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Kovalenko Svetlana Olegovna tarafından tıbbi olarak gözden geçirilmiştir, Eczane Son güncelleme: 09.04.2022
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Aynı bileşenlere sahip en iyi 20 ilaç:
Azor, kan basıncını düşürmek için tek başına veya diğer antihipertansif ajanlarla hipertansiyon tedavisi için endikedir. Kan basıncının düşürülmesi, öncelikle felç ve miyokard enfarktüsü olmak üzere ölümcül ve ölümcül olmayan kardiyovasküler olay riskini azaltır. Bu faydalar, bu ilacın esas olarak ait olduğu sınıf da dahil olmak üzere çok çeşitli farmakolojik sınıflardan gelen antihipertansif ilaçların kontrollü çalışmalarında görülmüştür. Azor ile risk azaltmayı gösteren kontrollü bir çalışma yoktur.
Yüksek tansiyonun kontrolü, uygun olduğu şekilde, lipit kontrolü, diyabet yönetimi, antitrombotik tedavi, sigarayı bırakma, egzersiz ve sınırlı sodyum alımı dahil olmak üzere kapsamlı kardiyovasküler risk yönetiminin bir parçası olmalıdır. Birçok hasta kan basıncı hedeflerine ulaşmak için birden fazla ilaca ihtiyaç duyacaktır. Hedefler ve yönetim hakkında özel tavsiyeler için, Ulusal Yüksek Tansiyon Eğitim Programı'nın Yüksek Tansiyonun Önlenmesi, Tespiti, Değerlendirilmesi ve Tedavisi Ortak Ulusal Komitesi (JNC) gibi yayınlanmış kılavuzlara bakın.
Çok sayıda antihipertansif ilaç, çeşitli farmakolojik sınıflardan ve farklı etki mekanizmalarına sahiptir, kardiyovasküler morbidite ve mortaliteyi azaltmak için randomize kontrollü çalışmalarda gösterilmiştir, ve bunun kan basıncını düşürdüğü sonucuna varılabilir, ve ilaçların başka bir farmakolojik özelliği değil, bu faydalardan büyük ölçüde sorumludur. En büyük ve en tutarlı kardiyovasküler sonuç yararı inme riskinde bir azalma olmuştur, ancak miyokard enfarktüsü ve kardiyovasküler mortalitede de düzenli olarak azalma görülmüştür.
Yüksek sistolik veya diyastolik basınç artmış kardiyovasküler riske neden olur ve mmHg başına mutlak risk artışı daha yüksek kan basınçlarında daha fazladır, böylece şiddetli hipertansiyonun mütevazı azalmaları bile önemli fayda sağlayabilir. Kan basıncının düşürülmesinden kaynaklanan göreceli risk azalması, değişen mutlak risk taşıyan popülasyonlarda benzerdir, bu nedenle hipertansiyonlarından bağımsız olarak daha yüksek risk altında olan hastalarda mutlak fayda daha fazladır (Örneğin, diyabet veya hiperlipidemili hastalar) ve bu tür hastaların daha düşük bir kan basıncı hedefine daha agresif tedaviden faydalanmaları beklenir.
Bazı antihipertansif ilaçların siyah hastalarda daha küçük kan basıncı etkileri (monoterapi olarak) vardır ve birçok antihipertansif ilacın ek onaylanmış endikasyonları ve etkileri vardır (ör.anjina, kalp yetmezliği veya diyabetik böbrek hastalığı üzerine). Bu düşünceler terapi seçimine rehberlik edebilir.
Azor, kan basıncı hedeflerine ulaşmak için birden fazla antihipertansif ajana ihtiyaç duyan hastalarda başlangıç tedavisi olarak da kullanılabilir.
Orta veya şiddetli hipertansiyonu olan hastalar kardiyovasküler olaylar (konturlar, kalp krizi ve kalp yetmezliği gibi), böbrek yetmezliği ve görme sorunları için nispeten yüksek risk altındadır, bu nedenle hızlı tedavi klinik olarak önemlidir. Başlangıç tedavisi olarak bir kombinasyon kullanma kararı kişiselleştirilmeli ve başlangıç kan basıncı, hedef hedef ve monoterapiye kıyasla bir kombinasyonla hedefe ulaşma olasılığı gibi düşüncelerle şekillendirilmelidir. Bireysel kan basıncı hedefleri hastanın riskine bağlı olarak değişebilir.
8 haftalık, plasebo kontrollü, paralel grup faktöriyel bir çalışmadan elde edilen veriler, amlodipin veya olmesartan medoksomil monoterapisine kıyasla Azor ile kan basıncı hedefine ulaşma olasılığının tahminlerini sunmaktadır. Aşağıdaki rakamlar, başlangıç sistolik veya diyastolik kan basıncına dayanan amlodipin veya olmesartan medoksomil monoterapisine kıyasla Azor 10/40 mg ile hedeflenen sistolik veya diyastolik kan basıncı hedeflerine ulaşma olasılığının tahminlerini sunmaktadır. Her tedavi grubunun eğrisi, o tedavi grubunun mevcut tüm verilerinden lojistik regresyon modellemesi ile tahmin edilmiştir. Her eğrinin sağ kuyruğu, yüksek taban çizgisi kan basıncı olan az sayıda denek nedeniyle daha az güvenilirdir.
Şekil 1: LOCF ile 8. Haftada Sistolik Kan Basıncı (SBP) <140 mmHg elde etme olasılığı
Şekil 2: LOCF ile 8. Haftada Diyastolik Kan Basıncı (DBP) <90 mmHg elde etme olasılığı
Şekil 3: LOCF ile 8. Haftada Sistolik Kan Basıncı (SBP) <130 mmHg elde etme olasılığı
Şekil 4: LOCF ile 8. Haftada Diyastolik Kan Basıncı (DBP) <80 mmHg elde etme olasılığı
Yukarıdaki rakamlar, hedeflenen bir kan basıncı hedefine ulaşma olasılığının yaklaşık bir tahminini vermektedir (ör., Çalışmada değerlendirilen yüksek doz tedavi grupları için 8. Hafta SBP <140 mmHg veya <130 mmHg veya bir DBP <90 mmHg veya <80 mmHg). En düşük doz kombinasyon tedavi grubu olan Azor 5/20 mg, en yüksek doz tekoterapileri, amlodipin 10 mg ve olmesartan medoksomil 40 mg ile karşılaştırıldığında kan basıncı hedefine ulaşma olasılığını arttırır.
Örneğin, başlangıç kan basıncı 160/100 mmHg olan bir hastanın <140 mmHg'lik bir hedefe ulaşma olasılığı yaklaşık% 48'dir (sistolik) ve <90 mmHg hedefine ulaşma olasılığı% 51'dir (diyastolik) 40 mg olmesartan medoksomil ile monoterapi üzerine, ve <140 mmHg hedefine ulaşma olasılığı yaklaşık% 46'dır (sistolik) ve <90 mmHg hedefine ulaşma olasılığı% 60'tır (diyastolik) amlodipin ile monoterapi üzerine 10 mg. Aynı hedeflere ulaşma olasılığı Azor 5/20 mg'da% 63 (sistolik) ve% 71 (diyastolik) ve Azor 10/40 mg'da% 68 (sistolik) ve% 85'e (diyastolik) yükselir.
Genel Düşünceler
Olmesartan medoksomilin yan etkileri genellikle nadirdir ve görünüşte dozdan bağımsızdır. Amlodipin olanlar genellikle doza bağımlıdır (çoğunlukla ödem).
Maksimum antihipertansif etkilere, doz değişikliğinden sonraki 2 hafta içinde ulaşılır.
Azor yiyecekle birlikte veya yiyeceksiz alınabilir.
Azor diğer antihipertansif ajanlarla uygulanabilir.
Dozaj 2 hafta sonra arttırılabilir. Önerilen maksimum Azor dozu 10/40 mg'dır.
Değiştirme Terapisi
Azor, ayrı ayrı titre edilmiş bileşenleri ile ikame edilebilir.
Tek tek bileşenler yerine konurken, kan basıncı kontrolü tatmin edici değilse, bileşenlerden birinin veya her ikisinin dozu arttırılabilir.
Eklenti Terapisi
Azor, tek başına amlodipin (veya başka bir dihidropiridin kalsiyum kanal blokeri) veya tek başına olmesartan medoksomil (veya başka bir anjiyotensin reseptör blokeri) ile yeterince kontrol edilmeyen hastalar için ek kan basıncını düşürmek için kullanılabilir.
İlk Terapi
Azor'un normal başlangıç dozu günde bir kez 5/20 mg'dır. Dozaj, 1 ila 2 haftalık tedaviden sonra, kan basıncını kontrol etmek için gerektiğinde günde bir kez maksimum 10/40 mg tablet dozuna yükseltilebilir.
Azor ile ilk tedavi ≥75 yaş ve üstü hastalarda veya karaciğer yetmezliği olan hastalarda önerilmez.
Do not co-administer aliskiren with Azor in patients with diabetes.
WARNINGS
Included as part of the "PRECAUTIONS" Section
PRECAUTIONS
Fetal Toxicity
Pregnancy Category D
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. 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 Azor as soon as possible.
Hypotension In Volume- Or Salt-Depleted Patients
Olmesartan Medoxomil
Symptomatic hypotension may be anticipated after initiation of treatment with olmesartan medoxomil. Patients with an activated renin-angiotensin system, such as volume-and/or salt-depleted patients (e.g., those being treated with high doses of diuretics) may be particularly vulnerable. Initiate treatment with Azor under close medical supervision. If hypotension does occur, place the patient in the supine position and, if necessary, give an intravenous infusion of normal saline. A transient hypotensive response is not a contraindication to further treatment, which usually can be continued without difficulty once the blood pressure has stabilized.
Vasodilation
Amlodipine
Since the vasodilation attributable to amlodipine in Azor is gradual in onset, acute hypotension has rarely been reported after oral administration. Nonetheless, exercise caution, as with any other peripheral vasodilator, when administering Azor, particularly in patients with severe aortic stenosis.
Patients With Severe Obstructive Coronary Artery Disease
Patients, particularly those with severe obstructive coronary artery disease, may develop increased frequency, duration, or severity of angina or acute myocardial infarction on starting calcium channel blocker therapy or at the time of dosage increase. The mechanism of this effect has not been elucidated.
Patients With Congestive Heart Failure
Amlodipine
Amlodipine (5–10 mg per day) has been studied in a placebo-controlled trial of 1153 patients with NYHA Class III or IV heart failure on stable doses of ACE inhibitor, digoxin, and diuretics. Follow-up was at least 6 months, with a mean of about 14 months. There was no overall adverse effect on survival or cardiac morbidity (as defined by life-threatening arrhythmia, acute myocardial infarction, or hospitalization for worsened heart failure). Amlodipine has been compared to placebo in four 8–12 week studies of patients with NYHA class II/III heart failure, involving a total of 697 patients. In these studies, there was no evidence of worsening of heart failure based on measures of exercise tolerance, NYHA classification, symptoms, or LVEF.
Patients With Impaired Renal Function
Azor
There are no studies of Azor in patients with renal impairment.
Olmesartan Medoxomil
Changes in renal function may be anticipated in susceptible individuals treated with olmesartan medoxomil as a consequence of inhibiting the renin-angiotensin-aldosterone system. 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 inhibitors and angiotensin receptor antagonists has been associated with oliguria or progressive azotemia and (rarely) with acute renal failure and/or death. Similar effects may occur in patients treated with Azor because of the olmesartan medoxomil component.
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 effects would be expected with olmesartan medoxomil and Azor.
Patients With Hepatic Impairment
Amlodipine
Since amlodipine is extensively metabolized by the liver and the plasma elimination half-life (t½) is 56 hours in patients with severely impaired hepatic function, exercise caution when administering Azor to patients with severe hepatic impairment.
Patients with hepatic impairment have decreased clearance of amlodipine. Starting amlodipine or adding amlodipine at 2.5 mg in hepatically impaired patients is recommended. The lowest dose of Azor is 5/20 mg; therefore, initial therapy with Azor is not recommended in hepatically impaired patients.
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 discontinuation of Azor in cases where no other etiology is identified.
Electrolyte Imbalances
Azor contains olmesartan, a drug that inhibits the renin-angiotensin system (RAS). Drugs that inhibit the RAS can cause hyperkalemia. Monitor serum electrolytes periodically.
Laboratory Tests
Azor
There was a greater decrease in hemoglobin and hematocrit in the combination product compared to either component. Other laboratory changes can usually be attributed to either monotherapy component.
Amlodipine
In post-marketing experience, hepatic enzyme elevations have been reported (6.2).
Olmesartan Medoxomil
In post-marketing experience, increased blood creatinine levels have been reported.
Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Amlodipine. Rats and mice treated with amlodipine maleate in the diet for up to two years, at concentrations calculated to provide daily dosage levels of amlodipine 0.5, 1.25, and 2.5 mg/kg/day showed no evidence of a carcinogenic effect of the drug. For the mouse, the highest dose was, on a mg/m2 basis, similar to the maximum recommended human dose (MRHD) of amlodipine 10 mg/day. For the rat, the highest dose was, on a mg/m2 basis, about two and a half times the MRHD. (Calculations based on a 60 kg patient.)
Mutagenicity studies conducted with amlodipine maleate revealed no drug related effects at either the gene or chromosome level.
There was no effect on the fertility of rats treated orally with amlodipine maleate (males for 64 days and females for 14 days prior to mating) at doses of amlodipine up to 10 mg/kg/day (about 10 times the MRHD of 10 mg/day on a mg/m2 basis).
Olmesartan Medoxomil
Olmesartan was not carcinogenic when administered by dietary administration to rats for up to 2 years. The highest dose tested (2000 mg/kg/day) was, on a mg/m2 basis, about 480 times the maximum recommended human dose (MRHD) of 40 mg/day. Two carcinogenicity studies conducted in mice, a 6-month gavage study in the p53 knockout mouse and a 6-month dietary administration study in the Hras2 transgenic mouse, at doses of up to 1000 mg/kg/day (about 120 times the MRHD), revealed no evidence of a carcinogenic effect of olmesartan. Both olmesartan medoxomil and olmesartan tested negative in the in vitro Syrian hamster embryo cell transformation assay and showed no evidence of genetic toxicity in the Ames (bacterial mutagenicity) test. However, both were shown to induce chromosomal aberrations in cultured cells in vitro (Chinese hamster lung) and tested positive for thymidine kinase mutations in the in vitro mouse lymphoma assay. Olmesartan medoxomil tested negative in vivo for mutations in the MutaMouse intestine and kidney and for clastogenicity in mouse bone marrow (micronucleus test) at oral doses of up to 2000 mg/kg (olmesartan not tested).
Fertility of rats was unaffected by administration of olmesartan at dose levels as high as 1000 mg/kg/day (240 times the MRHD) in a study in which dosing was begun 2 (female) or 9 (male) weeks prior to mating.
Use In Specific Populations
Pregnancy
Pregnancy Category D
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. 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 Azor as soon as possible. These adverse outcomes are usually associated with use of these drugs in the second and third trimester of pregnancy. 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. Appropriate management of maternal hypertension during pregnancy is important to optimize outcomes for both mother and fetus.
In the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus. Perform serial ultrasound examinations to assess the intraamniotic environment. If oligohydramnios is observed, discontinue Azor, unless it is considered lifesaving for the mother. Fetal testing may be appropriate, based on the week of pregnancy. 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 utero exposure to Azor for hypotension, oliguria, and hyperkalemia.
Olmesartan
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 auricular, 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.
Amlodipine
No evidence of teratogenicity or other embryo/fetal toxicity was found when pregnant rats and rabbits were treated orally with amlodipine maleate at doses of up to 10 mg amlodipine/kg/day (respectively about 10 and 20 times the maximum recommended human dose of 10 mg amlodipine on a mg/m2 basis) during their respective periods of major organogenesis. (Calculations based on a patient weight of 60 kg). However, litter size was significantly decreased (by about 50%) and the number of intrauterine deaths was significantly increased (about 5-fold) in rats receiving amlodipine maleate at a dose equivalent to 10 mg amlodipine/kg/day for 14 days before mating and throughout mating and gestation. Amlodipine maleate has been shown to prolong both the gestational period and the duration of labor in rats at this dose. There are no adequate and well-controlled studies in pregnant women. Amlodipine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Nursing Mothers
It is not known whether the amlodipine or olmesartan medoxomil components of Azor are excreted in human milk, but olmesartan is secreted at low concentration in the milk of lactating rats. 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.
Pediatric Use
Neonates With A History Of In Utero Exposure To Azor
If oliguria or hypotension occurs, direct attention toward support of blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function.
The safety and effectiveness of Azor in pediatric patients have not been established.
Amlodipine
The effect of amlodipine on blood pressure in patients less than 6 years of age is not known.
Olmesartan medoxomil
Safety and effectiveness of olmesartan medoxomil in pediatric patients have not been established.
Geriatric Use
Of the total number of subjects in the double-blind clinical study of Azor, 20% (384/1940) were 65 years of age or older and 3% (62/1940) were 75 years or older. No overall differences in safety or effectiveness were observed between subjects 65 years of age or older and younger subjects.
Elderly patients have decreased clearance of amlodipine. Starting amlodipine or adding amlodipine at 2.5 mg in patients ≥75 years old is recommended. The lowest dose of Azor is 5/20 mg; therefore, initial therapy with Azor is not recommended in patients ≥75 years old.
Amlodipine
Reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Elderly patients have decreased clearance of amlodipine with a resulting increase of AUC of approximately 40% to 60%, and a lower initial dose may be required.
Olmesartan Medoxomil
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.
Hepatic Impairment
There are no studies of Azor in patients with hepatic insufficiency, but both amlodipine and olmesartan medoxomil show moderate increases in exposure in patients with hepatic impairment. Use caution when administering Azor to patients with severe hepatic impairment.
Patients with hepatic impairment have decreased clearance of amlodipine. Starting amlodipine or adding amlodipine at 2.5 mg in patients with hepatic impairment is recommended. The lowest dose of Azor is 5/20 mg; therefore, initial therapy with Azor is not recommended in hepatically impaired patients.
Renal Impairment
There are no studies of Azor in patients with renal impairment.
Amlodipine
The pharmacokinetics of amlodipine are not significantly influenced by renal impairment. Patients with renal failure may therefore receive the usual initial dose.
Olmesartan Medoxomil
Patients with renal insufficiency have elevated serum concentrations of olmesartan compared with patients with normal renal function. After repeated dosing, 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).
Black Patients
Of the total number of subjects in the double-blind clinical study of Azor, 25% (481/1940) were black patients. Azor was effective in treating black patients (usually a low-renin population), and the magnitude of blood pressure reduction in black patients approached that observed for non-black patients.
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.
Azor
The data described below reflect exposure to Azor in more than 1600 patients including more than 1000 exposed for at least 6 months and more than 700 exposed for 1 year. Azor was studied in one placebo-controlled factorial trial (See Clinical Studies). The population had a mean age of 54 years and included approximately 55% males. Seventy-one percent were Caucasian and 25% were Black. Patients received doses ranging from 5/20 mg to 10/40 mg orally once daily.
The overall incidence of adverse reactions on therapy with Azor was similar to that seen with corresponding doses of the individual components of Azor, and to placebo. The reported adverse reactions were generally mild and seldom led to discontinuation of treatment (2.6% for Azor and 6.8% for placebo).
Edema
Edema is a known, dose-dependent adverse effect of amlodipine but not of olmesartan medoxomil.
The placebo-subtracted incidence of edema during the 8-week, randomized, double-blind treatment period was highest with amlodipine 10 mg monotherapy. The incidence was significantly reduced when 20 mg or 40 mg of olmesartan medoxomil was added to the 10 mg amlodipine dose.
Placebo-Subtracted Incidence of Edema During the Double-Blind Treatment Period
Olmesartan Medoxomil | ||||
Placebo | 20 mg | 40 mg | ||
Amlodipine | Placebo | -* | -2.4% | 6.2% |
5 mg | 0.7% | 5.7% | 6.2% | |
10 mg | 24.5% | 13.3% | 11.2% | |
*12.3% = actual placebo incidence |
Across all treatment groups, the frequency of edema was generally higher in women than men, as has been observed in previous studies of amlodipine.
Adverse reactions seen at lower rates during the double-blind period also occurred in the patients treated with Azor at about the same or greater incidence as in patients receiving placebo. These included hypotension, orthostatic hypotension, rash, pruritus, palpitation, urinary frequency, and nocturia.
The adverse event profile obtained from 44 weeks of open-label combination therapy with amlodipine plus olmesartan medoxomil was similar to that observed during the 8-week, double-blind, placebo-controlled period.
Initial Therapy
Analyzing the data described above specifically for initial therapy, it was observed that higher doses of Azor caused slightly more hypotension and orthostatic symptoms, but not at the recommended starting dose of Azor 5/20 mg. No increase in the incidence of syncope or near syncope was observed. The incidences of discontinuation because of any treatment emergent adverse events in the double blind phase are summarized in the table below.
Discontinuation for any Treatment Emergent Adverse Event1
Olmesartan Medoxomil | |||||
Placebo | 10 mg | 20 mg | 40 mg | ||
Amlodipine | Placebo | 4.9% | 4.3% | 5.6% | 3.1% |
5 mg | 3.7% | 0.0% | 1.2% | 3.7% | |
10 mg | 5.5% | 6.8% | 2.5% | 5.6% | |
1 Hypertension is counted as treatment failure and not as treatment emergent adverse event. N=160-163 subjects per treatment group. |
Amlodipine
Amlodipine has been evaluated for safety in more than 11,000 patients in U.S. and foreign clinical trials. Most adverse reactions reported during therapy with amlodipine were of mild or moderate severity. In controlled clinical trials directly comparing amlodipine (N=1730) in doses up to 10 mg to placebo (N=1250), discontinuation of amlodipine due to adverse reactions was required in only about 1.5% of amlodipinetreated patients and about 1% of placebo-treated patients. The most common side effects were headache and edema. The incidence (%) of dose-related side effects was as follows:
Adverse Event | Placebo N=520 | 2.5 mg N=275 | 5.0 mg N=296 | 10.0 mg N=268 |
Edema | 0.6 | 1.8 | 3.0 | 10.8 |
Dizziness | 1.5 | 1.1 | 3.4 | 3.4 |
Flushing | 0.0 | 0.7 | 1.4 | 2.6 |
Palpitation | 0.6 | 0.7 | 1.4 | 4.5 |
For several adverse experiences that appear to be drug- and dose-related, there was a greater incidence in women than men associated with amlodipine treatment as shown in the following table:
Adverse Event | Placebo | Amlodipine | ||
Male=% (N=914) | Female=% (N=336) | Male=% (N=1218) | Female=% (N=512) | |
Edema | 1.4 | 5.1 | 5.6 | 14.6 |
Flushing | 0.3 | 0.9 | 1.5 | 4.5 |
Palpitation | 0.9 | 0.9 | 1.4 | 3.3 |
Somnolence | 0.8 | 0.3 | 1.3 | 1.6 |
Olmesartan Medoxomil
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 treated for at least 1 year. Treatment with olmesartan medoxomil was well tolerated, with an incidence of adverse events similar to that seen with placebo. Events were generally mild, transient, and without relationship to the dose of olmesartan medoxomil.
The overall frequency of adverse events was not dose-related. Analysis of gender, age, and race groups demonstrated no differences between olmesartan medoxomil- and placebo-treated patients. The rate of withdrawals due to adverse events 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 event that occurred in more than 1% of patients treated with olmesartan medoxomil and at a higher incidence in olmesartan medoxomil treated patients vs. placebo was dizziness (3% vs 1%).
Post-Marketing Experience
The following adverse reactions have been identified during post-approval use of the individual components of Azor. 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.
Amlodipine
The following post-marketing event has been reported infrequently where a causal relationship is uncertain: gynecomastia. In post-marketing experience, jaundice and hepatic enzyme elevations (mostly consistent with cholestasis or hepatitis), in some cases severe enough to require hospitalization, have been reported in association with use of amlodipine.
Olmesartan Medoxomil
The following adverse reactions have been reported in post- marketing experience:
Body as a Whole: asthenia, angioedema, anaphylactic reactions, peripheral edema
Gastrointestinal: vomiting, diarrhea, sprue-like enteropathy
Metabolic and Nutritional Disorders: hyperkalemia
Musculoskeletal: rhabdomyolysis
Urogenital System: acute renal failure
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.
İnsanlarda Azor ile aşırı doz hakkında bilgi yoktur.
Amlodipin
Farelerde ve sıçanlarda sırasıyla 40 mg amlodipin / kg ve 100 mg amlodipin / kg'a eşdeğer tek oral amlodipin maleat dozları ölümlere neden oldu. Köpeklerde 4 veya daha fazla mg amlodipin / kg veya daha yüksek bir tek oral amlodipin maleat dozları (mg / m'de önerilen maksimum insan dozunun 11 veya daha fazla)2 temeli) belirgin bir periferik vazodilatasyon ve hipotansiyona neden oldu.
Doz aşımının belirgin hipotansiyon ve muhtemelen refleks taşikardi ile aşırı periferik vazodilatasyona neden olması beklenebilir. İnsanlarda, amlodipinin kasıtlı doz aşımı ile ilgili deneyim sınırlıdır.
Büyük doz aşımı meydana gelirse, aktif kardiyak ve solunum izleme yapılmalıdır. Sık kan basıncı ölçümleri gereklidir. Hipotansiyon meydana gelirse, ekstremitelerin yükselmesi ve sıvıların mantıklı uygulanması dahil kardiyovasküler destek başlatılmalıdır. Hipotansiyon bu konservatif önlemlere yanıt vermiyorsa, vazopresörlerin (fenilefrin gibi) uygulanması dolaşım hacmine ve idrar çıkışına dikkat edilerek düşünülmelidir. İntravenöz kalsiyum glukonat, kalsiyum giriş blokajının etkilerini tersine çevirmeye yardımcı olabilir. Amlodipin yüksek oranda proteine bağlı olduğundan, hemodiyalizin yararlı olması muhtemel değildir.
Olmesartan medoksomil. İnsanlarda aşırı doz ile ilgili sınırlı veri mevcuttur. Doz aşımının en olası belirtileri hipotansiyon ve taşikardi olacaktır; parasempatik (vagal) stimülasyon meydana gelirse bradikardi ile karşılaşılabilir. Semptomatik hipotansiyon meydana gelirse, destekleyici tedavi başlatılmalıdır. Olmesartanın diyaliz edilebilirliği bilinmemektedir.
Amlodipine
Following administration of therapeutic doses to patients with hypertension, amlodipine produces vasodilation resulting in a reduction of supine and standing blood pressures. These decreases in blood pressure are not accompanied by a significant change in heart rate or plasma catecholamine levels with chronic dosing.
With chronic once daily oral administration, antihypertensive effectiveness is maintained for at least 24 hours. Plasma concentrations correlate with effect in both young and elderly patients. The magnitude of reduction in blood pressure with amlodipine is also correlated with the height of pretreatment elevation; thus, individuals with moderate hypertension (diastolic pressure 105-114 mmHg) had about a 50% greater response than patients with mild hypertension (diastolic pressure 90-104 mmHg). Normotensive subjects experienced no clinically significant change in blood pressures (+1/-2 mmHg).
In hypertensive patients with normal renal function, therapeutic doses of amlodipine resulted in a decrease in renal vascular resistance and an increase in glomerular filtration rate and effective renal plasma flow without change in filtration fraction or proteinuria.
As with other calcium channel blockers, hemodynamic measurements of cardiac function at rest and during exercise (or pacing) in patients with normal ventricular function treated with amlodipine have generally demonstrated a small increase in cardiac index without significant influence on dP/dt or on left ventricular end diastolic pressure or volume. In hemodynamic studies, amlodipine has not been associated with a negative inotropic effect when administered in the therapeutic dose range to intact animals and man, even when co-administered with beta-blockers to man. Similar findings, however, have been observed in normals or well-compensated patients with heart failure with agents possessing significant negative inotropic effects.
Amlodipine does not change sinoatrial nodal function or atrioventricular conduction in intact animals or man. In clinical studies in which amlodipine was administered in combination with beta-blockers to patients with either hypertension or angina, no adverse effects on electrocardiographic parameters were observed.
Olmesartan Medoxomil
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.
The pharmacokinetics of amlodipine and olmesartan medoxomil from Azor are equivalent to the pharmacokinetics of amlodipine and olmesartan medoxomil when administered separately. The bioavailability of both components is well below 100%, but neither component is affected by food. The effective half-lives of amlodipine (45±11 hours) and olmesartan (7±1 hours) result in a 2- to 3- fold accumulation for amlodipine and negligible accumulation for olmesartan with once-daily dosing.
Amlodipine
After oral administration of therapeutic doses of amlodipine, absorption produces peak plasma concentrations between 6 and 12 hours. Absolute bioavailability is estimated as between 64% and 90%.
Olmesartan Medoxomil
Olmesartan medoxomil is rapidly and completely bioactivated by ester hydrolysis to olmesartan during absorption from the gastrointestinal tract. The absolute bioavailability of olmesartan medoxomil is approximately 26%. After oral administration, the peak plasma concentration (Cmax) of olmesartan is reached after 1 to 2 hours. Food does not affect the bioavailability of olmesartan medoxomil.
Distribution
Amlodipine
Ex vivo studies have shown that approximately 93% of the circulating drug is bound to plasma proteins in hypertensive patients. Steady-state plasma levels of amlodipine are reached after 7 to 8 days of consecutive daily dosing.
Olmesartan medoxomil
The volume of distribution of olmesartan is approximately 17 L. Olmesartan is highly bound to plasma proteins (99%) and does not penetrate red blood cells. The protein binding is constant at plasma olmesartan concentrations well above the range achieved with recommended doses.
In rats, olmesartan crossed the blood-brain barrier poorly, if at all. Olmesartan passed across the placental barrier in rats and was distributed to the fetus. Olmesartan was distributed to milk at low levels in rats.
Metabolism And Excretion
Amlodipine
Amlodipine is extensively (about 90%) converted to inactive metabolites via hepatic metabolism. Elimination from the plasma is biphasic with a terminal elimination half-life of about 30 to 50 hours. Ten percent of the parent compound and 60% of the metabolites are excreted in the urine.
Olmesartan medoxomil
Following the rapid and complete conversion of olmesartan medoxomil to olmesartan during absorption, there is virtually no further metabolism of olmesartan. Total plasma clearance of olmesartan is 1.3 L/h, with a renal clearance of 0.6 L/h. Approximately 35% to 50% of the absorbed dose is recovered in urine while the remainder is eliminated in feces via the bile.
Olmesartan appears to be eliminated in a biphasic manner with a terminal elimination half-life of approximately 13 hours. Olmesartan shows linear pharmacokinetics following single oral doses of up to 320 mg and multiple oral doses of up to 80 mg. Steady-state levels of olmesartan are achieved within 3 to 5 days and no accumulation in plasma occurs with once-daily dosing.
Geriatric
The pharmacokinetic properties of Azor in the elderly are similar to those of the individual components.
Amlodipine
Elderly patients have decreased clearance of amlodipine with a resulting increase in AUC of approximately 40% to 60%, and a lower initial dose may be required.
Olmesartan medoxomil
The pharmacokinetics of olmesartan medoxomil were studied in the elderly (≥65 years). Overall, maximum plasma concentrations of olmesartan were similar in young adults and the elderly. Modest accumulation of olmesartan was observed in the elderly with repeated dosing; AUCss, τ was 33% higher in elderly patients, corresponding to an approximate 30% reduction in CLR.
Pediatric
Amlodipine
Sixty-two hypertensive patients aged 6 to 17 years received doses of amlodipine between 1.25 mg and 20 mg. Weight-adjusted clearance and volume of distribution were similar to values in adults.
Olmesartan medoxomil
The pharmacokinetics of olmesartan medoxomil have not been investigated in patients <18 years of age.
Gender
Population pharmacokinetic analysis indicated that female patients had approximately 15% smaller clearances of olmesartan than male patients. Gender had no effect on the clearance of amlodipine.
Olmesartan medoxomil
Minor differences were observed in the pharmacokinetics of olmesartan medoxomil in women compared to men. AUC and Cmax were 10% to 15% higher in women than in men.
Renal Insufficiency
Amlodipine
The pharmacokinetics of amlodipine are not significantly influenced by renal impairment. Patients with renal failure may therefore receive the usual initial dose.
Olmesartan medoxomil
In patients with renal insufficiency, serum concentrations of olmesartan were elevated 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). The pharmacokinetics of olmesartan medoxomil in patients undergoing hemodialysis has not been studied. No initial dosage adjustment is recommended for patients with moderate to marked renal impairment (creatinine clearance <40 mL/min).
Hepatic Insufficiency
Amlodipine
Patients with hepatic insufficiency have decreased clearance of amlodipine with a resulting increase in AUC of approximately 40% to 60%.
Olmesartan medoxomil
Increases in AUC0-∞ and Cmax were observed in patients with moderate hepatic impairment compared to those in matched controls, with an increase in AUC of about 60%.
Heart Failure
Amlodipine
Patients with heart failure have decreased clearance of amlodipine with a resulting increase in AUC of approximately 40% to 60%.