Olmesartan: Fachinformation – Dosierung, Gegenanzeigen, Wechselwirkungen, Nebenwirkungen

Für Fachkreise

Anwendungsgebiete

Olmesartanmedoxomil-Tabletten sind indiziert zur Behandlung der Hypertonie bei Erwachsenen und Kindern ab sechs Jahren, um den Blutdruck zu senken. Die Senkung des Blutdrucks verringert das Risiko tödlicher und nicht tödlicher kardiovaskulärer Ereignisse, vor allem Schlaganfälle und Myokardinfarkte. Dieser Nutzen wurde in kontrollierten Studien mit Antihypertensiva aus einer Vielzahl pharmakologischer Klassen beobachtet, einschließlich der Klasse, zu der dieses Arzneimittel hauptsächlich gehört. Es liegen keine kontrollierten Studien vor, die eine Risikoreduktion mit Olmesartanmedoxomil-Tabletten belegen.

Die Behandlung des Bluthochdrucks sollte Teil eines umfassenden kardiovaskulären Risikomanagements sein, das gegebenenfalls Lipidkontrolle, Diabetesbehandlung, antithrombotische Therapie, Raucherentwöhnung, körperliche Aktivität und eine eingeschränkte Natriumaufnahme umfasst. Viele Patienten benötigen mehr als ein Arzneimittel, um die Blutdruckziele zu erreichen. Für spezifische Empfehlungen zu Zielen und Behandlung siehe veröffentlichte Leitlinien, etwa die des Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC) des National High Blood Pressure Education Program.

Für zahlreiche Antihypertensiva aus verschiedenen pharmakologischen Klassen und mit unterschiedlichen Wirkmechanismen wurde in randomisierten kontrollierten Studien eine Senkung der kardiovaskulären Morbidität und Mortalität nachgewiesen, und es kann geschlossen werden, dass im Wesentlichen die Blutdrucksenkung und nicht eine andere pharmakologische Eigenschaft der Arzneimittel für diesen Nutzen verantwortlich ist. Der größte und konsistenteste Nutzen in Bezug auf kardiovaskuläre Endpunkte war eine Verringerung des Schlaganfallrisikos, aber auch Verringerungen von Myokardinfarkten und kardiovaskulärer Mortalität wurden regelmäßig beobachtet.

Ein erhöhter systolischer oder diastolischer Blutdruck führt zu einem erhöhten kardiovaskulären Risiko, und der absolute Risikoanstieg pro mmHg ist bei höheren Blutdruckwerten größer, sodass selbst moderate Senkungen einer schweren Hypertonie einen erheblichen Nutzen bringen können. Die relative Risikoreduktion durch Blutdrucksenkung ist in Populationen mit unterschiedlichem absolutem Risiko ähnlich, sodass der absolute Nutzen bei Patienten mit einem unabhängig von ihrer Hypertonie höheren Risiko (zum Beispiel Patienten mit Diabetes oder Hyperlipidämie) größer ist und bei solchen Patienten ein Nutzen durch eine aggressivere Behandlung bis zu einem niedrigeren Blutdruckziel zu erwarten ist.

Einige Antihypertensiva haben bei schwarzen Patienten geringere Blutdruckwirkungen (als Monotherapie), und viele Antihypertensiva haben zusätzliche zugelassene Indikationen und Wirkungen (z. B. bei Angina pectoris, Herzinsuffizienz oder diabetischer Nephropathie). Diese Überlegungen können bei der Therapieauswahl hilfreich sein.

Olmesartanmedoxomil kann allein oder in Kombination mit anderen Antihypertensiva angewendet werden.

Englisches Original anzeigen

Olmesartan medoxomil tablets are indicated for the treatment of hypertension in adults and children six years of age and older, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes including the class to which this drug principally belongs. There are no controlled trials demonstrating risk reduction with olmesartan medoxomil tablets.

Control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake. Many patients will require more than one drug to achieve blood pressure goals. For specific advice on goals and management, see published guidelines, such as those of the National High Blood Pressure Education Program's Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC).

Numerous antihypertensive drugs, from a variety of pharmacologic classes and with different mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other pharmacologic property of the drugs, that is largely responsible for those benefits. The largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular mortality also have been seen regularly.

Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per mmHg is greater at higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit. Relative risk reduction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit is greater in patients who are at higher risk independent of their hypertension (for example, patients with diabetes or hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to a lower blood pressure goal.

Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and many antihypertensive drugs have additional approved indications and effects (e.g., on angina, heart failure, or diabetic kidney disease). These considerations may guide selection of therapy.

It may be used alone or in combination with other antihypertensive agents.

Dosierung und Art der Anwendung

2.1 Hypertonie bei Erwachsenen

Die Dosierung muss individuell angepasst werden. Die übliche empfohlene Anfangsdosis von Olmesartanmedoxomil-Tabletten beträgt 20 mg einmal täglich bei Anwendung als Monotherapie bei Patienten ohne Volumenmangel. Bei Patienten, die nach 2 Wochen Therapie eine weitere Blutdrucksenkung benötigen, kann die Dosis von Olmesartanmedoxomil-Tabletten auf 40 mg erhöht werden. Dosen über 40 mg scheinen keine stärkere Wirkung zu haben. Eine zweimal tägliche Gabe bietet gegenüber der gleichen Gesamtdosis einmal täglich keinen Vorteil.

Bei Patienten mit möglichem intravasalem Volumenmangel (z. B. mit Diuretika behandelte Patienten, insbesondere solche mit eingeschränkter Nierenfunktion) die Behandlung mit Olmesartanmedoxomil-Tabletten unter engmaschiger ärztlicher Überwachung beginnen und die Anwendung einer niedrigeren Anfangsdosis in Erwägung ziehen [siehe Warnhinweise und Vorsichtsmaßnahmen (5.3)].

2.2 Hypertonie bei Kindern und Jugendlichen (ab 6 Jahren)

Die Dosierung muss individuell angepasst werden. Für Kinder, die Tabletten schlucken können, beträgt die übliche empfohlene Anfangsdosis von Olmesartanmedoxomil-Tabletten 10 mg einmal täglich bei Patienten mit einem Körpergewicht von 20 bis <35 kg (44 bis 77 lb) bzw. 20 mg einmal täglich bei Patienten mit einem Körpergewicht von ≥35 kg. Bei Patienten, die nach 2 Wochen Therapie eine weitere Blutdrucksenkung benötigen, kann die Dosis von Olmesartanmedoxomil-Tabletten bei Patienten mit einem Körpergewicht von <35 kg auf maximal 20 mg einmal täglich bzw. bei Patienten mit einem Körpergewicht von ≥35 kg auf maximal 40 mg einmal täglich erhöht werden.

Die Anwendung von Olmesartanmedoxomil-Tabletten bei Kindern <1 Jahr wird nicht empfohlen [siehe Warnhinweise und Vorsichtsmaßnahmen (5.2) und Anwendung bei besonderen Patientengruppen (8.4)].

Für Kinder, die keine Tabletten schlucken können, kann dieselbe Dosis mithilfe einer wie unten beschriebenen ex tempore hergestellten Suspension gegeben werden [siehe Klinische Pharmakologie (12.3)].

Zur Anwendung von Olmesartanmedoxomil-Tabletten als Suspension die nachstehende Anleitung zur Herstellung der Suspension befolgen.

Herstellung der Suspension (für 200 ml einer Suspension mit 2 mg/ml)

50 ml gereinigtes Wasser in eine braune Flasche aus Polyethylenterephthalat (PET) geben, die zwanzig Olmesartanmedoxomil-Tabletten zu 20 mg enthält, und mindestens 5 Minuten stehen lassen. Den Behälter mindestens 1 Minute lang schütteln und die Suspension mindestens 1 Minute lang stehen lassen. Das 1-minütige Schütteln und 1-minütige Stehenlassen noch viermal wiederholen. 100 ml ORA-Sweet ® und 50 ml ORA-Plus ® (ORA-Sweet ® und ORA-Plus ® sind eingetragene Marken von Paddock Laboratories, Inc.) zur Suspension hinzufügen und mindestens 1 Minute lang gut schütteln. Die Suspension sollte bei 2-8 °C (36-46 °F) im Kühlschrank aufbewahrt werden und kann bis zu 4 Wochen gelagert werden. Die Suspension vor jeder Anwendung gut schütteln und umgehend wieder in den Kühlschrank stellen.

Englisches Original anzeigen

2.1 Adult Hypertension

Dosage must be individualized. The usual recommended starting dose of olmesartan medoxomil tablets is 20 mg once daily when used as monotherapy in patients who are not volume-contracted. For patients requiring further reduction in blood pressure after 2 weeks of therapy, the dose of olmesartan medoxomil tablets may be increased to 40 mg. Doses above 40 mg do not appear to have greater effect. Twice-daily dosing offers no advantage over the same total dose given once daily.

For patients with possible depletion of intravascular volume (e.g., patients treated with diuretics, particularly those with impaired renal function), initiate olmesartan medoxomil tablets under close medical supervision and give consideration to use of a lower starting dose [see Warnings and Precautions (5.3)] .

2.2 Pediatric Hypertension (6 Years of Age and Older)

Dosage must be individualized. For children who can swallow tablets, the usual recommended starting dose of olmesartan medoxomil tablets is 10 mg once daily for patients who weigh 20 to <35 kg (44 to 77 lb), or 20 mg once daily for patients who weigh ≥35 kg. For patients requiring further reduction in blood pressure after 2 weeks of therapy, the dose of olmesartan medoxomil tablets may be increased to a maximum of 20 mg once daily for patients who weigh <35 kg or 40 mg once daily for patients who weigh ≥35 kg.

Use of olmesartan medoxomil tablets in children <1 year of age is not recommended [see Warnings and Precautions (5.2)and Use in Specific Populations (8.4)] .

For children who cannot swallow tablets, the same dose can be given using an extemporaneous suspension as described below [see Clinical Pharmacology (12.3)] .

Follow the suspension preparation instructions below to administer olmesartan medoxomil tablets as a suspension.

Preparation of Suspension (for 200 mL of a 2 mg/mL suspension)

Add 50 mL of Purified Water to an amber polyethylene terephthalate (PET) bottle containing twenty olmesartan medoxomil tablets 20 mg tablets and allow to stand for a minimum of 5 minutes. Shake the container for at least 1 minute and allow the suspension to stand for at least 1 minute. Repeat 1-minute shaking and 1-minute standing for four additional times. Add 100 mL of ORA-Sweet ®and 50 mL of ORA-Plus ® ORA-Sweet ® and ORA-Plus ® are registered trademarks of Paddock Laboratories, Inc. to the suspension and shake well for at least 1 minute. The suspension should be refrigerated at 2-8°C (36-46°F) and can be stored for up to 4 weeks. Shake the suspension well before each use and return promptly to the refrigerator.

Darreichungsformen und Stärken

5 mg white or almost white round film-coated tablets, debossed “L20” on one side while blank on the other side.
20 mg white or almost white round film-coated tablets, debossed “L18” on one side while blank on the other side.
40 mg white or almost white round film-coated tablets, debossed “L17” on one side while blank on the other side.

Gegenanzeigen

Aliskiren darf bei Patienten mit Diabetes nicht gleichzeitig mit Olmesartanmedoxomil-Tabletten angewendet werden [siehe Wechselwirkungen (7.3)].

Englisches Original anzeigen

Do not co-administer aliskiren with olmesartan medoxomil tablets in patients with diabetes [see Drug Interactions (7.3)].

Nebenwirkungen

6.1 Clinical Trials Experience

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.

Adult Hypertension

Olmesartan medoxomil has been evaluated for safety in more than 3825 patients/subjects, including more than 3275 patients treated for hypertension in controlled trials. This experience included about 900 patients treated for at least 6 months and more than 525 for at least 1 year. Events generally were mild, transient and had no relationship to the dose of olmesartan medoxomil.

Analysis of gender, age and race groups demonstrated no differences between olmesartan medoxomil and placebo-treated patients. The rate of withdrawals due to adverse reactions in all trials of hypertensive patients was 2.4% (i.e., 79/3278) of patients treated with olmesartan medoxomil and 2.7% (i.e., 32/1179) of control patients. In placebo-controlled trials, the only adverse reaction that occurred in more than 1% of patients treated with olmesartan medoxomil and at a higher incidence versus placebo was dizziness (3% vs. 1%).

Facial edema was reported in five patients receiving olmesartan medoxomil. Angioedema has been reported with angiotensin II antagonists.

Pediatric Hypertension

No relevant differences were identified between the adverse experience profile for pediatric patients aged 1 to 16 years and that previously reported for adult patients.

6.2 Post-Marketing Experience

The following adverse reactions have been reported in post-marketing experience. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Body as a Whole:Asthenia, angioedema, anaphylactic reactions

Gastrointestinal:Vomiting, sprue-like enteropathy [see Warnings and Precautions (5.5)]

Metabolic and Nutritional Disorders:Hyperkalemia

Musculoskeletal:Rhabdomyolysis

Urogenital System:Acute renal failure, increased blood creatinine levels

Skin and Appendages:Alopecia, pruritus, urticaria

Data from one controlled trial and an epidemiologic study have suggested that high-dose olmesartan may increase cardiovascular (CV) risk in diabetic patients, but the overall data are not conclusive. The randomized, placebo-controlled, double-blind ROADMAP trial (Randomized Olmesartan And Diabetes MicroAlbuminuria Prevention trial, n=4447) examined the use of olmesartan, 40 mg daily, vs. placebo in patients with type 2 diabetes mellitus, normoalbuminuria, and at least one additional risk factor for CV disease. The trial met its primary endpoint, delayed onset of microalbuminuria, but olmesartan had no beneficial effect on decline in glomerular filtration rate (GFR). There was a finding of increased CV mortality (adjudicated sudden cardiac death, fatal myocardial infarction, fatal stroke, revascularization death) in the olmesartan group compared to the placebo group (15 olmesartan vs. 3 placebo, HR 4.9, 95% confidence interval [CI], 1.4, 17), but the risk of non-fatal myocardial infarction was lower with olmesartan (HR 0.64, 95% CI 0.35, 1.18).

The epidemiologic study included patients 65 years and older with overall exposure of > 300,000 patient-years. In the sub-group of diabetic patients receiving high-dose olmesartan (40 mg/d) for > 6 months, there appeared to be an increased risk of death (HR 2.0, 95% CI 1.1, 3.8) compared to similar patients taking other angiotensin receptor blockers. In contrast, high-dose olmesartan use in non-diabetic patients appeared to be associated with a decreased risk of death (HR 0.46, 95% CI 0.24, 0.86) compared to similar patients taking other angiotensin receptor blockers. No differences were observed between the groups receiving lower doses of olmesartan compared to other angiotensin blockers or those receiving therapy for < 6 months.

Overall, these data raise a concern of a possible increased CV risk associated with the use of high-dose olmesartan in diabetic patients. There are, however, concerns with the credibility of the finding of increased CV risk, notably the observation in the large epidemiologic study for a survival benefit in non-diabetics of a magnitude similar to the adverse finding in diabetics.

Warnhinweise und Vorsichtsmaßnahmen

5.1 Fetal Toxicity

Olmesartan medoxomil tablets can cause fetal harm when administered to a pregnant woman. Use of drugs that act on the renin-angiotensin system (RAS) during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue olmesartan medoxomil as soon as possible [see Use in Specific Populations (8.1)].

5.2 Morbidity in Infants

Use of olmesartan medoxomil tablets in children <1 year of age is not recommended. Drugs that act directly on the renin-angiotensin-aldosterone system (RAAS) can have effects on the development of immature kidneys [see Use in Specific Populations (8.4)].

5.3 Hypotension in Volume- or Salt-Depleted Patients

In patients with an activated renin-angiotensin-aldosterone system, such as volume- and/or salt-depleted patients (e.g., those being treated with high doses of diuretics), symptomatic hypotension may be anticipated after initiation of treatment with olmesartan medoxomil. Initiate treatment under close medical supervision and consider starting at a lower dose. If hypotension does occur, place the patient in the supine position and, if necessary, give an intravenous infusion of normal saline [see Dosage and Administration (2.1)] . A transient hypotensive response is not a contraindication to further treatment, which usually can be continued without difficulty once the blood pressure has stabilized.

5.4 Impaired Renal Function

As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in susceptible individuals treated with olmesartan medoxomil. In patients whose renal function may depend upon the activity of the renin-angiotensin-aldosterone system (e.g., patients with severe congestive heart failure), treatment with angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor antagonists has been associated with oliguria and/or progressive azotemia and rarely with acute renal failure and/or death. Similar results may be anticipated in patients treated with olmesartan medoxomil [see Dosage and Administration (2.1), Drug Interactions (7.3), Use in Specific Populations (8.7)and Clinical Pharmacology (12.3)] .

In studies of ACE inhibitors in patients with unilateral or bilateral renal artery stenosis, increases in serum creatinine or blood urea nitrogen (BUN) have been reported. There has been no long-term use of olmesartan medoxomil in patients with unilateral or bilateral renal artery stenosis, but similar results may be expected.

5.5 Sprue-like Enteropathy

Severe, chronic diarrhea with substantial weight loss has been reported in patients taking olmesartan months to years after drug initiation. Intestinal biopsies of patients often demonstrated villous atrophy. If a patient develops these symptoms during treatment with olmesartan, exclude other etiologies. Consider alternative antihypertensive therapy in cases where no other etiology is identified.

5.6 Hyperkalemia

Serum potassium should be monitored in patients receiving olmesartan medoxomil tablets. Drugs that inhibit the renin angiotensin system can cause hyperkalemia. Risk factors for the development of hyperkalemia include renal insufficiency, diabetes mellitus, and the concomitant use of potassium-sparing diuretics, potassium supplements and/or potassium-containing salt substitutes [see Drug Interactions (7.3)] .

Wechselwirkungen

7.1 Agents Increasing Serum Potassium

Concomitant use of olmesartan with other agents that block the renin-angiotensin system, potassium-sparing diuretics (e.g., spironolactone, triamterene, amiloride), potassium supplements, salt substitutes containing potassium or other drugs that may increase potassium levels (e.g., heparin) may lead to increases in serum potassium. If co-medication is considered necessary, monitoring of serum potassium is advisable.

7.2 Non-Steroidal Anti-Inflammatory Agents Including Selective Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors)

In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, co-administration of NSAIDs, including selective COX-2 inhibitors, with angiotensin II receptor antagonists, including olmesartan medoxomil, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving olmesartan medoxomil and NSAID therapy.

The antihypertensive effect of angiotensin II receptor antagonists, including olmesartan medoxomil, may be attenuated by NSAIDs including selective COX-2 inhibitors.

7.3 Dual Blockade of the Renin-Angiotensin System (RAS)

Dual blockade of the RAS with angiotensin receptor blockers, ACE inhibitors, or aliskiren is associated with increased risks of hypotension, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy. Most patients receiving the combination of two RAS inhibitors do not obtain any additional benefit compared to monotherapy. In general, avoid combined use of RAS inhibitors. Closely monitor blood pressure, renal function and electrolytes in patients on olmesartan medoxomil and other agents that affect the RAS.

Do not co-administer aliskiren with olmesartan medoxomil in patients with diabetes [see Contraindications (4)]. Avoid use of aliskiren with olmesartan medoxomil in patients with renal impairment (GFR <60 ml/min).

7.4 Lithium

Increases in serum lithium concentrations and lithium toxicity have been reported during concomitant administration of lithium with angiotensin II receptor antagonists, including olmesartan medoxomil tablets. Monitor serum lithium levels during concomitant use.

7.5 Colesevelam Hydrochloride

Concurrent administration of bile acid sequestering agent colesevelam hydrochloride reduces the systemic exposure and peak plasma concentration of olmesartan. Administration of olmesartan at least 4 hours prior to colesevelam hydrochloride decreased the drug interaction effect. Consider administering olmesartan at least 4 hours before the colesevelam hydrochloride dose [see Clinical Pharmacology (12.3)] .

Schwangerschaft, Stillzeit, Kinder, ältere Menschen

8.1 Pregnancy

Risk Summary

Olmesartan medoxomil tablets can cause fetal harm when administered to a pregnant woman. Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents. In animal reproduction studies, olmesartan medoxomil tablets treatment during organogenesis resulted in increased embryofetal toxicity in rats at doses lower than maternally toxic doses.

When pregnancy is detected, discontinue olmesartan medoxomil tablets as soon as possible. Consider alternative antihypertensive therapy during pregnancy.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%–4% and 15%–20%, respectively.

Clinical Considerations

Disease-Associated Maternal and/or Embryo/Fetal Risk

Hypertension in pregnancy increases the maternal risk for pre-eclampsia, gestational diabetes, premature delivery, and delivery complications (e.g., need for cesarean section and post-partum hemorrhage). Hypertension increases the fetal risk for intrauterine growth restriction and intrauterine death. Pregnant women with hypertension should be carefully monitored and managed accordingly.

Fetal/Neonatal Adverse Reactions

Oligohydramnios in pregnant women who use drugs affecting the renin-angiotensin system in the second and third trimesters of pregnancy can result in the following: reduced fetal renal function leading to anuria and renal failure, fetal lung hypoplasia, skeletal deformations, including skull hypoplasia, hypotension and death.

In patients taking olmesartan medoxomil tablets during pregnancy, perform serial ultrasound examinations to assess the intra-amniotic environment. Fetal testing may be appropriate, based on the week of gestation. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury.

Closely observe infants with histories of in uteroexposure to olmesartan medoxomil tablets for hypotension, oliguria, and hyperkalemia. In neonates with a history of in uteroexposure to olmesartan medoxomil tablets, if oliguria or hypotension occurs, utilize measures to maintain adequate blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as a means of reversing hypotension and supporting renal function.

Data

Animal Data

No teratogenic effects were observed when olmesartan medoxomil was administered to pregnant rats at oral doses up to 1000 mg/kg/day (240 times the maximum recommended human dose (MRHD) on a mg/m² basis) or pregnant rabbits at oral doses up to 1 mg/kg/day (half the MRHD on a mg/m² basis; higher doses could not be evaluated for effects on fetal development as they were lethal to the does). In rats, significant decreases in pup birth weight and weight gain were observed at doses ≥1.6 mg/kg/day, and delays in developmental milestones (delayed separation of ear auricula, eruption of lower incisors, appearance of abdominal hair, descent of testes, and separation of eyelids) and dose-dependent increases in the incidence of dilation of the renal pelvis were observed at doses ≥ 8 mg/kg/day. The no observed effect dose for developmental toxicity in rats is 0.3 mg/kg/day, about one-tenth the MRHD of 40 mg/day.

8.2 Lactation

Risk Summary

There is no information regarding the presence of olmesartan in human milk, the effects on the breastfed infant, or the effects on milk production. Olmesartan is secreted at low concentration in the milk of lactating rats (see Data) . Because of the potential for adverse effects on the nursing infant, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Data

Presence of olmesartan in milk was observed after a single oral administration of 5 mg/kg [¹⁴ C] olmesartan medoxomil to lactating rats.

8.4 Pediatric Use

The antihypertensive effects of olmesartan medoxomil were evaluated in one randomized, double-blind clinical study in pediatric patients 1 to 16 years of age [see Clinical Studies (14.2)] . The pharmacokinetics of olmesartan medoxomil were evaluated in pediatric patients 1 to 16 years of age [see Clinical Pharmacology (12.3)] . Olmesartan medoxomil was generally well tolerated in pediatric patients, and the adverse experience profile was similar to that described for adults.

Olmesartan medoxomil has not been shown to be effective for hypertension in children <6 years of age.

Use of olmesartan medoxomil tablets in children <1 year of age is not recommended [see Warnings and Precautions (5.2)] . The renin-angiotensin-aldosterone system (RAAS) plays a critical role in kidney development. RAAS blockade has been shown to lead to abnormal kidney development in very young mice. Administering drugs that act directly on the renin- angiotensin aldosterone system (RAAS) can alter normal renal development.

8.5 Geriatric Use

Of the total number of hypertensive patients receiving olmesartan medoxomil in clinical studies, more than 20% were 65 years of age and over, while more than 5% were 75 years of age and older. No overall differences in effectiveness or safety were observed between elderly patients and younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out [see Clinical Pharmacology (12.3)] .

8.6 Hepatic Impairment

Increases in AUC 0-∞and C maxwere observed in patients with moderate hepatic impairment compared to those in matched controls, with an increase in AUC of about 60%. No initial dosage adjustment is recommended for patients with moderate to marked hepatic dysfunction [see Clinical Pharmacology (12.3)] .

8.7 Renal Impairment

Patients with renal insufficiency have elevated serum concentrations of olmesartan compared to subjects with normal renal function. After repeated dosing, the AUC was approximately tripled in patients with severe renal impairment (creatinine clearance <20 mL/min). No initial dosage adjustment is recommended for patients with moderate to marked renal impairment (creatinine clearance <40 mL/min) [see Dosage and Administration (2.1), Warnings and Precautions (5.4)and Clinical Pharmacology (12.3)] .

8.8 Black Patients

The antihypertensive effect of olmesartan medoxomil was smaller in black patients (usually a low-renin population), as has been seen with ACE inhibitors, beta-blockers and other angiotensin receptor blockers.

Überdosierung

Limited data are available related to overdosage in humans. The most likely manifestations of overdosage would be hypotension and tachycardia; bradycardia could be encountered if parasympathetic (vagal) stimulation occurs. If symptomatic hypotension occurs, initiate supportive treatment. The dialyzability of olmesartan is unknown.

Klinische Pharmakologie

12.1 Mechanism of Action

Angiotensin II is formed from angiotensin I in a reaction catalyzed by angiotensin converting enzyme (ACE, kininase II). Angiotensin II is the principal pressor agent of the renin-angiotensin system, with effects that include vasoconstriction, stimulation of synthesis and release of aldosterone, cardiac stimulation and renal reabsorption of sodium. Olmesartan blocks the vasoconstrictor effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT ₁receptor in vascular smooth muscle. Its action is, therefore, independent of the pathways for angiotensin II synthesis.

An AT ₂receptor is found also in many tissues, but this receptor is not known to be associated with cardiovascular homeostasis. Olmesartan has more than a 12,500-fold greater affinity for the AT ₁receptor than for the AT ₂receptor.

Blockade of the renin-angiotensin system with ACE inhibitors, which inhibit the biosynthesis of angiotensin II from angiotensin I, is a mechanism of many drugs used to treat hypertension. ACE inhibitors also inhibit the degradation of bradykinin, a reaction also catalyzed by ACE. Because olmesartan medoxomil does not inhibit ACE (kininase II), it does not affect the response to bradykinin. Whether this difference has clinical relevance is not yet known.

Blockade of the angiotensin II receptor inhibits the negative regulatory feedback of angiotensin II on renin secretion, but the resulting increased plasma renin activity and circulating angiotensin II levels do not overcome the effect of olmesartan on blood pressure.

12.2 Pharmacodynamics

Olmesartan medoxomil doses of 2.5 mg to 40 mg inhibit the pressor effects of angiotensin I infusion. The duration of the inhibitory effect was related to dose, with doses of olmesartan medoxomil >40 mg giving >90% inhibition at 24 hours.

Plasma concentrations of angiotensin I and angiotensin II and plasma renin activity (PRA) increase after single and repeated administration of olmesartan medoxomil to healthy subjects and hypertensive patients. Repeated administration of up to 80 mg olmesartan medoxomil had minimal influence on aldosterone levels and no effect on serum potassium.

12.3 Pharmacokinetics

Absorption

Olmesartan medoxomil is rapidly and completely bioactivated by ester hydrolysis to olmesartan during absorption from the gastrointestinal tract.

Olmesartan medoxomil tablets and the suspension formulation prepared from olmesartan medoxomil tablets are bioequivalent [see Dosage and Administration (2.2)] .

The absolute bioavailability of olmesartan is approximately 26%. After oral administration, the peak plasma concentration (C max) of olmesartan is reached after 1 to 2 hours. Food does not affect the bioavailability of olmesartan. Olmesartan medoxomil tablets may be administered with or without food.

Distribution

Auszug – vollständiger Text im Originaldokument. Original auf DailyMed (FDA/NLM)

Quelle: U.S. Food and Drug Administration (FDA), Prescribing Information, über DailyMed (NLM); gemeinfrei. Keine Werbung, keine Therapieempfehlung. Bei Fragen zur eigenen Behandlung: Ärztin, Arzt oder Apotheke.