Sanoral hct

Overdose

Symptoms:

The maximum dose of Sanoral HCT is 40 mg/10 mg/25 mg once daily. There is no information on overdosage with Sanoral HCT in humans. The most likely effect of Sanoral HCT overdosage is hypotension.

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.

Overdosage with hydrochlorothiazide is associated with electrolyte depletion (hypokalaemia, hypochloraemia) and dehydration resulting from excessive diuresis.

The most common signs and symptoms of overdose are nausea and somnolence. Hypokalaemia may result in muscle spasm and/or accentuate cardiac arrhythmias associated with the concomitant use of digitalis glycosides or certain anti-arrhythmic medicinal products.

Treatment:

In the event of overdosage with Sanoral HCT, treatment should be symptomatic and supportive. Management depends upon the time since ingestion and the severity of the symptoms.

If intake is recent, gastric lavage may be considered. In healthy subjects, the administration of activated charcoal immediately or up to 2 hours after ingestion of amlodipine has been shown to reduce substantially the absorption of amlodipine.

Clinically significant hypotension due to an overdose of Sanoral HCT 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. Intravenous calcium gluconate may be beneficial in reversing the effects of calcium channel blockade.

Serum electrolytes and creatinine should be monitored frequently. If hypotension occurs, the patient should be placed in a supine position, with salt and volume replacements given quickly.

Since amlodipine is highly protein-bound, dialysis is not likely to be of benefit. The dialysability of olmesartan or hydrochlorothiazide is unknown.

The degree to which olmesartan and hydrochlorothiazide are removed by haemodialysis has not been established.

Contraindications

Hypersensitivity to the active substances, to dihydropyridine derivates or to sulfonamide-derived substances (since hydrochlorothiazide is a sulfonamide-derived drug) or to any of the excipients listed in section 6.1.

Severe renal impairment.

Refractory hypokalaemia, hypercalcaemia, hyponatraemia and symptomatic hyperuricaemia.

Severe hepatic insufficiency, cholestasis and biliary obstructive disorders.

2nd and 3rd trimester of pregnancy.

The concomitant use of Sanoral HCT with aliskiren-containing products is contraindicated in patients with diabetes mellitus or renal impairment (GFR < 60 mL/min/1.73 m2).

Due to the amlodipine component, Sanoral HCT is contraindicated in patients with:

- Shock (including cardiogenic shock).

- Severe hypotension

- Obstruction of the outflow tract of the left ventricle (e.g. high grade aortic stenosis).

- Haemodynamically unstable heart failure after acute myocardial infarction.

Incompatibilities

Not applicable.

Undesirable effects

The safety of Sanoral HCT was investigated in clinical trials in 7826 patients receiving olmesartan medoxomil in combination with amlodipine and hydrochlorothiazide.

Adverse reactions from clinical trials, post-authorization safety studies and spontaneous reporting are summarized in table 1 for Sanoral HCT as well as for the individual components olmesartan medoxomil, amlodipine and hydrochlorothiazide based on the known safety profile of the single components.

The most commonly reported adverse reactions during treatment with Sanoral HCT are peripheral oedema, headache and dizziness.

The following terminologies have been used in order to classify the occurrence of undesirable effects:

Very common (>1/10)

Common (>1/100 to <1/10)

Uncommon (>1/1,000 to <1/100)

Rare (>1/10,000 to <1/1,000)

Very rare (<1/10,000)

Not known (cannot be estimated from the available data)

Table 1: Overview of adverse reactions with Sanoral HCT and the single components

Preclinical safety data

Olmesartan medoxomil/ Amlodipine /Hydrochlorothiazide combination

Repeated dose toxicity study in rats demonstrated that the combined administration of olmesartan medoxomil, amlodipine and hydrochlorothiazide neither augmented any of the previously reported and existing toxicities of the individual agents, nor induced any new toxicity, and no toxicologically synergistic effects were observed.

No additional mutagenicity, carcinogenicity, and reproductive toxicity studies for Sanoral HCT have been conducted based on the well-understood safety profile of the individual active ingredients.

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.

Like other AT1 receptor antagonists olmesartan medoxomil was found to increase the incidence of chromosome breaks in cell cultures in vitro, but not in vivo. 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 rats or 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 and pelvic dilatation of the kidney was seen after exposure of the dams in late pregnancy and lactation. In rabbits there was no indication of a fetotoxic effect.

Amlodipine

Reproductive toxicology

Reproductive studies in rats and mice have shown delayed date of delivery, prolonged duration of labour and decreased pup survival at dosages approximately 50 times greater than the maximum recommended dosage for humans based on mg/kg.

Impairment of fertility

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). In another rat study in which male rats were treated with amlodipine besilate for 30 days at a dose comparable with the human dose based on mg/kg, decreased plasma follicle-stimulating hormone and testosterone were found as well as decreases in sperm density and in the number of mature spermatids and Sertoli cells.

Carcinogenesis, mutagenesis

Rats and mice treated with amlodipine in the diet for two years, at concentrations calculated to provide daily dosage levels of 0.5, 1.25, and 2.5 mg/kg/day showed no evidence of carcinogenicity. The highest dose (for mice, similar to, and for rats twice* the maximum recommended clinical dose of 10 mg on a mg/m2 basis) was close to the maximum tolerated dose for mice but not for rats.

Mutagenicity studies revealed no drug related effects at either the gene or chromosome levels.

Hydrochlorothiazide

Studies with hydrochlorothiazide have shown equivocal evidence for a genotoxic or carcinogenic effect in some experimental models. However, the extensive human experience with hydrochlorothiazide has failed to show an association between its use and an increase in neoplasma.

Therapeutic indications

Treatment of essential hypertension.

Add-on therapy

Sanoral HCT is indicated in adult patients whose blood pressure is not adequately controlled on the combination of olmesartan medoxomil and amlodipine taken as dual-component formulation.

Substitution therapy

Sanoral HCT is indicated as substitution therapy in adult patients whose blood pressure is adequately controlled on the combination of olmesartan medoxomil, amlodipine and hydrochlorothiazide, taken as a dual-component (olmesartan medoxomil and amlodipine or olmesartan medoxomil and hydrochlorothiazide) and a single-component formulation (hydrochlorothiazide or amlodipine).

Pharmacotherapeutic group

Pharmacodynamic properties

Pharmacotherapeutic group: Angiotensin II antagonists, calcium channel blockers and diuretics.

ATC code: C09DX03.

Sanoral HCT is a combination of an angiotensin II receptor antagonist, olmesartan medoxomil, a calcium channel blocker, amlodipine besilate and a thiazide diuretic, hydrochlorothiazide. The combination of these ingredients has an additive antihypertensive effect, reducing blood pressure to a greater degree than each component alone.

Olmesartan medoxomil is an orally active, selective angiotensin II receptor (type AT1) antagonist. 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 blood pressure. There has been no evidence of first-dose hypotension, of tachyphylaxis during long-term treatment, or of rebound hypertension after abrupt cessation of therapy.

Once daily dosing with olmesartan medoxomil provides an effective and smooth reduction in blood pressure over the 24 hour dose interval. Once daily dosing produced similar decreases in blood pressure as twice daily dosing at the same total daily dose.

With continuous treatment, maximum reductions in blood pressure are achieved by 8 weeks after the initiation of therapy, although a substantial proportion of the blood pressure lowering effect is already observed after 2 weeks of treatment.

The effect of olmesartan medoxomil on mortality and morbidity is not yet known.

The Randomised Olmesartan and Diabetes Microalbuminuria Prevention (ROADMAP) study in 4447 patients with type 2 diabetes, normo-albuminuria and at least one additional cardiovascular risk factor, investigated whether treatment with olmesartan could delay the onset of microalbuminuria. During the median follow-up duration of 3.2 years, patients received either olmesartan or placebo in addition to other antihypertensive agents, except ACE inhibitors or ARBs.

For the primary endpoint, the study demonstrated a significant risk reduction in the time to onset of microalbuminuria, in favour of olmesartan. After adjustment for BP differences this risk reduction was no longer statistically significant. 8.2% (178 of 2160) of the patients in the olmesartan group and 9.8% (210 of 2139) in the placebo group developed microalbuminuria.

For the secondary endpoints, cardiovascular events occurred in 96 patients (4.3%) with olmesartan and in 94 patients (4.2%) with placebo. The incidence of cardiovascular mortality was higher with olmesartan compared to placebo treatment (15 patients (0.7%) vs. 3 patients (0.1%)), despite similar rates for non-fatal stroke (14 patients (0.6%) vs. 8 patients (0.4%)), non-fatal myocardial infarction (17 patients (0.8%) vs. 26 patients (1.2%)) and non-cardiovascular mortality (11 patients (0.5%) vs. 12 patients (0.5%)). Overall mortality with olmesartan was numerically increased (26 patients (1.2%) vs. 15 patients (0.7%)), which was mainly driven by a higher number of fatal cardiovascular events.

The Olmesartan Reducing Incidence of End-stage Renal Disease in Diabetic Nephropathy Trial (ORIENT) investigated the effects of olmesartan on renal and cardiovascular outcomes in 577 randomized Japanese and Chinese type 2 diabetic patients with overt nephropathy. During a median follow-up of 3.1 years, patients received either olmesartan or placebo in addition to other antihypertensive agents including ACE inhibitors.

The primary composite endpoint (time to first event of the doubling of serum creatinine, end-stage renal disease, all-cause death) occurred in 116 patients in the olmesartan group (41.1%) and 129 patients in the placebo group (45.4%) (HR 0.97 (95% CI 0.75 to 1.24); p=0.791). The composite secondary cardiovascular endpoint occurred in 40 olmesartan-treated patients (14.2%) and 53 placebo-treated patients (18.7%). This composite cardiovascular endpoint included cardiovascular death in 10 (3.5%) patients receiving olmesartan versus 3 (1.1%) receiving placebo, overall mortality 19 (6.7%) versus 20 (7.0%), non-fatal stroke 8 (2.8%) versus 11 (3.9%) and non-fatal myocardial infarction 3 (1.1%) versus 7 (2.5%), respectively.

The amlodipine component of Sanoral HCT 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 blood pressure.

In hypertensive patients, amlodipine causes a dose-dependent, long-lasting reduction in arterial blood pressure. There has been no evidence of first-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 blood pressure 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.

A placebo-controlled study (PRAISE) designed to evaluate patients with NYHA class III-IV heart failure receiving digitalis, diuretics and ACE inhibitors, has shown that amlodipine did not lead to an increase in the risk of mortality and morbidity in patients with heart failure.

In a follow-up, long-term, placebo controlled study (PRAISE-2) of amlodipine in patients with NYHA III and IV heart failure without clinical symptoms or objective findings suggestive of underlying ischaemic disease, on stable doses of ACE inhibitors, digitalis, and diuretics, amlodipine had no effect on total or cardiovascular mortality. In this same population amlodipine was associated with increased reports of pulmonary oedema despite no significant difference in the incidence of worsening heart failure as compared to placebo.

A randomized double-blind morbidity-mortality study called the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) was performed to compare newer drug therapies: amlodipine 2.5-10 mg/d (calcium channel blocker) or lisinopril 10-40 mg/d (ACE-inhibitor) as first-line therapies to that of the thiazide-diuretic, chlorthalidone 12.5-25 mg/d in mild to moderate hypertension.”

A total of 33,357 hypertensive patients aged 55 or older were randomized and followed for a mean of 4.9 years. The patients had at least one additional CHD risk factor, including: previous myocardial infarction or stroke (> 6 months prior to enrollment) or documentation of other atherosclerotic CVD (overall 51.5%), type 2 diabetes (36.1%), HDL-C < 35 mg/dL (11.6%), left ventricular hypertrophy diagnosed by electrocardiogram or echocardiography (20.9%), current cigarette smoking (21.9%).

The primary endpoint was a composite of fatal CHD or non-fatal myocardial infarction. There was no significant difference in the primary endpoint between amlodipine-based therapy and chlorthalidone-based therapy: RR 0.98 95% CI (0.90-1.07) p=0.65. Among secondary endpoints, the incidence of heart failure (component of a composite combined cardiovascular endpoint) was significantly higher in the amlodipine group as compared to the chlorthalidone group (10.2% vs. 7.7%, RR 1.38, 95% CI [1.25-1.52] p<0.001). However, there was no significant difference in all-cause mortality between amlodipine-based therapy and chlorthalidone-based therapy. RR 0.96 95% CI [0.89-1.02] p=0.20.

Hydrochlorothiazide is a thiazide diuretic. The mechanism of the antihypertensive effect of thiazide diuretics is not fully known. Thiazides affect the renal tubular mechanisms of electrolyte reabsorption, directly increasing excretion of sodium and chloride in approximately equivalent amounts. The diuretic action of hydrochlorothiazide reduces plasma volume, increases plasma renin activity and increases aldosterone secretion, with consequent increases in urinary potassium and bicarbonate loss, and decreases in serum potassium. The renin-aldosterone link is mediated by angiotensin II and therefore coadministration of an angiotensin II receptor antagonist tends to reverse the potassium loss associated with thiazide diuretics. With hydrochlorothiazide, onset of diuresis occurs at about 2 hours and peak effect occurs at about 4 hours post-dose, whilst the action persists for approximately 6-12 hours.

Epidemiological studies have shown that long-term treatment with hydrochlorothiazide monotherapy reduces the risk of cardiovascular mortality and morbidity.

Results of Clinical Studies

In a 12-week, double-blind, randomised, parallel-group study in 2492 patients (67% Caucasian patients), treatment with Sanoral HCT 40 mg/10 mg/25 mg resulted in significantly greater reductions in diastolic and systolic blood pressures than treatment with either of the corresponding dual combinations, olmesartan medoxomil 40 mg plus amlodipine 10 mg, olmesartan medoxomil 40 mg plus hydrochlorothiazide 25 mg and amlodipine 10 mg plus hydrochlorothiazide 25 mg, respectively.

The additional blood pressure lowering effect from Sanoral HCT 40 mg/10 mg/25 mg compared to the analogous dual combinations was between -3.8 and -6.7 mmHg for seated diastolic and between -7.1 and -9.6 mmHg for seated systolic blood pressure and occurred within the first 2 weeks.

The proportions of patients reaching blood pressure goal (< 140/90 mmHg for non-diabetic patients and < 130/80 mmHg for diabetic patients) at week 12 ranged from 34.9% to 46.6% for the dual combination treatment groups compared to 64.3% for Sanoral HCT 40 mg/10 mg/25 mg.

In a second double-blind, randomised, parallel-group study in 2690 patients (99.9% Caucasian patients), treatment with Sanoral HCT (20 mg/5 mg/12.5 mg, 40 mg/5 mg/12.5 mg, 40 mg/5 mg/25 mg, 40 mg/10 mg/12.5 mg, 40 mg/10 mg/25 mg) resulted in significantly greater reductions in diastolic and systolic blood pressure compared to the corresponding dual combinations, olmesartan medoxomil 20 mg plus amlodipine 5 mg, olmesartan medoxomil 40 mg plus 5 mg amlodipine and olmesartan medoxomil 40 mg plus 10 mg amlodipine, respectively, after 10 weeks of treatment.

The additional blood pressure lowering effect from Sanoral HCT compared to the corresponding dual combinations was between -1.3 and -1.9 mmHg for seated diastolic and between -2.7 and -4.9 mmHg for seated systolic blood pressure.

The proportions of patients reaching blood pressure goal (< 140/90 mmHg for non-diabetic patients and < 130/80 mmHg for diabetic patients) at week 10 ranged from 42.7% to 49.6% for the dual combination treatment groups compared to 52.4% to 58.8% for Sanoral HCT.

In a randomised, double-blind, add-on study in 808 patients (99.9 % Caucasian patients) not adequately controlled after 8-weeks therapy with olmesartan medoxomil 40 mg plus amlodipine 10 mg dual combination treatment with Sanoral HCT resulted in numerically additional seated blood pressure reduction of -1.8/-1.0 mmHg when treated with Sanoral HCT 40 mg/10 mg/12.5 mg and a statistically significant additional seated blood pressure reduction of -3.6/-2.8 mmHg when treated with Sanoral HCT 40 mg/10 mg/25 mg compared to the olmesartan medoxomil 40 mg plus amlodipine 10 mg dual combination.

Treatment with Sanoral HCT 40 mg/10 mg/25 mg triple-combination therapy resulted in a statistically significantly greater percentage of subjects reaching their blood pressure goal compared to olmesartan medoxomil 40 mg plus amlodipine 10 mg dual combination therapy (41.3% vs. 24.2%); while the treatment with Sanoral HCT 40 mg/10 mg/12.5 mg triple-combination therapy resulted in a numerically greater percentage of subjects reaching their blood pressure goal compared to olmesartan medoxomil 40 mg plus amlodipine 10 mg dual-combination therapy (29.5% vs. 24.2%) in subjects not adequately controlled on dual-combination therapy.

The antihypertensive effect of Sanoral HCT was similar irrespective of age and gender, and was similar in patients with and without diabetes.

Other information:

Two large randomised, controlled trials (ONTARGET (ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial) and VA NEPHRON-D (The Veterans Affairs Nephropathy in Diabetes)) have examined the use of the combination of an ACE-inhibitor with an angiotensin II receptor blocker.

ONTARGET was a study conducted in patients with a history of cardiovascular or cerebrovascular disease, or type 2 diabetes mellitus accompanied by evidence of end-organ damage. VA NEPHRON-D was a study in patients with type 2 diabetes mellitus and diabetic nephropathy.

These studies have shown no significant beneficial effect on renal and/or cardiovascular outcomes and mortality, while an increased risk of hyperkalaemia, acute kidney injury and/or hypotension as compared to monotherapy was observed. Given their similar pharmacodynamic properties, these results are also relevant for other ACE-inhibitors and angiotensin II receptor blockers.

ACE-inhibitors and angiotensin II receptor blockers should therefore not be used concomitantly in patients with diabetic nephropathy.

ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints) was a study designed to test the benefit of adding aliskiren to a standard therapy of an ACE-inhibitor or an angiotensin II receptor blocker in patients with type 2 diabetes mellitus and chronic kidney disease, cardiovascular disease, or both. The study was terminated early because of an increased risk of adverse outcomes. Cardiovascular death and stroke were both numerically more frequent in the aliskiren group than in the placebo group and adverse events and serious adverse events of interest (hyperkalaemia, hypotension and renal dysfunction) were more frequently reported in the aliskiren group than in the placebo group.

Pharmacokinetic properties

Concomitant administration of olmesartan medoxomil, amlodipine and hydrochlorothiazide had no clinically-relevant effects on the pharmacokinetics of either component in healthy subjects.

Following oral administration of Sanoral HCT in normal healthy adults, peak plasma concentrations of olmesartan, amlodipine and hydrochlorothiazide are reached in about 1.5 to 3 hours, 6 to 8 hours, and 1.5 to 2 hours, respectively. The rate and extent of absorption of olmesartan medoxomil, amlodipine and hydrochlorothiazide from Sanoral HCT are the same as when administered as a dual-fixed combination of olmesartan medoxomil and amlodipine together with a hydrochlorothiazide single-component tablet or when administered as a dual-fixed combination of olmesartan medoxomil and hydrochlorothiazide together with an amlodipine single-component tablet with the same dosages. Food does not affect the bioavailability of Sanoral HCT.

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. 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 hours 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 intravenous dosing is low (16 - 29 L).

Biotransformation and elimination:

Total plasma clearance of olmesartan was typically 1.3 L/h (CV 19%) and was relatively slow compared to hepatic blood flow (ca 90 L/h). 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 hours 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 hepato-biliary 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.

The terminal elimination half life of olmesartan varied between 10 and 15 hours after multiple oral dosing. Steady state was reached after 2-5 days of dosing and no further accumulation was evident after 14 days of repeated dosing. Renal clearance was approximately 0.5 - 0.7 L/h and was independent of dose.

Drug interactions:

Bile acid sequestering agent colesevelam:

Concomitant administration of 40 mg olmesartan medoxomil and 3750 mg colesevelam hydrochloride in healthy subjects resulted in 28% reduction in Cmax and 39% reduction in AUC of olmesartan. Lesser effects, 4% and 15% reduction in Cmax and AUC respectively, were observed when olmesartan medoxomil was administered 4 hours prior to colesevelam hydrochloride. Elimination half life of olmesartan was reduced by 50 - 52% irrespectively of whether administered concomitantly or 4 hours prior to colesevelam hydrochloride.

Amlodipine:

Absorption and distribution:

After oral administration of therapeutic doses, amlodipine is well absorbed with peak blood levels between 6-12 hours post dose. Absolute bioavailability has been estimated to be between 64 and 80%. The volume of distribution is approximately 21 l/kg. In vitro studies have shown that approximately 97.5% of circulating amlodipine is bound to plasma proteins.

The absorption of amlodipine is unaffected by the concomitant intake of food.

Biotransformation and elimination:

The terminal plasma elimination half life is about 35-50 hours and is consistent with once daily dosing.

Amlodipine is extensively metabolised by the liver to inactive metabolites with 10% of the parent compound and 60% of metabolites excreted in the urine.

Hydrochlorothiazide:

Absorption and distribution:

Following oral administration of olmesartan medoxomil and hydrochlorothiazide in combination, the median time to peak concentrations of hydrochlorothiazide was 1.5 to 2 hours after dosing. Hydrochlorothiazide is 68% protein bound in the plasma and its apparent volume of distribution is 0.83 - 1.14 L/kg.

Biotransformation and elimination:

Hydrochlorothiazide is not metabolised in man and is excreted almost entirely as unchanged active substance in urine. About 60% of the oral dose is eliminated as unchanged active substance within 48 hours. Renal clearance is about 250 - 300 mL/min. The terminal elimination half-life of hydrochlorothiazide is 10 - 15 hours.

Pharmacokinetics in special populations

Paediatric Population:

The European Medicines Agency has waived the obligation to submit the results of studies with Sanoral HCT in all subsets of the paediatric population in essential hypertension.

Elderly (age 65 years or over):

In hypertensive patients, the olmesartan AUC at steady state was increased by ca 35% in elderly people (65 - 75 years old) and by ca 44% in very elderly people (> 75 years old) compared with the younger age group.

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 people is, however, the same, although caution should be exercised when increasing the dosage.

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 people. Increases in AUC and elimination half life in patients with congestive heart failure were as expected for the patient age group in this study.

Limited data suggest that the systemic clearance of hydrochlorothiazide is reduced in both healthy and hypertensive elderly people compared to young healthy volunteers.

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. The pharmacokinetics of olmesartan medoxomil in patients undergoing haemodialysis has not been studied.

Amlodipine is extensively metabolised to inactive metabolites. Ten percent 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.

The half-life of hydrochlorothiazide is prolonged in patients with impaired renal function.

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 hours 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.

Very limited clinical data are available regarding amlodipine administration in patients with hepatic impairment. The clearance of amlodipine is decreased and the half-life is prolonged in patients with impaired hepatic function, resulting in an increase in AUC of about 40% - 60%.

Hepatic impairment does not significantly influence the pharmacokinetics of hydrochlorothiazide.

Name of the medicinal product

Qualitative and quantitative composition

Special warnings and precautions for use

Patients with hypovolaemia or sodium depletion:

Symptomatic hypotension may occur in patients who are volume and/or sodium depleted as a result of vigorous diuretic therapy, dietary salt restriction, diarrhoea or vomiting, especially after the first dose. Correction of this condition prior to administration of Sanoral HCT 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 (e. g. patients with severe congestive heart failure or underlying renal disease, including renal artery stenosis), treatment with medicinal products that affect this system 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 Sanoral HCT is used in patients with impaired renal function, periodic monitoring of serum concentrations of potassium and creatinine is recommended.

Use of Sanoral HCT is not recommended in patients with severe renal impairment (creatinine clearance < 30 mL/min).

Thiazide diuretic-associated azotaemia may occur in patients with impaired renal function.

If progressive renal impairment becomes evident, careful reappraisal of therapy is necessary, with consideration given to discontinuing diuretic therapy.

There is no experience of the administration of Sanoral HCT in patients with a recent kidney transplant or in patients with end-stage renal impairment (i. e. creatinine clearance < 12 mL/min).

Dual blockade of the renin-angiotensin-aldosterone system (RAAS):

There is evidence that the concomitant use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren increases the risk of hypotension, hyperkalaemia and decreased renal function (including acute renal failure). Dual blockade of RAAS through the combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is therefore not recommended.

If dual blockade therapy is considered absolutely necessary, this should only occur under specialist supervision and subject to frequent close monitoring of renal function, electrolytes and blood pressure.

ACE-inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy.

Hepatic impairment:

Exposure to amlodipine and olmesartan medoxomil is increased in patients with hepatic impairment.

Furthermore, minor alterations of fluid and electrolyte balance during thiazide therapy may precipitate hepatic coma in patients with impaired hepatic function or progressive liver disease.

Care should be taken when Sanoral HCT is administered in patients with mild to moderate hepatic impairment.

In patients with moderate hepatic impairment, the dose of olmesartan medoxomil should not exceed 20 mg.

In patients with impaired hepatic function, amlodipine should be initiated at the lower end of the dosing range and caution should be used, both on initial treatment and when increasing the dose.

Use of Sanoral HCT is contraindicated in patients with severe hepatic impairment, cholestasis or biliary obstruction.

Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy:

Due to the amlodipine component of Sanoral HCT, as with other vasodilators, special caution is indicated in patients suffering from aortic or mitral stenosis, or obstructive hypertrophic cardiomyopathy.

Primary aldosteronism:

Patients with primary aldosteronism generally will not respond to anti-hypertensive medicinal products acting through inhibition of the renin-angiotensin system. Therefore, the use of Sanoral HCT is not recommended in such patients.

Metabolic and endocrine effects:

Thiazide therapy may impair glucose tolerance. In diabetic patients dosage adjustments of insulin or oral hypoglycaemic agents may be required. Latent diabetes mellitus may become manifest during thiazide therapy.

Increases in cholesterol and triglyceride levels are undesirable effects known to be associated with thiazide diuretic therapy.

Hyperuricaemia may occur or frank gout may be precipitated in some patients receiving thiazide therapy.

Electrolyte imbalance:

As for any patient receiving diuretic therapy, periodic determination of serum electrolytes should be performed at appropriate intervals.

Thiazides, including hydrochlorothiazide, can cause fluid or electrolyte imbalance (including hypokalaemia, hyponatraemia and hypochloraemic alkalosis). Warning signs of fluid or electrolyte imbalance are dryness of the mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pain or cramps, muscle fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea or vomiting.

The risk of hypokalaemia is greatest in patients with cirrhosis of the liver, in patients experiencing brisk diuresis, in patients who are receiving inadequate oral intake of electrolytes and in patients receiving concomitant therapy with corticosteroids or ACTH.

Conversely, due to antagonism at the angiotensin-II receptors (AT1) through the olmesartan medoxomil component of Sanoral HCT hyperkalaemia may occur, especially in the presence of renal impairment and/or heart failure, and diabetes mellitus. Close monitoring of serum potassium in patients at risk is recommended. Potassium-sparing diuretics, potassium supplements or potassium-containing salt substitutes and other medicinal products that may increase serum potassium levels (e. g. heparin) should be co-administered cautiously with Sanoral HCT and with frequent monitoring of potassium levels.

There is no evidence that olmesartan medoxomil would reduce or prevent diuretic-induced hyponatraemia. Chloride deficit is generally mild and usually does not require treatment.

Thiazides may decrease urinary calcium excretion and cause an intermittent and slight elevation of serum calcium in the absence of known disorders of calcium metabolism.

Hypercalcaemia may be evidence of hidden hyperparathyroidism. Thiazides should be discontinued before carrying out tests for parathyroid function.

Thiazides have been shown to increase the urinary excretion of magnesium, which may result in hypomagnesaemia.

Dilutional hyponatraemia may occur in oedematous patients in hot weather.

Lithium:

As with other angiotensin II receptor antagonists, the coadministration of Sanoral HCT and lithium is not recommended.

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 angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor antagonists has been associated with oliguria and/or progressive azotaemia and (rarely) with acute renal failure and/or death.

Patients with heart failure should be treated with caution. In a long-term, placebo controlled study of amlodipine in patients with severe heart failure (NYHA III and IV), the reported incidence of pulmonary oedema was higher in the amlodipine group than in the placebo group. Calcium channel blockers, including amlodipine, should be used with caution in patients with congestive heart failure, as they may increase the risk of future cardiovascular events and mortality.

Sprue-like enteropathy:

In very rare cases severe, chronic diarrhoea with substantial weight loss has been reported in patients taking olmesartan few months to years after drug initiation, possibly caused by a localized delayed hypersensitivity reaction. Intestinal biopsies of patients often demonstrated villous atrophy. If a patient develops these symptoms during treatment with olmesartan, and in the absence of other apparent etiologies, olmesartan treatment should be immediately discontinued and should not be restarted. If diarrhoea does not improve during the week after the discontinuation, further specialist (e.g. a gastro-enterologist) advice should be considered.

Acute Myopia and Secondary Angle-Closure Glaucoma

Hydrochlorothiazide, a sulfonamide, can cause an idiosyncratic reaction, resulting in acute transient myopia and acute angle-closure glaucoma. Symptoms include acute onset of decreased visual acuity or ocular pain and typically occur within hours to weeks of drug initiation. Untreated acute angle-closure glaucoma can lead to permanent vision loss. The primary treatment is to discontinue hydrochlorothiazide as rapidly as possible. Prompt medical or surgical treatments may need to be considered if the intraocular pressure remains uncontrolled. Risk factors for developing acute angle-closure glaucoma may include a history of sulfonamide or penicillin allergy.

Pregnancy:

Angiotensin II receptor antagonists should not be initiated during pregnancy. Unless continued angiotensin II receptor antagonists therapy is considered essential, patients planning pregnancy should be changed to alternative anti-hypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with angiotensin II receptor antagonists should be stopped immediately, and, if appropriate, alternative therapy should be started.

Paediatric population:

Sanoral HCT is not indicated in children and adolescents under the age of 18 years.

Elderly:

In the elderly, increase of the dosage should take place with care.

Photosensitivity:

Cases of photosensitivity reactions have been reported with thiazide diuretics. If photosensitivity reaction occurs during treatment with Sanoral HCT, it is recommended to stop the treatment. If re-administration of the diuretic is deemed necessary, it is recommended to protect the areas exposed to the sun or to artificial UVA.

Other:

As with any antihypertensive agent, excessive blood pressure reduction in patients with ischaemic heart disease or ischaemic cerebrovascular disease could result in a myocardial infarction or stroke.

Hypersensitivity reactions to hydrochlorothiazide may occur in patients with or without a history of allergy or bronchial asthma, but are more likely in patients with such a history.

Exacerbation or activation of systemic lupus erythematosus has been reported with the use of thiazide diuretics.

As with all other angiotensin II receptor antagonists, the blood pressure lowering effect of olmesartan is somewhat less in black patients than in non-black patients, however, this effect was not seen in one of the three clinical trials with Sanoral HCT that included black patients (30 %), see also section 5.1.

Effects on ability to drive and use machines

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, headache, nausea or fatigue may occasionally occur in patients taking antihypertensive therapy and that these symptoms may impair the ability to react. Caution is recommended especially at the start of treatment.

Dosage (Posology) and method of administration

Posology

Adults

The recommended dose of Sanoral HCT is 1 tablet per day.

Add-on therapy

Sanoral HCT 20 mg/5 mg/12.5 mg may be administered in patients whose blood pressure is not adequately controlled on olmesartan medoxomil 20 mg and amlodipine 5 mg taken as dual-component combination.

Sanoral HCT 40 mg/5 mg/12.5 mg may be administered in patients whose blood pressure is not adequately controlled on olmesartan medoxomil 40 mg and amlodipine 5 mg taken as dual-component combination or in patients whose blood pressure is not adequately controlled on Sanoral HCT 20 mg/5 mg/12.5 mg.

Sanoral HCT 40 mg/5 mg/25 mg may be administered in patients whose blood pressure is not adequately controlled on Sanoral HCT 40 mg/5 mg/12.5 mg.

Sanoral HCT 40 mg/10 mg/12.5 mg may be administered in patients whose blood pressure is not adequately controlled on olmesartan medoxomil 40 mg and amlodipine 10 mg taken as dual-component combination or by Sanoral HCT 40 mg/5 mg/12.5 mg.

Sanoral HCT 40 mg/10 mg/25 mg may be administered in patients whose blood pressure is not adequately controlled on Sanoral HCT 40 mg/10 mg/12.5 mg or by Sanoral HCT 40 mg/5 mg/25 mg.

A step-wise titration of the dosage of the individual components is recommended before changing to the triple-component combination. When clinically appropriate, direct change from dual-component combination to the triple-component combination may be considered.

Substitution therapy

Patients controlled on stable doses of olmesartan medoxomil, amlodipine and hydrochlorothiazide taken at the same time as a dual-component (olmesartan medoxomil and amlodipine or olmesartan medoxomil and hydrochlorothiazide) and a single-component formulation (hydrochlorothiazide or amlodipine) may be switched to Sanoral HCT containing the same component doses.

The maximum recommended dose of Sanoral HCT is 40 mg/10 mg/25 mg per day.

Elderly (age 65 years or over)

Caution, including more frequent monitoring of blood pressure, is recommended in elderly people, particularly at the maximum dose of Sanoral HCT 40 mg/10 mg/25 mg per day.

An increase of the dosage should take place with care in elderly people.

Very limited data are available on the use of Sanoral HCT in patients aged 75 years or older. Extreme caution, including more frequent monitoring of blood pressure, is recommended.

Renal impairment

The maximum dose in patients with mild to moderate renal impairment (creatinine clearance of 30 - 60 mL/min) is Sanoral HCT 20 mg/5 mg/12.5 mg, owing to limited experience of the 40 mg olmesartan medoxomil dosage in this patient group.

Monitoring of serum concentrations of potassium and creatinine is advised in patients with moderate renal impairment.

The use of Sanoral HCT in patients with severe renal impairment (creatinine clearance < 30 mL/min) is contraindicated.

Hepatic impairment

Sanoral HCT should be used with caution in patients with mild hepatic impairment.

In patients with moderate hepatic impairment the maximum dose should not exceed Sanoral HCT 20 mg/5 mg/12.5 mg once daily. Close monitoring of blood pressure and renal function is advised in patients with hepatic impairment.

As with all calcium antagonists, amlodipine's half-life is prolonged in patients with impaired liver function and dosage recommendations have not been established. Sanoral HCT should therefore be administered with caution in these patients. The pharmacokinetics of amlodipine have not been studied in severe hepatic impairment. Amlodipine should be initiated at the lowest dose and titrated slowly in patients with impaired liver function.

Use of Sanoral HCT is contraindicated in patients with severe hepatic impairment , cholestasis or biliary obstruction.

Paediatric population

Sanoral HCT is not recommended for use in patients aged below 18 years due to a lack of data on safety and efficacy.

Method of administration:

The tablet should be swallowed with a sufficient amount of fluid (e. g. one glass of water). The tablet should not be chewed and should be taken at the same time each day.

Sanoral HCT can be taken with or without food.

Special precautions for disposal and other handling

No special requirements.