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治療オプション:
Oliinyk Elizabeth Ivanovna 、薬局による医学的評価、 最終更新日:12.03.2022
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同じ成分を持つトップ20の薬:
Azorは、高血圧の治療に単独で、または他の降圧剤とともに、血圧を下げることが適応です。. 血圧を下げると、致命的および非致命的な心血管イベント、主に脳卒中や心筋 ⁇ 塞のリスクが軽減されます。. これらの利点は、この薬が主に属するクラスを含む、さまざまな薬理クラスの降圧薬の対照試験で見られました。. Azorによるリスク低減を示す対照試験はありません。.
高血圧の制御は、必要に応じて、脂質制御、糖尿病管理、抗血栓療法、禁煙、運動、限られたナトリウム摂取など、包括的な心血管リスク管理の一部である必要があります。. 多くの患者は血圧目標を達成するために複数の薬を必要とします。. 目標と管理に関する具体的なアドバイスについては、国家高血圧教育プログラムの高血圧の予防、検出、評価、治療に関する合同全国委員会(JNC)のガイドラインなど、公開されているガイドラインを参照してください。.
数多くの降圧薬。, さまざまな薬理学的クラスから、さまざまな作用メカニズムがあります。, 心血管の ⁇ 患率と死亡率を減らすためにランダム化比較試験で示されました。, そしてそれは血圧低下であると結論付けることができます。, 薬物の他の薬理学的特性ではありません。, それはそれらの利点の主な原因です。. 最大かつ最も一貫した心血管転帰の利点は脳卒中のリスクの減少でしたが、心筋 ⁇ 塞と心血管死亡率の減少も定期的に見られています。.
収縮期または拡張期の圧力の上昇は心血管リスクの増加を引き起こし、mmHgあたりの絶対リスクの増加はより高い血圧で大きくなるため、重度の高血圧の適度な減少でさえ大きな利益をもたらす可能性があります。. 血圧低下による相対リスクの低減は、絶対リスクが変動する集団間で類似しています。, したがって、高血圧に関係なくリスクが高い患者では、絶対的なメリットが大きくなります。 (例えば。, 糖尿病または高脂血症の患者。) そして、そのような患者は、より低い血圧の目標へのより積極的な治療から恩恵を受けると期待されます。.
一部の降圧薬は、黒人患者の血圧効果が(単剤療法として)小さく、多くの降圧薬には、追加の承認された適応症と効果があります(例:.、狭心症、心不全、または糖尿病性腎疾患について)。. これらの考慮事項は、治療の選択を導く可能性があります。.
Azorは、血圧目標を達成するために複数の降圧剤を必要とする可能性が高い患者の初期治療としても使用できます。.
中等度または重度の高血圧の患者は、心血管イベント(脳卒中、心臓発作、心不全など)、腎不全、視力の問題のリスクが比較的高いため、迅速な治療が臨床的に関連します。. 併用療法を初期療法として使用する決定は個別化する必要があり、ベースラインの血圧、目標目標、および単剤療法と比較して併用で目標を達成する可能性の増加などの考慮事項によって形成する必要があります。. 個々の血圧の目標は、患者のリスクによって異なる場合があります。.
8週間のプラセボ対照並行群の階乗研究のデータは、アムロジピンまたはオルメサルタンメドキソミル単剤療法と比較して、アゾールで血圧目標に到達する確率の推定を提供します。. 以下の図は、ベースラインの収縮期または拡張期の血圧に基づいて、アムロジピンまたはオルメサルタンメドキソミル単剤療法と比較して、Azor 10/40 mgで標的型収縮期または拡張期の血圧目標を達成する可能性の推定値を示しています。. 各治療グループの曲線は、その治療グループの利用可能なすべてのデータからのロジスティック回帰モデリングによって推定されました。. ベースライン血圧が高い被験者が少ないため、各曲線の右尾の信頼性が低くなります。.
図1:LOCFを使用して第8週に収縮期血圧(SBP)<140 mmHgを達成する可能性。
図2:LOCFを使用して8週目に拡張期血圧(DBP)<90 mmHgを達成する可能性。
図3:LOCFを使用して第8週に収縮期血圧(SBP)<130 mmHgを達成する可能性。
図4:LOCFを使用して8週目に拡張期血圧(DBP)<80 mmHgを達成する可能性。
上記の数値は、目標とする血圧目標に到達する可能性の概算を示しています(例:.、試験で評価された高用量治療群の8週目SBP <140 mmHgまたは<130 mmHgまたはDBP <90 mmHgまたは<80 mmHg)。. 最低用量の併用治療群であるAzor 5/20 mgは、最高用量の単剤療法、アムロジピン10 mgおよびオルメサルタンメドキソミル40 mgと比較して、血圧目標に到達する確率を高めます。.
例えば。, ベースライン血圧が160/100 mmHgの患者は、目標が140 mmHg未満になる可能性が約48%あります。 (収縮期。) 目標が90 mmHg未満になる可能性は51%です。 (拡張期。) オルメサルタンメドキソミル40 mgの単剤療法。, 140 mmHg未満の目標を達成する可能性は約46%です。 (収縮期。) 90 mmHg未満の目標を達成する可能性は60%です。 (拡張期。) アムロジピン10 mgによる単剤療法。. これらの同じ目標を達成する可能性は、Azor 5/20 mgで63%(収縮期)および71%(拡張期)に、Azor 10/40 mgで68%(収縮期)および85%(拡張期)に増加します。.
一般的な考慮事項。
オルメサルタンメドキソミルの副作用は一般にまれであり、明らかに用量とは無関係です。. アムロジピンのものは一般的に用量依存的です(主に浮腫)。.
最大降圧効果は、用量の変更後2週間以内に達成されます。.
Azorは、食事の有無にかかわらず服用できます。.
アゾールは他の降圧剤と一緒に投与されることがあります。.
投与量は2週間後に増加する可能性があります。. Azorの最大推奨用量は10/40 mgです。.
補充療法。
Azorは、個別に滴定されたコンポーネントの代わりに使用できます。.
個々の成分を置き換える場合、血圧管理が満足のいくものでなければ、成分の一方または両方の用量を増やすことができます。.
アドオン療法。
アゾールは、アムロジピン(または別のジヒドロピリジンカルシウムチャネルブロッカー)単独またはオルメサルタンメドキソミル(または別のアンジオテンシン受容体ブロッカー)単独では適切に制御されていない患者に追加の血圧低下を提供するために使用できます。.
初期療法。
Azorの通常の開始用量は、1日1回5/20 mgです。. 投与量は、1〜2週間の治療後に、血圧を制御するために必要に応じて、1日1回10/40 mg錠剤1錠の最大用量まで増やすことができます。.
Azorによる初期治療は、75歳以上の患者や肝障害のある患者には推奨されません。.
糖尿病患者では、アリスキレンとアゾールを併用しないでください。.
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.
臨床試験の経験。
臨床試験はさまざまな条件下で行われるため、薬物の臨床試験で観察された副作用率は、他の薬物の臨床試験の率と直接比較することはできず、実際に観察された率を反映しない場合があります。.
アゾール。
以下に説明するデータは、少なくとも6か月間暴露された1000人以上、1年間暴露された700人以上を含む1600人以上の患者におけるAzorへの暴露を反映しています。. Azorは、1つのプラセボ対照階乗試験で研究されました(参照。 臨床研究。)。. 人口の平均年齢は54歳で、約55%の男性が含まれていました。. 71%は白人で、25%は黒人でした。. 患者は、1日1回、5/20 mgから10/40 mgの範囲の用量を経口投与されました。.
Azorによる治療に対する副作用の全体的な発生率は、Azorの個々の成分の対応する用量で見られるものと、プラセボと同様でした。. 報告された副作用は一般に軽度であり、治療の中止に至ることはめったにありません(Azorで2.6%、プラセボで6.8%)。.
浮腫。
浮腫は、アムロジピンの既知の用量依存的な副作用ですが、オルメサルタンメドキソミルはそうではありません。.
8週間の無作為化二重盲検治療期間中のプラセボ減算浮腫の発生率は、アムロジピン10 mg単剤療法で最も高かった。. 20 mgまたは40 mgのオルメサルタンメドキソミルを10 mgのアムロジピン用量に追加した場合、発生率は大幅に減少しました。.
二重盲検治療期間中の浮腫のプラセボ転倒発生率。
オルメサルタンメドキソミル。 | ||||
プラセボ。 | 20 mg。 | 40 mg。 | ||
アムロジピン。 | プラセボ。 | -* | -2.4%。 | 6.2%。 |
5 mg。 | 0.7%。 | 5.7%。 | 6.2%。 | |
10 mg。 | 24.5%。 | 13.3%。 | 11.2%。 | |
* 12.3%=実際のプラセボ発生率。 |
アムロジピンの以前の研究で観察されたように、すべての治療グループ全体で、浮腫の頻度は一般に男性よりも女性で高かった。.
二重盲検期間中に低い率で見られた副作用は、プラセボを投与された患者とほぼ同じかそれ以上の発生率でアゾールで治療された患者でも発生しました。. これらには、低血圧、起立性低血圧、発疹、そう ⁇ 、動 ⁇ 、尿頻度、および夜間頻尿が含まれます。.
アムロジピンとオルメサルタンメドキソミルによる44週間の非盲検併用療法から得られた有害事象プロファイルは、8週間の二重盲検プラセボ対照期間中に観察されたものと同様でした。.
初期療法。
特に初期治療のために上記のデータを分析すると、高用量のアゾールがわずかに多くの低血圧および起立性症状を引き起こすが、推奨される開始用量のアゾール5/20 mgではないことが観察されました。. 失神または失神に近い発生率の増加は観察されなかった。. 二重盲検相での治療による緊急事象による中止の発生率を以下の表にまとめます。.
治療緊急有害事象の中止。1
オルメサルタンメドキソミル。 | |||||
プラセボ。 | 10 mg。 | 20 mg。 | 40 mg。 | ||
アムロジピン。 | プラセボ。 | 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 高血圧は治療の失敗としてカウントされ、治療緊急有害事象としてカウントされません。. N = 160-163被験者/治療グループ。. |
アムロジピン。
アムロジピンは、米国および外国の臨床試験で11,000人を超える患者の安全性について評価されています。. アムロジピンによる治療中に報告されたほとんどの副作用は、軽度または中程度の重症度でした。. 10 mgまでの用量のアムロジピン(N = 1730)をプラセボ(N = 1250)と直接比較する対照臨床試験では、副作用によるアムロジピンの中止は、アムロジピネトリートメント患者の約1.5%とプラセボの約1%で必要でした。 -治療された患者。. 最も一般的な副作用は頭痛と浮腫でした。. 用量関連の副作用の発生率(%)は次のとおりです。
有害事象。 | プラセボ。 N = 520。 | 2.5 mg。 N = 275。 | 5.0 mg。 N = 296。 | 10.0 mg。 N = 268。 |
浮腫。 | 0.6。 | 1.8。 | 3.0。 | 10.8。 |
めまい。 | 1.5。 | 1.1。 | 3.4。 | 3.4。 |
フラッシング。 | 0.0。 | 0.7。 | 1.4。 | 2.6。 |
動 ⁇ 。 | 0.6。 | 0.7。 | 1.4。 | 4.5。 |
薬物および用量に関連していると思われるいくつかの有害な経験について、次の表に示すように、アムロジピン治療に関連する男性よりも女性の方が発生率が高かった。
有害事象。 | プラセボ。 | アムロジピン。 | ||
男性=%。 (N = 914)。 | 女性=%。 (N = 336)。 | 男性=%。 (N = 1218)。 | 女性=%。 (N = 512)。 | |
浮腫。 | 1.4。 | 5.1。 | 5.6。 | 14.6。 |
フラッシング。 | 0.3。 | 0.9。 | 1.5。 | 4.5。 |
動 ⁇ 。 | 0.9。 | 0.9。 | 1.4。 | 3.3。 |
傾眠。 | 0.8。 | 0.3。 | 1.3。 | 1.6。 |
オルメサルタンメドキソミル。
オルメサルタンメドキソミルは、対照試験で高血圧の治療を受けた3275人以上の患者を含む、3825人以上の患者/被験者の安全性が評価されています。. この経験には、少なくとも6か月間治療された約900人の患者と、少なくとも1年間治療された525人以上の患者が含まれていました。. オルメサルタンメドキソミルによる治療は忍容性が高く、プラセボと同様の有害事象の発生率がありました。. イベントは一般的に穏やかで一過性であり、オルメサルタンメドキソミルの用量とは関係がありませんでした。.
有害事象の全体的な頻度は用量に関連していませんでした。. 性別、年齢、人種グループの分析では、オルメサルタンメドキソミルとプラセボで治療された患者の間に違いはありませんでした。. 高血圧患者のすべての試験での有害事象による離脱率は2.4%でした(つまり、.、79/3278)オルメサルタンメドキソミルで治療された患者の2.7%(すなわち.、32/1179)対照患者。. プラセボ対照試験では、オルメサルタンメドキソミルで治療された患者の1%以上で、オルメサルタンメドキソミル治療を受けた患者でより高い発生率で発生した唯一の有害事象. プラセボはめまいでした(3%対1%)。.
市販後の経験。
Azorの個々のコンポーネントの承認後の使用中に、以下の副作用が確認されています。. これらの反応は不確実なサイズの集団から自発的に報告されるため、その頻度を確実に推定したり、薬物曝露との因果関係を確立したりすることは常に可能ではありません。.
アムロジピン。
因果関係が不確かな場合、次の市販後のイベントはまれに報告されています:女性化乳房。. 市販後の経験では、黄 ⁇ および肝酵素の上昇(主に胆 ⁇ うっ滞または肝炎と一致)が、場合によっては入院を必要とするほど重症であり、アムロジピンの使用に関連して報告されています。.
オルメサルタンメドキソミル。
以下の副作用が市販後の経験で報告されています。
全体としての体。: 無力症、血管性浮腫、アナフィラキシー反応、末 ⁇ 性浮腫。
消化器。: ⁇ 吐、下 ⁇ 、偽のような腸症。
代謝および栄養障害。: 高カリウム血症。
筋骨格。: 横紋筋融解症。
⁇ 尿生殖器系。: 急性腎不全。
皮膚と付属物。: 脱毛症、そう ⁇ 症、じんま疹。
1つの対照試験と疫学研究のデータは、高用量のオルメサルタンが糖尿病患者の心血管(CV)リスクを高める可能性があることを示唆していますが、全体的なデータは決定的ではありません。. 無作為化プラセボ対照二重盲検ROADMAP試験(無作為化オルメサルタンおよび糖尿病ミクロアルブミン尿予防試験、n = 4447)では、オルメサルタン、毎日40 mgの使用と. 2型糖尿病、正常アルブミン尿症、およびCV疾患の少なくとも1つの追加の危険因子がある患者のプラセボ。. 試験はその主要評価項目であるミクロアルブミン尿の発症を遅らせましたが、オルメサルタンは糸球体 ⁇ 過率(GFR)の低下に有益な効果はありませんでした。. プラセボ群と比較して、オルメサルタン群でCV死亡率の増加(心臓突然死、致命的な心筋 ⁇ 塞、致命的な脳卒中、血行再建死)の発見がありました(15オルメサルタン対. 3プラセボ、HR 4.9、95%信頼区間[CI]、1.4、17)、しかし、非致死的心筋 ⁇ 塞のリスクはオルメサルタンでは低かった(HR 0.64、95%CI 0.35、1.18)。.
疫学研究には、65歳以上の患者が含まれ、全体の曝露は30万患者年を超えました。. 高用量のオルメサルタン(40 mg / d)を6か月以上投与している糖尿病患者のサブグループでは、他の同様の患者を服用している患者と比較して、死亡リスク(HR 2.0、95%CI 1.1、3.8)が増加しているようですアンジオテンシン受容体遮断薬。. 対照的に、非糖尿病患者での高用量のオルメサルタンの使用は、他のアンジオテンシン受容体遮断薬を服用している同様の患者と比較して、死亡リスクの低下(HR 0.46、95%CI 0.24、0.86)と関連しているようです。. 他のアンジオテンシン遮断薬と比較して低用量のオルメサルタンを投与されているグループ、または6か月未満治療を受けているグループ間で違いは観察されませんでした。.
全体として、これらのデータは、糖尿病患者における高用量オルメサルタンの使用に関連するCVリスクの増加の可能性を懸念しています。. しかし、CVリスクの増加の発見の信頼性、特に糖尿病患者の不利な発見と同様の規模の非糖尿病患者の生存利益に関する大規模な疫学研究での観察には懸念があります。.
There is no information on overdosage with Azor in humans.
Amlodipine
Single oral doses of amlodipine maleate equivalent to 40 mg amlodipine/kg and 100 mg amlodipine/kg in mice and rats, respectively, caused deaths. Single oral amlodipine maleate doses equivalent to 4 or more mg amlodipine/kg or higher in dogs (11 or more times the maximum recommended human dose on a mg/m2 basis) caused a marked peripheral vasodilation and hypotension.
Overdosage might be expected to cause excessive peripheral vasodilation with marked hypotension and possibly a reflex tachycardia. In humans, experience with intentional overdosage of amlodipine is limited.
If massive overdose should occur, active cardiac and respiratory monitoring should be instituted. Frequent blood pressure measurements are essential. Should hypotension occur, cardiovascular support including elevation of the extremities and the judicious administration of fluids should be initiated. If hypotension remains unresponsive to these conservative measures, administration of vasopressors (such as phenylephrine) should be considered with attention to circulating volume and urine output. Intravenous calcium gluconate may help to reverse the effects of calcium entry blockade. As amlodipine is highly protein bound, hemodialysis is not likely to be of benefit.
Olmesartan medoxomil. 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 should occur, supportive treatment should be initiated. The dialyzability of olmesartan is unknown.
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%.