution.
CYP3A4 Inhibitors: A study in elderly patients showed that diltiazem inhibits the metabolism of amlodipine, probably via CYP3A4, since plasma concentrations of amlodipine increased by approximately 50% and its effect was increased. The possibility that more potent CYP3A4 inhibitors (eg, ketoconazole, itraconazole, ritonavir) may increase the plasma concentration of amlodipine to a greater extent than diltiazem cannot be excluded.
CYP3A4 Inducers [anticonvulsants (eg, carbamazepine, phenobarbital, phenytoin, fosphenytoin, primidone), rifampicin, hypericum perforatum]: Concomitant administration may decrease the plasma concentration of amlodipine. Clinical monitoring is indicated, with possible adjustment of amlodipine dosage during treatment with the CYP3A4 inducer and after its withdrawal.
Sildenafil: When amlodipine and sildenafil were used in combination, each agent independently exerted its own blood pressure lowering effect.
Additional Information: Concomitant administration of grapefruit juice 240 mL with a single oral dose of amlodipine 10 mg in 20 healthy volunteers did not show a significant effect on the pharmacokinetic properties of amlodipine.
Co-administration of amlodipine with cimetidine had no significant effect on the pharmacokinetics of amlodipine.
Co-administration of amlodipine with atorvastatin, digoxin, warfarin or cyclosporin had no significant effect on the pharmacokinetics or pharmacodynamics of these agents.
Incompatibilities: Not applicable.

Store below 25°C.
Shelf-Life: 3 years.

Angiotensin II Antagonists / Anti-Anginal Drugs / Calcium Antagonists

C09DB02 - olmesartan medoxomil and amlodipine ; Belongs to the class of angiotensin II receptor blockers (ARBs) and calcium channel blockers. Used in the treatment of cardiovascular disease.

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