Omten

Behandlung von essentieller Hypertonie.

Behandlung von Bluthochdruck bei Kindern und Jugendlichen im Alter von 6 bis weniger als 18 Jahren.

Posologie

Erwachsene

Die empfohlene Anfangsdosis von Omten beträgt 10 mg einmal täglich. Bei Patienten, deren Blutdruck bei dieser Dosis nicht ausreichend kontrolliert wird, kann die Omten-Dosis als optimale Dosis einmal täglich auf 20 mg erhöht werden. Wenn eine zusätzliche Blutdrucksenkung erforderlich ist, kann die Omten-Dosis auf maximal 40 mg täglich erhöht oder eine Hydrochlorothiazid-Therapie hinzugefügt werden.

Die blutdrucksenkende Wirkung von Omten ist innerhalb von 2 Wochen nach Beginn der Therapie im Wesentlichen vorhanden und maximal etwa 8 Wochen nach Beginn der Therapie. Dies sollte berücksichtigt werden, wenn über eine Änderung des Dosierungsschemas für einen Patienten nachgedacht wird.

Ältere (65 Jahre oder älter)

Bei älteren Menschen ist im Allgemeinen keine Dosisanpassung erforderlich (Dosisempfehlungen bei Patienten mit eingeschränkter Nierenfunktion finden Sie weiter unten). Wenn eine Aufwärtsbetitelung auf die maximale Dosis von 40 mg täglich erforderlich ist, sollte der Blutdruck engmaschig überwacht werden.

Nierenfunktionsstörung

Die maximale Dosis bei Patienten mit leichter bis mittelschwerer Nierenfunktionsstörung (Kreatinin-Clearance von 20 - 60 ml / min) beträgt 20 mg Omten einmal täglich, da in dieser Patientengruppe nur begrenzte Erfahrungen mit höheren Dosierungen vorliegen. Die Anwendung von Omten bei Patienten mit schwerer Nierenfunktionsstörung (Kreatinin-Clearance <20 ml / min) wird nicht empfohlen, da in dieser Patientengruppe nur begrenzte Erfahrungen vorliegen.

Leberfunktionsstörung

Bei Patienten mit leichter Leberfunktionsstörung ist keine Anpassung der Dosierungsempfehlungen erforderlich. Bei Patienten mit mittelschwerer Leberfunktionsstörung wird eine Anfangsdosis von 10 mg Omten einmal täglich empfohlen, und die Höchstdosis sollte 20 mg einmal täglich nicht überschreiten. Bei hepatisch beeinträchtigten Patienten, die bereits Diuretika und / oder andere blutdrucksenkende Mittel erhalten, wird eine genaue Überwachung des Blutdrucks und der Nierenfunktion empfohlen. Es liegen keine Erfahrungen mit Omten bei Patienten mit schwerer Leberfunktionsstörung vor, daher wird die Anwendung in dieser Patientengruppe nicht empfohlen. Omten sollte nicht bei Patienten mit Gallenobstruktion angewendet werden.

Pädiatrische Bevölkerung

Kinder und Jugendliche von 6 bis weniger als 18 Jahren

Die empfohlene Anfangsdosis von Omten bei Kindern im Alter von 6 bis weniger als 18 Jahren beträgt 10 mg Omten einmal täglich. Bei Kindern, deren Blutdruck bei dieser Dosis nicht ausreichend kontrolliert wird, kann die Omten-Dosis einmal täglich auf 20 mg erhöht werden. Wenn eine zusätzliche Blutdrucksenkung erforderlich ist, kann bei Kindern mit einem Gewicht von> 35 kg die Omten-Dosis auf maximal 40 mg erhöht werden. Bei Kindern mit einem Gewicht von <35 kg sollte die Tagesdosis 20 mg nicht überschreiten.

Andere pädiatrische Bevölkerung

Die Sicherheit und Wirksamkeit von Omten bei Kindern im Alter von 1 bis 5 Jahren wurde noch nicht nachgewiesen.1 und 5.2, es kann jedoch keine Empfehlung zu einer Posologie abgegeben werden.

Omten sollte aufgrund von Sicherheitsbedenken und Datenmangel in dieser Altersgruppe nicht bei Kindern unter 1 Jahr angewendet werden.

Art der Verabreichung:

Um die Einhaltung zu unterstützen, wird empfohlen, Omten jeden Tag ungefähr zur gleichen Zeit mit oder ohne Nahrung einzunehmen, beispielsweise zum Frühstück. Die Tablette sollte mit einer ausreichenden Menge an Flüssigkeit geschluckt werden (z. ein Glas Wasser). Die Tablette sollte nicht gekaut werden.

Zweites und drittes Schwangerschaftstrimester.

Gallenstauung.

Die gleichzeitige Anwendung von Omten mit Aliskiren-haltigen Produkten ist bei Patienten mit Diabetes mellitus oder Nierenfunktionsstörung (GFR <60 ml / min / 1,73 m) kontraindiziert²).

Intravascular volume depletion:

Symptomatic hypotension, especially after the first dose, may occur in patients who are volume and/or sodium depleted by vigorous diuretic therapy, dietary salt restriction, diarrhoea or vomiting. Such conditions should be corrected before the administration of Omten.

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-angiotensinaldosterone system (e.g. patients with severe congestive heart failure or underlying renal disease, including renal artery stenosis), treatment with other drugs that affect this system has been associated with acute hypotension, azotaemia, oliguria or, rarely, acute renal failure. The possibility of similar effects cannot be excluded with angiotensin II receptor antagonists.

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-angiotensinaldosterone system.

Renal impairment and kidney transplantation:

When Omten is used in patients with impaired renal function, periodic monitoring of serum potassium and creatinine levels is recommended. Use of Omten is not recommended in patients with severe renal impairment (creatinine clearance < 20 mL/min). There is no experience of the administration of Omten in patients with a recent kidney transplant or in patients with end-stage renal impairment (ie creatinine clearance <12 mL/min).

Hepatic impairment:

Hyperkalaemia

The use of medicinal products that affect the renin-angiotensin-aldosterone system may cause hyperkalaemia.

The risk, that may be fatal, is increased in older people, in patients with renal insufficiency and in diabetic patients, in patients concomitantly treated with other medicinal products that may increase potassium levels, and/or in patients with intercurrent events.

Before considering the concomitant use of medicinal products that affect the rennin angiotensin - aldosterone system, the benefit risk ratio should be evaluated and other alternatives considered. (see also below section “Dual blockade of the reninangiotensin-aldosterone system (RAAS)”).

The main risk factors for hyperkalaemia to be considered are:

- Diabetes, renal impairment, age (> 70 years)

- Combination with one or more other medicinal products that affect the renin-angiotensin- aldosterone system and/or potassium supplements. Some medicinal products or therapeutic class of medicinal products may provoke a hyperkalaemia: salt substitutes containing potassium, potassium-sparing diuretics, ACE inhibitors, angiotensin II receptors antagonists, non steroidal anti-inflammatory drugs (including selective COX-2 inhibitors), heparin, immunosuppressor as ciclosporin or tacrolimus, trimethoprim.

- Intercurrent events, in particular dehydration, acute cardiac decompensation, metabolic acidosis, worsening of renal function, sudden worsening of the renal condition (e.g. infectious diseases), cellular lysis (e.g, acute limb ischemia, rhabdomyolysis, extended trauma).

Close-monitoring of serum potassium in at risk patients is recommended.

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.

Lithium:

As with other angiotensin-II receptor antagonists, the combination of lithium and Omten is not recommended.

Aortic or mitral valve stenosis; obstructive hypertrophic cardiomyopathy:

As with 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 drugs acting through inhibition of the renin-angiotensin system. Therefore, the use of Omten is not recommended in such patients.

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.

Ethnic differences:

As with all other angiotensin II antagonists, the blood pressure lowering effect of Omten is 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 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 antagonists should be stopped immediately and, if appropriate, alternative therapy should be started.

Other:

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

This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp-lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

Omten has minor or moderate influence on the ability to drive and use machines. Dizziness or fatigue may occasionally occur in patients taking antihypertensive therapy, which may impair the ability to react.

Summary of the safety profile:

The most commonly reported adverse reactions during treatment with Omten Tablets are headache (7.7%), influenza-like symptoms (4.0%) and dizziness (3.7%).

In placebo-controlled monotherapy studies, the only adverse drug reaction that was unequivocally related to treatment was dizziness (2.5% incidence on Omten and 0.9% on placebo).

The incidence was also somewhat higher on Omten compared with placebo for hypertriglyceridaemia (2.0% versus 1.1%) and for raised creatine phosphokinase (1.3% versus 0.7%).

Tabulated list of adverse reactions:

Adverse reactions from Omten in clinical trials, post-authorisation safety studies and spontaneous reporting are summarized in the below table.

The following terminologies have been used in order to classify the occurrence of adverse reactionsvery common (>1/10); common (>1/100, <1/10); uncommon (>1/1,000, <1/100); rare (>1/10,000, <1/1,000); very rare (<1/10,000).

Single cases of rhabdomyolysis have been reported in temporal association with the intake of angiotensin II receptor blockers.

Additional information on special populations

Paediatric population

The safety of olmesartan was monitored in 361 children and adolescents, aged 1-17 years old during 2 clinical trials. Whilst the nature and severity of the adverse events are similar to that of the adults, the frequency of the following is higher in the children:

- Epistaxis is a common adverse event in children (i.e. > 1/100 to < 1/10) that has not been reported in adults.

- During the 3 weeks of double blind study, the incidence of treatment emergent dizziness and headache nearly doubled in children 6-17 years of age in the high olmesartan dose group.

The overall safety profile for olmesartan in paediatric patients does not differ significantly from the safety profile in adults.

Elderly (age 65 years or over)

In elderly people the frequency of hypotension is slightly increased from rare to uncommon.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.

Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard

Über Überdosierung beim Menschen liegen nur begrenzte Informationen vor. Der wahrscheinlichste Effekt einer Überdosierung ist die Hypotonie. Im Falle einer Überdosierung sollte der Patient sorgfältig überwacht werden und die Behandlung sollte symptomatisch und unterstützend sein.

Über die Dialysierbarkeit von Olmesartan liegen keine Informationen vor.

Pharmacotherapeutic group: Angiotensin II antagonists, ATC code: C09CA08

Mechanism of action / Pharmacodynamic effects

Omten is a potent, orally active, selective angiotensin II receptor (type AT₁) antagonist. It is expected to block all actions of angiotensin II mediated by the AT₁ receptor, regardless of the source or route of synthesis of angiotensin II. The selective antagonism of the angiotensin II (AT₁) receptors results in increases in plasma renin levels and angiotensin I and II concentrations, and some decrease in plasma aldosterone concentrations.

Angiotensin II is the primary vasoactive hormone of the renin-angiotensin-aldosterone system and plays a significant role in the pathophysiology of hypertension via the type 1 (AT₁) receptor.

Clinical efficacy and safety

In hypertension, Omten 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 cessation of therapy.

Once daily dosing with Omten 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. When used together with hydrochlorothiazide, the reduction in blood pressure is additive and co administration is well tolerated.

The effect of Olmesartan 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, allcause 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.

Paediatric population

The antihypertensive effects of Omten in the paediatric population were evaluated in a randomized, double-blind, placebo-controlled study in 302 hypertensive patients aged 6 to 17 years. The study population consisted of an all black cohort of 112 patients and a mixed racial cohort of 190 patients, including 38 blacks. The aetiology of the hypertension was predominantly essential hypertension (87% of the black cohort and 67% of the mixed cohort). Patients who weighed 20 to <35 kg were randomized to 2.5 mg (low dose) or 20 mg (high dose) of Omten once daily and patients who weighed >35 kg were randomized to 5 mg (low dose) or 40 mg (high dose)of Omten once daily. Omten significantly reduced both systolic and diastolic blood pressure in a weight-adjusted dose-dependent manner. Omten at both low and high doses significantly reduced systolic blood pressure by 6.6 and 11.9 mmHg from the baseline, respectively. This effect was also observed during the 2 weeks randomized withdrawal phase, whereby both mean systolic and diastolic blood pressures demonstrated a statistically significant rebound in the placebo group compared to olmesartan group. The treatment was effective in both, paediatric patients with primary and secondary hypertension. As observed in adult populations, the blood pressure reductions were smaller in black patients.

In the same study, 59 patients aged 1 to 5 years who weighed >5 kg received 0.3 mg/kg of Omten once daily for three weeks in an open label phase and then were randomized to receiving Omten or placebo in a double-blind phase. At the end of the second week of withdrawal, the mean systolic/diastolic blood pressure at trough was 3/3 mmHg lower in the group randomized to Omten; this difference in blood pressure was not statistically significant (95% C.I. -2 to 7/-1 to 7).

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.

Absorption and distribution

Omten 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 Omten 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 hours after oral dosing with Omten, 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 Omten 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 coadministered drugs is low (as confirmed by the lack of a clinically significant interaction between Omten and warfarin). The binding of olmesartan to blood cells is negligible. The mean volume of distribution after intravenous dosing is low (16 - 29L).

Biotransformation and elimination

Total plasma clearance 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 Omten, 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 the first few doses 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.

Pharmacokinetics in special populations

Paediatric population:

The pharmacokinetics of olmesartan was studied in paediatric hypertensive patients aged 1 to 16 years. The clearance of olmesartan in paediatric patients was similar to that in adult patients when adjusted by the body weight.

There is no pharmacokinetic information available in renally impaired paediatric subjects.

Elderly (age 65 years or older):

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

Renal impairment:

In renally impaired patients, the AUC at steady state increased by 62%, 82% and 179% in patients with mild, moderate and severe renal impairment, respectively, compared to healthy controls.

Hepatic impairment:

After single oral administration, olmesartan AUC values were 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 was 0.26%, 0.34% and 0.41%, respectively. Following repeated dosing in patients with moderate hepatic impairment, olmesartan mean AUC was again about 65% higher than in matched healthy controls. olmesartan mean C_max values were similar in hepatically-impaired and healthy subjects. Omten has not been evaluated in patients with severe hepatic impairment.

Drug interactions

Bile acid sequestering agent colesevelam:

Concomitant administration of 40 mg Omten 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 Omten 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.

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Keine besonderen Anforderungen für die Entsorgung.

Nicht verwendetes Arzneimittel oder Abfallmaterial sollte gemäß den örtlichen Anforderungen entsorgt werden.