Perindopril arginine, amlodipine besylate: Difference between revisions

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|drugClass=combination of an [[angiotensin converting enzyme inhibitor]] and a [[dihydropyridine]] [[calcium channel blocker]]
|drugClass=combination of an [[angiotensin converting enzyme inhibitor]] and a [[dihydropyridine]] [[calcium channel blocker]]
|indicationType=treatment
|indicationType=treatment
|indication=[[hypertension]] to lower [[blood pressure]] in patients not adequately controlled with [[monotherapy]] or as initial therapy in patients likely to need multiple drugs to achieve their [[blood pressure]] goals
|indication=[[hypertension]] to lower [[blood pressure]] in patients not adequately controlled with [[monotherapy]], or as initial therapy in patients likely to need multiple drugs to achieve their [[blood pressure]] goals
|hasBlackBoxWarning=Yes
|hasBlackBoxWarning=Yes
|adverseReactions=[[headache]], [[cough]], [[peripheral edema]], and [[pulmonary edema]]
|adverseReactions=[[headache]], [[cough]], [[peripheral edema]], and [[pulmonary edema]]
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*Consider use in patients unable to achieve adequate [[antihypertensive]] effect with [[amlodipine]] [[monotherapy]] because of dose-limiting [[peripheral edema]] caused by [[amlodipine]]. Administered as [[monotherapy]], [[perindopril]] erbumine is an effective treatment for [[hypertension]] in once-daily doses ranging from 4 mg to 16 mg daily. [[Amlodipine]] is effective in once-daily doses of 5 mg and 10 mg. Adverse reactions related to [[perindopril]] are generally uncommon and independent of dose, while those related to [[amlodipine]] are a mixture of dose-dependent phenomena (primarily [[peripheral edema]]) and dose-independent phenomena, the former much more common than the latter.
*Consider use in patients unable to achieve adequate [[antihypertensive]] effect with [[amlodipine]] [[monotherapy]] because of dose-limiting [[peripheral edema]] caused by [[amlodipine]]. Administered as [[monotherapy]], [[perindopril]] erbumine is an effective treatment for [[hypertension]] in once-daily doses ranging from 4 mg to 16 mg daily. [[Amlodipine]] is effective in once-daily doses of 5 mg and 10 mg. Adverse reactions related to [[perindopril]] are generally uncommon and independent of dose, while those related to [[amlodipine]] are a mixture of dose-dependent phenomena (primarily [[peripheral edema]]) and dose-independent phenomena, the former much more common than the latter.
*Dosage adjustment in [[renal impairment]]
*Dosage adjustment in [[renal impairment]]
**[[Perindopril]] arginine and [[amlodipine besylate]] is not recommended in patients with creatinine clearances <30 mL/min. For patients with creatinine clearance between 30 and 80 mL/min (mild or moderate [[renal impairment]]), do not exceed 7/5 mg.
**[[Perindopril]] arginine and [[amlodipine besylate]] is not recommended in patients with [[creatinine clearance|creatinine clearances]] <30 mL/min. For patients with [[creatinine clearance]] between 30 and 80 mL/min (mild or moderate [[renal impairment]]), do not exceed 7/5 mg.
|offLabelAdultGuideSupport=There is limited information regarding ''Off-Label Guideline-Supported Use'' of [[Perindopril]] arginine, [[amlodipine besylate]] in adult patients.
|offLabelAdultGuideSupport=There is limited information regarding ''Off-Label Guideline-Supported Use'' of [[Perindopril]] arginine, [[amlodipine besylate]] in adult patients.
|offLabelAdultNoGuideSupport=There is limited information regarding ''Off-Label Non–Guideline-Supported Use'' of [[Perindopril]] arginine, [[amlodipine besylate]] in adult patients.
|offLabelAdultNoGuideSupport=There is limited information regarding ''Off-Label Non–Guideline-Supported Use'' of [[Perindopril]] arginine, [[amlodipine besylate]] in adult patients.
|offLabelPedGuideSupport=There is limited information regarding ''Off-Label Guideline-Supported Use'' of [[Perindopril]] arginine, [[amlodipine besylate]] in pediatric patients.
|offLabelPedGuideSupport=There is limited information regarding ''Off-Label Guideline-Supported Use'' of [[Perindopril]] arginine, [[amlodipine besylate]] in pediatric patients.
|offLabelPedNoGuideSupport=There is limited information regarding ''Off-Label Non–Guideline-Supported Use'' of [[Perindopril]] arginine, [[amlodipine besylate]] in pediatric patients.
|offLabelPedNoGuideSupport=There is limited information regarding ''Off-Label Non–Guideline-Supported Use'' of [[Perindopril]] arginine, [[amlodipine besylate]] in pediatric patients.
|contraindications=*[[Perindopril]] arginine and [[amlodipine besylate]] tablets are contraindicated in patients with:
|contraindications=*[[Perindopril]] arginine and [[amlodipine besylate]] tablets are contraindicated in patients:
**[[Hereditary]] or [[idiopathic]] [[angioedema]], with or without previous [[ACE inhibitor]] treatment
**With [[Hereditary]] or [[idiopathic]] [[angioedema]], with or without previous [[ACE inhibitor]] treatment.
**In patients who are [[hypersensitive]] to [[perindopril]], to any other [[ACE inhibitor]], or to [[amlodipine]].
**Who are [[hypersensitive]] to [[perindopril]], to any other [[ACE inhibitor]], or to [[amlodipine]].
*Do not co-administer [[aliskiren]] with [[ACE inhibitor|ACE inhibitors]], including [[perindopril]] arginine and [[amlodipine besylate]], in patients with [[diabetes]]
*Do not co-administer [[aliskiren]] with [[ACE inhibitor|ACE inhibitors]], including [[perindopril]] arginine and [[amlodipine besylate]], in patients with [[diabetes]].
|warnings=*Fetal toxicity
|warnings=*Fetal toxicity
**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.  
**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.  
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*Anaphylactoid and Possibly Related Reactions
*Anaphylactoid and Possibly Related Reactions
**[[Angiotensin converting enzyme inhibitors]] affect the [[metabolism]] of [[eicosanoids]] and [[polypeptides]], including [[endogenous]] [[bradykinin]]. Patients taking [[ACE inhibitor|ACE inhibitors]] (including the one in [[perindopril]] arginine and [[amlodipine besylate]]) may, therefore, be subject to a variety of [[bradykinin]]- or [[prostaglandin]]-mediated adverse reactions, some of them serious. Black patients receiving [[ACE inhibitor|ACE inhibitors]] have a higher incidence of [[angioedema]] compared with non-blacks.
**[[Angiotensin converting enzyme inhibitors]] affect the [[metabolism]] of [[eicosanoids]] and [[polypeptides]], including [[endogenous]] [[bradykinin]]. Patients taking [[ACE inhibitor|ACE inhibitors]] (including the one in [[perindopril]] arginine and [[amlodipine besylate]]) may, therefore, be subject to a variety of [[bradykinin]]- or [[prostaglandin]]-mediated adverse reactions, some of them serious. Black patients receiving [[ACE inhibitor|ACE inhibitors]] have a higher incidence of [[angioedema]] compared with non-blacks.
**Head and Neck [[Angioedema]]: [[Angioedema]] of the face, [[extremities]], [[lips]], [[tongue]], [[glottis]], and [[larynx]] has been reported in patients treated with [[ACE inhibitor|ACE inhibitors]] (0.1% of patients treated with [[perindopril]] in U.S. clinical trials). [[Angioedema]] associated with involvement of the [[tongue]], [[glottis]] or [[larynx]] may be fatal. In such cases, discontinue [[perindopril]] treatment immediately and observe until the swelling disappears. When involvement of the [[tongue]], [[glottis]], or [[larynx]] appears likely to cause airway obstruction, administer appropriate therapy, such as subcutaneous [[epinephrine]] solution 1:1000 (0.3 to 0.5 mL), promptly.
**Head and Neck [[Angioedema]]: [[Angioedema]] of the face, [[extremities]], [[lips]], [[tongue]], [[glottis]], and [[larynx]] has been reported in patients treated with [[ACE inhibitor|ACE inhibitors]] (0.1% of patients treated with [[perindopril]] in U.S. clinical trials). [[Angioedema]] associated with involvement of the [[tongue]], [[glottis]] or [[larynx]] may be fatal. In such cases, discontinue [[perindopril]] treatment immediately and observe until the swelling disappears. When involvement of the [[tongue]], [[glottis]], or [[larynx]] appears likely to cause airway obstruction, administer appropriate therapy, such as [[subcutaneous]] [[epinephrine]] solution 1:1000 (0.3 to 0.5 mL), promptly.
**Patients taking concomitant mTOR inhibitor (e.g. [[temsirolimus]]) therapy may be at increased risk for [[angioedema]].
**Patients taking concomitant mTOR inhibitor (e.g. [[temsirolimus]]) therapy may be at increased risk for [[angioedema]].
**Intestinal [[Angioedema]]: Intestinal [[angioedema]] has been reported in patients treated with [[ACE inhibitor|ACE inhibitors]]. These patients presented with abdominal pain (with or without [[nausea]] or vomiting), and the [[angioedema]] was diagnosed by imaging studies such as abdominal [[CT]] or [[ultrasound]], or at surgery. In some cases there was no prior history of facial [[angioedema]], and C-1 esterase levels were normal. Symptoms resolved after stopping the [[ACE inhibitor]]. Intestinal [[angioedema]] should be included in the differential diagnosis of patients on [[ACE inhibitor|ACE inhibitors]] presenting with abdominal pain.
**Intestinal [[Angioedema]]: Intestinal [[angioedema]] has been reported in patients treated with [[ACE inhibitor|ACE inhibitors]]. These patients presented with abdominal pain (with or without [[nausea]] or [[vomiting]]), and the [[angioedema]] was diagnosed by imaging studies such as abdominal [[CT]] or [[ultrasound]], or at surgery. In some cases there was no prior history of facial [[angioedema]], and C-1 esterase levels were normal. Symptoms resolved after stopping the [[ACE inhibitor]]. Intestinal [[angioedema]] should be included in the differential diagnosis of patients on [[ACE inhibitor|ACE inhibitors]] presenting with abdominal pain.
*Increased [[Angina]] and/or [[myocardial infarction|Myocardial Infarction]]
*Increased [[Angina]] and/or [[myocardial infarction|Myocardial Infarction]]
**Worsening [[angina]] and [[acute myocardial infarction]] can develop after starting or increasing the dose of [[perindopril]] arginine and [[amlodipine besylate]], particularly in patients with severe obstructive coronary artery disease.
**Worsening [[angina]] and [[acute myocardial infarction]] can develop after starting or increasing the dose of [[perindopril]] arginine and [[amlodipine besylate]], particularly in patients with severe [[obstructive coronary artery disease]].
*Hypotension
*[[Hypotension]]
**[[Perindopril]] arginine and [[amlodipine besylate]] can cause symptomatic hypotension. Symptomatic hypotension is most likely to occur in patients who have been volume- or salt-depleted as a result of prolonged diuretic therapy, dietary salt restriction, dialysis, diarrhea, or vomiting.
**[[Perindopril]] arginine and [[amlodipine besylate]] can cause symptomatic [[hypotension]]. Symptomatic [[hypotension]] is most likely to occur in patients who have been volume- or salt-depleted as a result of prolonged [[diuretic]] therapy, dietary [[salt]] restriction, [[dialysis]], [[diarrhea]], or [[vomiting]].
**In patients at risk of excessive hypotension, start [[perindopril]] arginine and [[amlodipine besylate]] therapy under close medical supervision. Follow patients closely for the first 2 weeks of treatment and whenever the dose of [[perindopril]] arginine and [[amlodipine besylate]] is increased or a diuretic is added or its dose increased.
**In patients at risk of excessive [[hypotension]], start [[perindopril]] arginine and [[amlodipine besylate]] therapy under close medical supervision. Follow patients closely for the first 2 weeks of treatment and whenever the dose of [[perindopril]] arginine and [[amlodipine besylate]] is increased or a [[diuretic]] is added or its dose increased.
**If excessive hypotension occurs, immediately place patient in a supine position and, if necessary, treat patient with an intravenous infusion of physiological saline. [[Perindopril]] arginine and [[amlodipine besylate]] treatment can usually be continued following restoration of volume and [[blood pressure]].
**If excessive [[hypotension]] occurs, immediately place patient in a supine position and, if necessary, treat patient with an [[intravenous]] infusion of physiological [[saline]]. [[Perindopril]] arginine and [[amlodipine besylate]] treatment can usually be continued following restoration of volume and [[blood pressure]].
**Patients with severe aortic stenosis may be more likely to experience symptomatic hypotension. Because of the gradual onset of action, acute hypotension is unlikely.
**Patients with severe [[aortic stenosis]] may be more likely to experience symptomatic [[hypotension]]. Because of the gradual onset of action, acute hypotension is unlikely.
**Surgery/Anesthesia
**Surgery/Anesthesia
***In patients undergoing major surgery or during anesthesia with agents that produce hypotension, [[perindopril]] arginine and [[amlodipine besylate]] may block angiotensin II formation secondary to compensatory renin release. If hypotension occurs and is considered to be due to this mechanism, it can be corrected by volume expansion.
***In patients undergoing major surgery or during anesthesia with agents that produce [[hypotension]], [[perindopril]] arginine and [[amlodipine besylate]] may block [[angiotensin II]] formation secondary to compensatory [[renin]] release. If hypotension occurs and is considered to be due to this mechanism, it can be corrected by volume expansion.
*Hyperkalemia
*[[Hyperkalemia]]
**Elevations of serum potassium have been observed in some patients treated with [[ACE inhibitor|ACE inhibitors]], including [[perindopril]] arginine and [[amlodipine besylate]].  
**Elevations of serum [[potassium]] have been observed in some patients treated with [[ACE inhibitor|ACE inhibitors]], including [[perindopril]] arginine and [[amlodipine besylate]].  
Risk factors for the development of hyperkalemia include renal insufficiency, [[diabetes mellitus]], and the concomitant use of agents such as potassium-sparing diuretics, potassium supplements, and/or potassium-containing salt substitutes.
**Risk factors for the development of [[hyperkalemia]] include renal insufficiency, [[diabetes mellitus]], and the concomitant use of agents such as potassium-sparing [[diuretics]], [[potassium]] supplements, and/or [[potassium]]-containing salt substitutes.
**Monitor serum potassium periodically in patients receiving [[perindopril]] arginine and [[amlodipine besylate]].
**Monitor serum [[potassium]] periodically in patients receiving [[perindopril]] arginine and [[amlodipine besylate]].
*Cough
*[[Cough]]
**Presumably because of the inhibition of the degradation of [[endogenous]] [[bradykinin]], persistent nonproductive cough has been reported with all [[ACE inhibitor|ACE inhibitors]], generally resolving after discontinuation of therapy. Consider [[ACE inhibitor]]-induced [[cough]] in the differential diagnosis of cough.
**Presumably because of the inhibition of the degradation of [[endogenous]] [[bradykinin]], persistent nonproductive [[cough]] has been reported with all [[ACE inhibitor|ACE inhibitors]], generally resolving after discontinuation of therapy. Consider [[ACE inhibitor]]-induced [[cough]] in the differential diagnosis of cough.
*Impaired [[renal function|Renal Function]]
*Impaired [[renal function|Renal Function]]
**Monitor [[renal function]] periodically in patients receiving [[perindopril]] arginine and [[amlodipine besylate]]. Drugs that affect the [[renin-angiotensin system]] can cause reductions in [[renal function]], including [[acute renal failure]]. Patients whose [[renal function]] may depend in part on the activity of the [[renin-angiotensin system]]—(e.g., patients with renal artery stenosis, severe heart failure, post-[[myocardial infarction]] or volume depletion) or who are on [[NSAIDs|non-steroidal anti-inflammatory agents]] (NSAIDS) or [[angiotensin receptor blockers]]—may be at particular risk of developing [[acute renal failure]] on [[perindopril]] arginine and [[amlodipine besylate]].  
**Monitor [[renal function]] periodically in patients receiving [[perindopril]] arginine and [[amlodipine besylate]]. Drugs that affect the [[renin-angiotensin system]] can cause reductions in [[renal function]], including [[acute renal failure]]. Patients whose [[renal function]] may depend in part on the activity of the [[renin-angiotensin system]]—(e.g., patients with [[renal artery stenosis]], severe [[heart failure]], post-[[myocardial infarction]] or volume depletion) or who are on [[NSAIDs|non-steroidal anti-inflammatory agents]] (NSAIDS) or [[angiotensin receptor blockers]]—may be at particular risk of developing [[acute renal failure]] on [[perindopril]] arginine and [[amlodipine besylate]].  
**Consider withholding or discontinuing therapy in patients who develop a clinically significant decrease in [[renal function]] on [[perindopril]] arginine and [[amlodipine besylate]].
**Consider withholding or discontinuing therapy in patients who develop a clinically significant decrease in [[renal function]] on [[perindopril]] arginine and [[amlodipine besylate]].
*[[hepatic failure|Hepatic Failure]]
*[[hepatic failure|Hepatic Failure]]
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*Discontinuations because of adverse events occurred in 3.6% of patients treated with [[perindopril]] arginine and [[amlodipine besylate]] 14/10 mg compared to 4.3% of patients treated with [[perindopril]] erbumine 16 mg and 4.6% of patients treated with [[amlodipine]] 10 mg. The most common reason for discontinuation of therapy with [[perindopril]] arginine and [[amlodipine besylate]] was [[peripheral edema]] (1.8%).
*Discontinuations because of adverse events occurred in 3.6% of patients treated with [[perindopril]] arginine and [[amlodipine besylate]] 14/10 mg compared to 4.3% of patients treated with [[perindopril]] erbumine 16 mg and 4.6% of patients treated with [[amlodipine]] 10 mg. The most common reason for discontinuation of therapy with [[perindopril]] arginine and [[amlodipine besylate]] was [[peripheral edema]] (1.8%).
*Common adverse events that occurred in at least 2% of patients treated with [[perindopril]] arginine and [[amlodipine besylate]] in the 6-week trial are presented in TABLE 1.
*Common adverse events that occurred in at least 2% of patients treated with [[perindopril]] arginine and [[amlodipine besylate]] in the 6-week trial are presented in TABLE 1.
TABLE 1
[[File:Perindopril arginine and amlodipine besylate T1.JPG|thumb|none|400px|This image is provided by the National Library of Medicine.]]
*The overall frequency of adverse reactions was similar between men and women, and black and non-black patients. In black patients, the incidence of [[peripheral edema]] was similar in the [[perindopril]] arginine and [[amlodipine besylate]] 14/10 mg and [[amlodipine]] 10 mg arms (3%).
*The overall frequency of adverse reactions was similar between men and women, and black and non-black patients. In black patients, the incidence of [[peripheral edema]] was similar in the [[perindopril]] arginine and [[amlodipine besylate]] 14/10 mg and [[amlodipine]] 10 mg arms (3%).
*Other adverse reactions in the controlled clinical trial with some plausible relationship to [[perindopril]] arginine and [[amlodipine besylate]] are listed below:
*Other adverse reactions in the controlled clinical trial with some plausible relationship to [[perindopril]] arginine and [[amlodipine besylate]] are listed below:
**Dermatologic: [[Rash]]
**Dermatologic: [[Rash]]
**Digestive: [[Nausea]], [[diarrhea]]
**Digestive: [[Nausea]], [[diarrhea]]
*The safety of the lowest dose of [[perindopril]] arginine and [[amlodipine besylate]] (3.5/2.5 mg) was evaluated in 249 patients with [[hypertension]] and compared with placebo and [[perindopril]] and [[amlodipine]] administered as monotherapies in an 8-week trial. The only emergent adverse event observed in at least 2% of patients treated with [[perindopril]] arginine and [[amlodipine besylate]] was [[hyperkalemia]] (2.4%). [[Peripheral edema]] was reported in 1.6% of patients receiving [[perindopril]] arginine and [[amlodipine besylate]] 3.5/2.5 mg.
*The safety of the lowest dose of [[perindopril]] arginine and [[amlodipine besylate]] (3.5/2.5 mg) was evaluated in 249 patients with [[hypertension]] and compared with placebo and [[perindopril]] and [[amlodipine]] administered as [[monotherapy|monotherapies]] in an 8-week trial. The only emergent adverse event observed in at least 2% of patients treated with [[perindopril]] arginine and [[amlodipine besylate]] was [[hyperkalemia]] (2.4%). [[Peripheral edema]] was reported in 1.6% of patients receiving [[perindopril]] arginine and [[amlodipine besylate]] 3.5/2.5 mg.


[[Monotherapy]] with [[perindopril]] or [[amlodipine]] has been evaluated for safety in clinical trials in over 3,000 and 11,000 patients, respectively, as summarized below.
[[Monotherapy]] with [[perindopril]] or [[amlodipine]] has been evaluated for safety in clinical trials in over 3,000 and 11,000 patients, respectively, as summarized below.
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***Hematopoietic: [[leukopenia]], [[purpura]], [[thrombocytopenia]].
***Hematopoietic: [[leukopenia]], [[purpura]], [[thrombocytopenia]].
*Clinical Laboratory Findings
*Clinical Laboratory Findings
**Perindopril
**[[Perindopril]]
***Hematology: Small decreases in hemoglobin and hematocrit occur frequently in hypertensive patients treated with [[perindopril]], but are rarely of clinical importance. In controlled clinical trials, no patient was discontinued from therapy due to the development of anemia. Leukopenia (including neutropenia) was observed in 0.1% of patients in U.S. clinical trials.
***Hematology: Small decreases in [[hemoglobin]] and [[hematocrit]] occur frequently in hypertensive patients treated with [[perindopril]], but are rarely of clinical importance. In controlled clinical trials, no patient was discontinued from therapy due to the development of [[anemia]]. [[Leukopenia]] (including [[neutropenia]]) was observed in 0.1% of patients in U.S. clinical trials.
***Liver Function Tests: Elevations in alanine transaminase (ALT; 1.6% [[perindopril]] erbumine vs. 0.9% placebo) and aspartate transaminase (AST; 0.5% [[perindopril]] erbumine vs. 0.4% placebo) have been observed in placebo-controlled clinical trials. The elevations were generally mild and transient and resolved after discontinuation of therapy.
***Liver Function Tests: Elevations in [[alanine transaminase]] (ALT; 1.6% [[perindopril]] erbumine vs. 0.9% placebo) and [[aspartate transaminase]] (AST; 0.5% [[perindopril]] erbumine vs. 0.4% placebo) have been observed in placebo-controlled clinical trials. The elevations were generally mild and transient and resolved after discontinuation of therapy.
|postmarketing=The following adverse reactions have been identified during post-approval use of the individual components of [[perindopril]] arginine and [[amlodipine besylate]]. 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.
|postmarketing=The following adverse reactions have been identified during post-approval use of the individual components of [[perindopril]] arginine and [[amlodipine besylate]]. 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.
*Perindopril
*[[Perindopril]]
**Voluntary reports of adverse events in patients taking [[perindopril]] that have been received since market introduction and are of unknown causal relationship to [[perindopril]] include: cardiac arrest, eosinophilic pneumonitis, neutropenia/agranulocytosis, pancytopenia, anemia (including hemolytic and aplastic), thrombocytopenia, [[acute renal failure]], nephritis, [[hepatic failure]], [[jaundice]] (hepatocellular or cholestatic), symptomatic hyponatremia, bullous pemphigoid, pemphigus, acute pancreatitis, falls, psoriasis, exfoliative dermatitis, and a syndrome that may include: arthralgia/arthritis, vasculitis, serositis, myalgia, fever, rash or other dermatologic manifestations, a positive antinuclear antibody (ANA), leukocytosis, eosinophilia, or an elevated erythrocyte sedimentation rate (ESR).
**Voluntary reports of adverse events in patients taking [[perindopril]] that have been received since market introduction and are of unknown causal relationship to [[perindopril]] include: [[cardiac arrest]], [[eosinophilic pneumonitis]], [[neutropenia]]/[[agranulocytosis]], [[pancytopenia]], [[anemia]] (including [[hemolytic anemia|hemolytic]] and [[aplastic anemia|aplastic]]), [[thrombocytopenia]], [[acute renal failure]], [[nephritis]], [[hepatic failure]], [[jaundice]] (hepatocellular or cholestatic), symptomatic [[hyponatremia]], [[bullous pemphigoid]], [[pemphigus]], [[acute pancreatitis]], [[falls]], [[psoriasis]], [[exfoliative dermatitis]], and a syndrome that may include: [[arthralgia]]/[[arthritis]], [[vasculitis]], [[serositis]], [[myalgia]], [[fever]], [[rash]] or other dermatologic manifestations, a positive antinuclear antibody (ANA), [[leukocytosis]], [[eosinophilia]], or an elevated [[erythrocyte sedimentation rate]] (ESR).
*Amlodipine
*[[Amlodipine]]
**The following postmarketing event has been reported infrequently where a causal relationship is uncertain: palpitations, gynecomastia, [[jaundice]] and hepatic enzyme elevations (mostly consistent with cholestasis or hepatitis), some requiring hospitalization.
**The following postmarketing event has been reported infrequently where a causal relationship is uncertain: [[palpitations]], [[gynecomastia]], [[jaundice]] and [[hepatic enzyme elevations]] (mostly consistent with [[cholestasis]] or [[hepatitis]]), some requiring hospitalization.
|drugInteractions=[[Perindopril]] arginine and [[amlodipine besylate]]:
|drugInteractions=[[Perindopril]] arginine and [[amlodipine besylate]]:
*The pharmacokinetics of [[perindopril]] and [[amlodipine]] are not altered when the drugs are co-administered.
*The pharmacokinetics of [[perindopril]] and [[amlodipine]] are not altered when the drugs are co-administered.
*No drug interaction studies have been conducted with [[perindopril]] arginine and [[amlodipine besylate]], although studies have been conducted with [[perindopril]] and [[amlodipine]].
*No drug interaction studies have been conducted with [[perindopril]] arginine and [[amlodipine besylate]], although studies have been conducted with [[perindopril]] and [[amlodipine]].
*mTOR Inhibitors: Patients taking concomitant mTOR inhibitor (e.g. [[temsirolimus]]) therapy may be at increased risk for [[angioedema]].  
*mTOR Inhibitors: Patients taking concomitant mTOR inhibitor (e.g. [[temsirolimus]]) therapy may be at increased risk for [[angioedema]].  
Perindopril:
[[Perindopril]]:
*Diuretics: Patients on diuretics, especially those in whom diuretic therapy was recently instituted, may occasionally experience an excessive reduction of [[blood pressure]] after initiation of therapy with [[perindopril]] arginine and [[amlodipine besylate]]. Provide close medical supervision with the first dose of [[perindopril]] arginine and [[amlodipine besylate]], for at least two hours and until [[blood pressure]] has stabilized for another hour. [[Perindopril]] can attenuate potassium loss caused by thiazide diuretics.
*[[Diuretics]]: Patients on [[diuretics]], especially those in whom [[diuretic]] therapy was recently instituted, may occasionally experience an excessive reduction of [[blood pressure]] after initiation of therapy with [[perindopril]] arginine and [[amlodipine besylate]]. Provide close medical supervision with the first dose of [[perindopril]] arginine and [[amlodipine besylate]], for at least two hours and until [[blood pressure]] has stabilized for another hour. [[Perindopril]] can attenuate [[potassium]] loss caused by [[thiazide diuretics]].
*Potassium Supplements and Potassium-Sparing Diuretics: Potassium-sparing diuretics (spironolactone, amiloride, triamterene, and others) or potassium supplements, or other drugs capable of increasing serum potassium (indomethacin, heparin, cyclosporine and others) can increase the risk of hyperkalemia. If concomitant use of such agents is indicated, the patient's serum potassium should be monitored frequently.
*[[Potassium]] Supplements and [[potassium-sparing diuretic|Potassium-Sparing Diuretics]]: [[Potassium-sparing diuretics]] ([[spironolactone]], [[amiloride]], [[triamterene]], and others) or [[potassium]] supplements, or other drugs capable of increasing serum [[potassium]] ([[indomethacin]], [[heparin]], [[cyclosporine]] and others) can increase the risk of [[hyperkalemia]]. If concomitant use of such agents is indicated, the patient's serum [[potassium]] should be monitored frequently.
*Lithium: Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving [[ACE inhibitor|ACE inhibitors]] during therapy with lithium. When co-administering [[perindopril]] arginine and [[amlodipine besylate]] and lithium, frequent monitoring of serum lithium levels is recommended. Use of a diuretic may further increase the risk of lithium toxicity.
*[[Lithium]]: Increased serum [[lithium]] levels and symptoms of [[lithium]] toxicity have been reported in patients receiving [[ACE inhibitor|ACE inhibitors]] during therapy with [[lithium]]. When co-administering [[perindopril]] arginine and [[amlodipine besylate]] and [[lithium]], frequent monitoring of serum [[lithium]] levels is recommended. Use of a [[diuretic]] may further increase the risk of [[lithium]] toxicity.
*Gold: Nitritoid reactions (symptoms include facial flushing, [[nausea]], [[vomiting]], and hypotension) have been reported rarely in patients on therapy with injectable gold (sodium aurothiomalate) and concomitant [[ACE inhibitor]] therapy.
*[[Gold]]: Nitritoid reactions (symptoms include facial flushing, [[nausea]], [[vomiting]], and [[hypotension]]) have been reported rarely in patients on therapy with injectable [[gold]] (sodium aurothiomalate) and concomitant [[ACE inhibitor]] therapy.
*[[NSAIDs|Non-Steroidal Anti-Inflammatory Agents]] (NSAIDs) 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 [[ACE inhibitor|ACE inhibitors]], including [[perindopril]], may result in deterioration of [[renal function]], including possible [[acute renal failure]]. These effects are usually reversible. Monitor [[renal function]] periodically in patients receiving [[perindopril]] and [[NSAID]] therapy.
*[[NSAIDs|Non-Steroidal Anti-Inflammatory Agents]] (NSAIDs) Including [[COX-2 inhibitor|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 inhibitor|COX-2 inhibitors]], with [[ACE inhibitor|ACE inhibitors]], including [[perindopril]], may result in deterioration of [[renal function]], including possible [[acute renal failure]]. These effects are usually reversible. Monitor [[renal function]] periodically in patients receiving [[perindopril]] and [[NSAID]] therapy.
*The [[antihypertensive]] effects of [[ACE inhibitor|ACE inhibitors]], including [[perindopril]], may be attenuated by [[NSAIDS]], including selective COX-2 inhibitors.
*The [[antihypertensive]] effects of [[ACE inhibitor|ACE inhibitors]], including [[perindopril]], may be attenuated by [[NSAIDS]], including selective [[COX-2 inhibitor|COX-2 inhibitors]].
*Dual Blockade of the [[renin-angiotensin system|Renin-Angiotensin System]] (RAS): Dual blockade of the RAS with [[angiotensin receptor blockers]], [[ACE inhibitor|ACE inhibitors]], or [[aliskiren]] is associated with increased risks of hypotension, hyperkalemia, and changes in [[renal function]] (including [[acute renal failure]]) compared to [[monotherapy]]. In most patients no benefit has been associated with using two RAS inhibitors concomitantly. In general, avoid combined use of RAS inhibitors. Closely monitor [[blood pressure]], [[renal function]], and electrolytes in patients on [[perindopril]] arginine and [[amlodipine besylate]] and other agents that affect the RAS.
*Dual Blockade of the [[renin-angiotensin system|Renin-Angiotensin System]] (RAS): Dual blockade of the RAS with [[angiotensin receptor blockers]], [[ACE inhibitor|ACE inhibitors]], or [[aliskiren]] is associated with increased risks of [[hypotension]], [[hyperkalemia]], and changes in [[renal function]] (including [[acute renal failure]]) compared to [[monotherapy]]. In most patients no benefit has been associated with using two RAS inhibitors concomitantly. In general, avoid combined use of RAS inhibitors. Closely monitor [[blood pressure]], [[renal function]], and electrolytes in patients on [[perindopril]] arginine and [[amlodipine besylate]] and other agents that affect the RAS.
*Do not co-administer [[aliskiren]] with [[perindopril]] arginine and [[amlodipine besylate]] in patients with [[diabetes]]. Avoid use of [[aliskiren]] with [[perindopril]] arginine and [[amlodipine besylate]] in patients with [[renal impairment]] (GFR <60 mL/min).
*Do not co-administer [[aliskiren]] with [[perindopril]] arginine and [[amlodipine besylate]] in patients with [[diabetes]]. Avoid use of [[aliskiren]] with [[perindopril]] arginine and [[amlodipine besylate]] in patients with [[renal impairment]] (GFR <60 mL/min).
Amlodipine
[[Amlodipine]]
*Simvastatin: Co-administration of multiple doses of 10 mg of [[amlodipine]] with 80 mg simvastatin resulted in a 77% increase in exposure to simvastatin compared to simvastatin administered alone. Limit the dose of simvastatin in patients on [[amlodipine]] to 20 mg daily.
*[[Simvastatin]]: Co-administration of multiple doses of 10 mg of [[amlodipine]] with 80 mg [[simvastatin]] resulted in a 77% increase in exposure to [[simvastatin]] compared to [[simvastatin]] administered alone. Limit the dose of [[simvastatin]] in patients on [[amlodipine]] to 20 mg daily.
*Cyclosporine: A prospective study in renal transplant patients showed an average 40% increase in trough cyclosporin levels during concomitant treatment with [[amlodipine]]. Frequent monitoring of trough blood levels of cyclosporine is recommended.
*[[Cyclosporine]]: A prospective study in [[renal transplant]] patients showed an average 40% increase in trough [[cyclosporin]] levels during concomitant treatment with [[amlodipine]]. Frequent monitoring of trough blood levels of [[cyclosporine]] is recommended.
*CYP3A Inhibitors: Co-administration of the moderate CYP3A inhibitor diltiazem increases the exposure to [[amlodipine]] by 60%. Co-administered erythromycin, also a moderate CYP3A inhibitor, does not impact the exposure to [[amlodipine]]. Strong CYP3A inhibitors (e.g., itraconazole) may increase the plasma concentrations of the CYP3A substrate [[amlodipine]] to a greater extent. Monitor for symptoms of hypotension and edema when [[amlodipine]] is co-administered with moderate or strong CYP3A inhibitors to determine the need for dose adjustment.
*[[CYP3A]] Inhibitors: Co-administration of the moderate [[CYP3A]] inhibitor [[Diltiazem (injection)|diltiazem]] increases the exposure to [[amlodipine]] by 60%. Co-administered [[erythromycin]], also a moderate [[CYP3A]] inhibitor, does not impact the exposure to [[amlodipine]]. Strong [[CYP3A]] inhibitors (e.g., itraconazole) may increase the plasma concentrations of the [[CYP3A]] substrate [[amlodipine]] to a greater extent. Monitor for symptoms of [[hypotension]] and edema when [[amlodipine]] is co-administered with moderate or strong [[CYP3A]] inhibitors to determine the need for dose adjustment.
*CYP3A Inducers: No information is available on the quantitative effects of CYP3A inducers on [[amlodipine]]. [[Blood pressure]] should be monitored when [[amlodipine]] is co-administered with CYP3A inducers.
*[[CYP3A]] Inducers: No information is available on the quantitative effects of [[CYP3A]] inducers on [[amlodipine]]. [[Blood pressure]] should be monitored when [[amlodipine]] is co-administered with [[CYP3A]] inducers.
|FDAPregCat=D
|FDAPregCat=D
|useInPregnancyFDA=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 [[perindopril]] arginine and [[amlodipine besylate]] 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.
|useInPregnancyFDA=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 [[perindopril]] arginine and [[amlodipine besylate]] 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 therapy with drugs affecting the [[renin-angiotensin system]] for a particular patient, apprise the mother of the potential risk to the fetus. Perform serial ultra-sound examinations to assess the intra-amniotic environment. If [[oligohydramnios]] is observed, discontinue [[perindopril]] arginine and [[amlodipine besylate]], 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 [[perindopril]] arginine and [[amlodipine besylate]] for hypotension, oliguria, and hyperkalemia.
In the unusual case that there is no appropriate alternative therapy with drugs affecting the [[renin-angiotensin system]] for a particular patient, apprise the mother of the potential risk to the fetus. Perform serial [[ulrasound|ultra-sound]] examinations to assess the [[amniotic sac|intra-amniotic environment]]. If [[oligohydramnios]] is observed, discontinue [[perindopril]] arginine and [[amlodipine besylate]], 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 [[perindopril]] arginine and [[amlodipine besylate]] for [[hypotension]], [[oliguria]], and [[hyperkalemia]].
Radioactivity was detectable in fetuses after administration of 14C-perindopril to pregnant rats.
Radioactivity was detectable in fetuses after administration of 14C-[[perindopril]] to pregnant rats.
|useInNursing=It is not known whether [[perindopril]] or [[amlodipine]] is excreted in human milk, but radioactivity was detected in the milk of lactating rats following administration of 14C-perindopril. Because of the potential for adverse effects on the nursing infant, decide whether to discontinue nursing or discontinue [[perindopril]] arginine and [[amlodipine besylate]].
 
|useInNursing=It is not known whether [[perindopril]] or [[amlodipine]] is excreted in human milk, but radioactivity was detected in the milk of lactating rats following administration of 14C-[[perindopril]]. Because of the potential for adverse effects on the nursing infant, decide whether to discontinue nursing or discontinue [[perindopril]] arginine and [[amlodipine besylate]].
|useInPed=Neonates with a history of in utero exposure to [[perindopril]] arginine and [[amlodipine besylate]]:
|useInPed=Neonates with a history of in utero exposure to [[perindopril]] arginine and [[amlodipine besylate]]:
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]].
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 [[perindopril]] arginine and [[amlodipine besylate]] in pediatric patients have not been established.
The safety and effectiveness of [[perindopril]] arginine and [[amlodipine besylate]] in pediatric patients have not been established.
|useInGeri=The mean [[blood pressure]] effect of [[perindopril]] was somewhat smaller in patients over 60 years of age than in younger patients, although the difference was not significant. Plasma concentrations of both [[perindopril]] and [[perindopril|perindoprilat]] in elderly patients (>65 years) are approximately twice those observed in younger patients. No adverse effects were clearly increased in older patients with the exception of dizziness and rash.
|useInGeri=The mean [[blood pressure]] effect of [[perindopril]] was somewhat smaller in patients over 60 years of age than in younger patients, although the difference was not significant. Plasma concentrations of both [[perindopril]] and [[perindopril|perindoprilat]] in elderly patients (>65 years) are approximately twice those observed in younger patients. No adverse effects were clearly increased in older patients with the exception of dizziness and rash.


Amlodipine is extensively metabolized in the liver. In the elderly, clearance of [[amlodipine]] is decreased with resulting increases in peak plasma levels, elimination half-life, and AUC.
[[Amlodipine]] is extensively [[metabolism|metabolized]] in the [[liver]]. In the elderly, clearance of [[amlodipine]] is decreased with resulting increases in peak plasma levels, elimination half-life, and AUC.


Experience with [[perindopril]] arginine and [[amlodipine besylate]] is limited in the elderly at doses exceeding 7/5 mg. If doses above 7/5 mg are required, monitor [[blood pressure]] up to two weeks following up [[titration]].
Experience with [[perindopril]] arginine and [[amlodipine besylate]] is limited in the elderly at doses exceeding 7/5 mg. If doses above 7/5 mg are required, monitor [[blood pressure]] up to two weeks following up [[titration]].
|useInRenalImpair=Pharmacokinetic data indicate that [[perindopril|perindoprilat]] elimination is decreased in renally impaired patients, with a marked increase in accumulation when creatinine clearance drops below 30 mL/min. [[Perindopril]] arginine and [[amlodipine besylate]] is not recommended in patients with creatinine clearances <30 mL/min. For patients with creatinine clearance between 30 and 80 mL/min (mild or moderate [[renal impairment]]), do not exceed 7/5 mg.
|useInRenalImpair=Pharmacokinetic data indicate that [[perindopril|perindoprilat]] elimination is decreased in renally impaired patients, with a marked increase in accumulation when [[creatinine clearance]] drops below 30 mL/min. [[Perindopril]] arginine and [[amlodipine besylate]] is not recommended in patients with [[creatinine clearance|creatinine clearances]] <30 mL/min. For patients with [[creatinine clearance]] between 30 and 80 mL/min (mild or moderate [[renal impairment]]), do not exceed 7/5 mg.
|administration=Lowering [[blood pressure]] reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and [[myocardial infarction|myocardial infarctions]].
|administration=Lowering [[blood pressure]] reduces the risk of fatal and nonfatal cardiovascular events, primarily [[strokes]] and [[myocardial infarction|myocardial infarctions]].


These benefits have been seen in controlled trials of [[antihypertensive drugs]] from a wide variety of pharmacologic classes, including [[amlodipine]] and the [[ACE inhibitor]] class to which [[perindopril]] principally belongs. There are no controlled trials demonstrating risk reduction with [[perindopril]] arginine and [[amlodipine besylate]].
These benefits have been seen in controlled trials of [[antihypertensive drugs]] from a wide variety of pharmacologic classes, including [[amlodipine]] and the [[ACE inhibitor]] class to which [[perindopril]] principally belongs. There are no controlled trials demonstrating risk reduction with [[perindopril]] arginine and [[amlodipine besylate]].


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).
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.
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 pressure|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.
Elevated [[systolic]] or [[diastolic]] pressure causes increased cardiovascular risk, and the absolute risk increase per mmHg is greater at higher [[blood pressure|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. In a clinical trial of [[perindopril]] arginine and [[amlodipine besylate]], treatment with [[perindopril]] arginine and [[amlodipine besylate]] 14/10 mg did not provide additional [[antihypertensive]] effect beyond that achieved with use of [[amlodipine]] 10 mg in black and diabetic patients.
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 [[diabetes|diabetic]] [[kidney disease]]). These considerations may guide selection of therapy. In a clinical trial of [[perindopril]] arginine and [[amlodipine besylate]], treatment with [[perindopril]] arginine and [[amlodipine besylate]] 14/10 mg did not provide additional [[antihypertensive]] effect beyond that achieved with use of [[amlodipine]] 10 mg in black and diabetic patients.
The choice of [[perindopril]] arginine and [[amlodipine besylate]] as initial therapy for [[hypertension]] should be based on an assessment of potential benefits and risks including whether the patient is likely to tolerate the starting dose of [[perindopril]] arginine and [[amlodipine besylate]].
The choice of [[perindopril]] arginine and [[amlodipine besylate]] as initial therapy for [[hypertension]] should be based on an assessment of potential benefits and risks including whether the patient is likely to tolerate the starting dose of [[perindopril]] arginine and [[amlodipine besylate]].


Patients with moderate-to-severe [[hypertension]] are at a relatively high risk of cardiovascular events (e.g., stroke, heart attack, and heart failure), kidney failure, and vision problems, so prompt treatment is clinically relevant. Consider the patient's baseline [[blood pressure]], target goal and the incremental likelihood of achieving the goal with a combination product, such as [[perindopril]] arginine and [[amlodipine besylate]], versus a [[monotherapy]] product when deciding upon initial therapy. Individual [[blood pressure]] goals may vary based on the patient's risk.
Patients with moderate-to-severe [[hypertension]] are at a relatively high risk of cardiovascular events (e.g., [[stroke]], [[heart attack]], and [[heart failure]]), [[kidney failure]], and vision problems, so prompt treatment is clinically relevant. Consider the patient's baseline [[blood pressure]], target goal and the incremental likelihood of achieving the goal with a combination product, such as [[perindopril]] arginine and [[amlodipine besylate]], versus a [[monotherapy]] product when deciding upon initial therapy. Individual [[blood pressure]] goals may vary based on the patient's risk.


Data from an 6-week, active-controlled trial provide estimates of the probability of reaching a target [[blood pressure]] with [[perindopril]] arginine and [[amlodipine besylate]] compared with [[perindopril]] erbumine or [[amlodipine]] [[monotherapy]].
Data from an 6-week, active-controlled trial provide estimates of the probability of reaching a target [[blood pressure]] with [[perindopril]] arginine and [[amlodipine besylate]] compared with [[perindopril]] erbumine or [[amlodipine]] [[monotherapy]].


FIGURES 1.A-1.D provide estimates of the likelihood of achieving target clinic systolic and [[diastolic blood pressure]] control with [[perindopril]] arginine and [[amlodipine besylate]] 14/10 mg tablets after 6 weeks, based on baseline systolic and [[diastolic blood pressure]]. The curve for each treatment group was estimated by logistic regression modeling and is less well defined in the tails.
FIGURES 1.A-1.D provide estimates of the likelihood of achieving target clinic [[systolic]] and [[diastolic blood pressure]] control with [[perindopril]] arginine and [[amlodipine besylate]] 14/10 mg tablets after 6 weeks, based on baseline [[systolic]] and [[diastolic blood pressure]]. The curve for each treatment group was estimated by logistic regression modeling and is less well defined in the tails.
FIGURE 1 A-D
[[File:Perindopril arginine and amlodipine besylate F1a.JPG|thumb|none|400px|This image is provided by the National Library of Medicine.]]
For example, a patient with a baseline [[blood pressure]] of 170/105 mmHg has approximately a 26% likelihood of achieving a goal of <140 mmHg (systolic) and 31% likelihood of achieving <90 mmHg (diastolic) on [[perindopril]] erbumine 16 mg. The likelihood of achieving these same goals on [[amlodipine]] 10 mg is approximately 40% (systolic) and 46% (diastolic). These likelihoods rise to 50% (systolic) and 65% (diastolic) with [[perindopril]] arginine and [[amlodipine besylate]] 14/10 mg.
[[File:Perindopril arginine and amlodipine besylate F1b.JPG|thumb|none|400px|This image is provided by the National Library of Medicine.]]
[[File:Perindopril arginine and amlodipine besylate F1c.JPG|thumb|none|400px|This image is provided by the National Library of Medicine.]]
[[File:Perindopril arginine and amlodipine besylate F1d.JPG|thumb|none|400px|This image is provided by the National Library of Medicine.]]
For example, a patient with a baseline [[blood pressure]] of 170/105 mmHg has approximately a 26% likelihood of achieving a goal of <140 mmHg (systolic) and 31% likelihood of achieving <90 mmHg ([[diastolic]]) on [[perindopril]] erbumine 16 mg. The likelihood of achieving these same goals on [[amlodipine]] 10 mg is approximately 40% ([[systolic]]) and 46% ([[diastolic]]). These likelihoods rise to 50% ([[systolic]]) and 65% ([[diastolic]]) with [[perindopril]] arginine and [[amlodipine besylate]] 14/10 mg.
|monitoring=Monitoring in Elderly Patients (Over 65 Years of Age):
|monitoring=Monitoring in Elderly Patients (Over 65 Years of Age):
Monitor [[blood pressure]] for up to two weeks following [[titration|titrations]] at dosages above 7/5 mg in patients over 65 years of age.
Monitor [[blood pressure]] for up to two weeks following [[titration|titrations]] at dosages above 7/5 mg in patients over 65 years of age.
|overdose=Perindopril:
|overdose=[[Perindopril]]:
In animals, doses of [[perindopril]] up to 2,500 mg/kg in mice, 3,000 mg/kg in rats and 1,600 mg/kg in dogs were non-lethal. Past experiences were scant but suggested that overdosage with other [[ACE inhibitor|ACE inhibitors]] was also fairly well tolerated by humans. The most likely manifestation is hypotension, and treatment should be symptomatic and supportive. Therapy with the [[ACE inhibitor]] should be discontinued, and the patient should be observed. Dehydration, electrolyte imbalance and hypotension should be treated by established procedures.


Among the reported cases of [[perindopril]] overdosage, patients who were known to have ingested a dose of 80 mg to 120 mg required assisted ventilation and circulatory support. One additional patient developed hypothermia, circulatory arrest and died following ingestion of up to 180 mg of [[perindopril]]. The intervention for [[perindopril]] overdose may require vigorous support.
In animals, doses of [[perindopril]] up to 2,500 mg/kg in mice, 3,000 mg/kg in rats and 1,600 mg/kg in dogs were non-lethal. Past experiences were scant but suggested that overdosage with other [[ACE inhibitor|ACE inhibitors]] was also fairly well tolerated by humans. The most likely manifestation is [[hypotension]], and treatment should be symptomatic and supportive. Therapy with the [[ACE inhibitor]] should be discontinued, and the patient should be observed. [[Dehydration]], [[electrolyte imbalance]] and [[hypotension]] should be treated by established procedures.


Laboratory determinations of serum levels of [[perindopril]] and its metabolites are not widely available, and such determinations have, in any event, no established role in the management of [[perindopril]] overdose. No data are available to suggest physiological maneuvers (e.g., maneuvers to change the pH of the urine) that might accelerate elimination of [[perindopril]] and its metabolites.
Among the reported cases of [[perindopril]] overdosage, patients who were known to have ingested a dose of 80 mg to 120 mg required assisted ventilation and circulatory support. One additional patient developed [[hypothermia]], [[circulatory arrest]] and died following ingestion of up to 180 mg of [[perindopril]]. The intervention for [[perindopril]] overdose may require vigorous support.


Angiotensin II could presumably serve as a specific antagonist-antidote in the settling of [[perindopril]] overdose, but angiotensin II is essentially unavailable outside of scattered research facilities. Because the hypotensive effect of [[perindopril]] is achieved through vasodilation and effective hypovolemia, it is reasonable to treat [[perindopril]] overdose by infusion of normal saline solution.
Laboratory determinations of serum levels of [[perindopril]] and its [[metabolites]] are not widely available, and such determinations have, in any event, no established role in the management of [[perindopril]] overdose. No data are available to suggest physiological maneuvers (e.g., maneuvers to change the pH of the urine) that might accelerate elimination of [[perindopril]] and its [[metabolites]].


Amlodipine:
[[Angiotensin II]] could presumably serve as a specific antagonist-antidote in the setting of [[perindopril]] overdose, but [[angiotensin II]] is essentially unavailable outside of scattered research facilities. Because the hypotensive effect of [[perindopril]] is achieved through [[vasodilation]] and effective [[hypovolemia]], it is reasonable to treat [[perindopril]] overdose by infusion of normal saline solution.
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.


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.
[[Amlodipine]]:


If massive overdose should occur, initiate active cardiac and respiratory monitoring. Frequent [[blood pressure]] measurements are essential. Should hypotension occur, provide cardiovascular support including elevation of the extremities and the judicious administration of fluids. If hypotension remains unresponsive to these conservative measures, consider administration of vasopressors (such as phenylephrine) with attention to circulating volume and urine output. As [[amlodipine]] is highly protein bound, hemodialysis is not likely to be of benefit.
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.
|drugBox={{Drugbox2
| Verifiedfields = changed
| verifiedrevid = 464199140
| IUPAC_name = (2''S'',3''aS'',7''aS'')-1-[(2''S'')-2-<nowiki/>{[(2''S'')-1-ethoxy-1-oxopentan-2-yl]amino}propanoyl]-octahydro-1''H''-indole-2-carboxylic acid
| image = Perindopril structure.svg
| width = 222


<!--Clinical data-->
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]].
| tradename = Coversyl, Coversum, Preterax, Aceon
| Drugs.com = {{drugs.com|monograph|aceon}}
| pregnancy_US = D
| legal_US = Rx-only
| routes_of_administration = Oral


<!--Pharmacokinetic data-->
If massive overdose should occur, initiate active cardiac and respiratory monitoring. Frequent [[blood pressure]] measurements are essential. Should [[hypotension]] occur, provide cardiovascular support including elevation of the extremities and the judicious administration of fluids. If [[hypotension]] remains unresponsive to these conservative measures, consider administration of [[vasopressors]] (such as [[phenylephrine]]) with attention to circulating volume and urine output. As [[amlodipine]] is highly protein bound, [[hemodialysis]] is not likely to be of benefit.
| bioavailability = 24%
|drugBox=[[File: Perindopril arginine drugbox.JPG|thumb|none|400px]]
| protein_bound = 20%
[[File: Amlodipine besylate drugbox.JPG|thumb|none|400px]]
| metabolism = Renal
|mechAction=[[Perindopril]]:
| elimination_half-life = 1&ndash;17 hours for perindoprilat (active metabolite)


<!--Identifiers-->
[[Perindopril]], a pro-drug, is hydrolyzed to [[perindopril|perindoprilat]], which inhibits [[ACE]] in humans and in animals. [[ACE]] is a peptidyl [[dipeptidase]] that catalyzes the conversion of the inactive [[decapeptide]], [[angiotensin I]], to the [[vasoconstrictor]] substance [[angiotensin II]]. [[Angiotensin II]] is a potent peripheral [[vasoconstrictor]], which stimulates [[aldosterone]] secretion by the [[adrenal cortex]], and provides negative feedback on [[renin]] secretion. Inhibition of [[ACE]] results in decreased plasma [[angiotensin II]], leading to decreased [[vasoconstriction]], increased plasma [[renin]] activity and decreased [[aldosterone]] secretion. The latter results in [[diuresis]] and [[natriuresis]] and may be associated with an increase in serum [[potassium]].
| IUPHAR_ligand = 6367
[[ACE]] is identical to [[kininase II]], an enzyme that degrades [[bradykinin]]. Whether increased levels of [[bradykinin]], a potent [[vasodepressor]] [[peptide]], play a role in the therapeutic effects of [[perindopril]] remains to be elucidated.
| CAS_number_Ref = {{cascite|changed|??}}
| CAS_number = 82834-16-0
| ATC_prefix = C09
| ATC_suffix = AA04
| ATC_supplemental = <br>{{ATC|C09|BA04}} (with [[diuretic]]s)<br>{{ATC|C09|BB04}} (with [[amlodipine]])
| PubChem = 107807
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB00790
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 96956
| UNII_Ref = {{fdacite|changed|FDA}}
| UNII = 1964X464OJ
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D03753
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 8024
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 1581


<!--Chemical data-->
While the principal mechanism of [[perindopril]] in [[blood pressure]] reduction is believed to be through the [[renin-angiotensin-aldosterone system]], [[ACE inhibitor|ACE inhibitors]] have some effect even in apparent low-renin [[hypertension]]. [[Perindopril]] has been studied in relatively few black patients, usually a low-renin population, and the average response of [[diastolic blood pressure]] to [[perindopril]] was about half the response seen in nonblack patients, a finding consistent with previous experience of other [[ACE inhibitor|ACE inhibitors]].
| C=19 | H=32 | N=2 | O=5
| molecular_weight = 368.468 g/mol
| smiles = O=C(OCC)[C@@H](N[C@H](C(=O)N1[C@H](C(=O)O)C[C@@H]2CCCC[C@H]12)C)CCC
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C19H32N2O5/c1-4-8-14(19(25)26-5-2)20-12(3)17(22)21-15-10-7-6-9-13(15)11-16(21)18(23)24/h12-16,20H,4-11H2,1-3H3,(H,23,24)/t12-,13-,14-,15-,16-/m0/s1
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = IPVQLZZIHOAWMC-QXKUPLGCSA-N
}}
{{Drugbox2
| verifiedrevid = 456689822
| IUPAC_name = (''RS'')-3-ethyl 5-methyl 2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate
| image = Amlodipine.svg
| width = 230
| image2 = Amlodipine 3D ball.png
| width2 = 200
| chirality = [[Racemic mixture]]
<!-- Clinical data -->
| pronounce = {{IPAc-en|æ|m|ˈ|l|oʊ|d|ə|ˌ|p|i|n}}<ref>{{cite web|title=Medical Definition of AMLODIPINE|url=https://www.merriam-webster.com/medical/amlodipine|website=www.merriam-webster.com|accessdate=5 July 2017|language=en}}</ref>
| tradename = Norvasc, others
| Drugs.com = {{drugs.com|monograph|amlodipine-besylate}}
| MedlinePlus = a692044
| license_US = Amlodipine
| license_EU = Amlodipine
| DailyMedID=Amlodipine
| pregnancy_AU = C
| pregnancy_US = C
<!--| legal_UK = POM
| legal_US = Rx-only
| legal_AU = S4 https://www.legislation.gov.au/Details/F2017L00605
| legal_CA = Rx-only http://napra.ca/pages/schedules/search.aspx
-->
| legal_status=Rx-only
| routes_of_administration = [[Oral administration|By mouth]]
<!-- Pharmacokinetic data -->
| bioavailability = 64–90%
| protein_bound = 93% <!-- <ref name=norvasc />-->
| metabolism = [[Liver]]
| metabolites = Various inactive pyrimidine metabolites
| onset = Highest availability 6–12 hours after oral dose <!-- drugs.com monograph -->
| elimination_half-life = 30–50 hours
| duration_of_action = At least 24 hours <!-- drugs.com monograph -->
| excretion = [[Urine]] <!-- drugs.com monograph -->
<!-- Identifiers -->
| IUPHAR_ligand = 6981
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 88150-42-9
| ATC_prefix = C08
| ATC_suffix = CA01
| PubChem = 2162
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB00381
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 2077
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = 1J444QC288
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D07450
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 2668
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 1491
| PDB_ligand = 6UB
<!-- Chemical data -->
| C=20 | H=25 | Cl=1 | N=2 | O=5
| molecular_weight = 408.879 g/mol
| smiles = Clc1ccccc1C2C(=C(/N/C(=C2/C(=O)OCC)COCCN)C)\C(=O)OC
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C20H25ClN2O5/c1-4-28-20(25)18-15(11-27-10-9-22)23-12(2)16(19(24)26-3)17(18)13-7-5-6-8-14(13)21/h5-8,17,23H,4,9-11,22H2,1-3H3
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = HTIQEAQVCYTUBX-UHFFFAOYSA-N
}}
|mechAction=Perindopril:
Perindopril, a pro-drug, is hydrolyzed to [[perindopril|perindoprilat]], which inhibits ACE in humans and in animals. ACE is a peptidyl dipeptidase that catalyzes the conversion of the inactive decapeptide, angiotensin I, to the vasoconstrictor substance angiotensin II. Angiotensin II is a potent peripheral vasoconstrictor, which stimulates aldosterone secretion by the adrenal cortex, and provides negative feedback on renin secretion. Inhibition of ACE results in decreased plasma angiotensin II, leading to decreased vasoconstriction, increased plasma renin activity and decreased aldosterone secretion. The latter results in diuresis and natriuresis and may be associated with an increase in serum potassium.
ACE is identical to kininase II, an enzyme that degrades [[bradykinin]]. Whether increased levels of [[bradykinin]], a potent vasodepressor peptide, play a role in the therapeutic effects of [[perindopril]] remains to be elucidated.


While the principal mechanism of [[perindopril]] in [[blood pressure]] reduction is believed to be through the renin-angiotensin-aldosterone system, [[ACE inhibitor|ACE inhibitors]] have some effect even in apparent low-renin [[hypertension]]. [[Perindopril]] has been studied in relatively few black patients, usually a low-renin population, and the average response of [[diastolic blood pressure]] to [[perindopril]] was about half the response seen in nonblack patients, a finding consistent with previous experience of other [[ACE inhibitor|ACE inhibitors]].
[[Amlodipine]]:


Amlodipine:
Amlodipine is a [[dihydropyridine]] [[calcium antagonist]] (calcium ion antagonist or slow channel blocker) that inhibits the transmembrane influx of [[calcium ions]] into vascular [[smooth muscle]] and [[cardiac muscle]]. Experimental data suggest that [[amlodipine]] binds to both [[dihydropyridine]] and nondihydropyridine binding sites. The contractile processes of [[cardiac muscle]] and vascular [[smooth muscle]] are dependent upon the movement of extracellular [[calcium ions]] into these cells through specific [[ion channels]]. [[Amlodipine]] inhibits [[calcium ion]] influx across cell membranes selectively, with a greater effect on vascular [[smooth muscle]] cells than on cardiac muscle cells. Negative [[inotropic]] effects can be detected in vitro but such effects have not been seen in intact animals at therapeutic doses.
Amlodipine is a [[dihydropyridine]] calcium antagonist (calcium ion antagonist or slow channel blocker) that inhibits the transmembrane influx of calcium ions into vascular smooth muscle and cardiac muscle. Experimental data suggest that [[amlodipine]] binds to both [[dihydropyridine]] and nondihydropyridine binding sites. The contractile processes of cardiac muscle and vascular smooth muscle are dependent upon the movement of extracellular calcium ions into these cells through specific ion channels. [[Amlodipine]] inhibits calcium ion influx across cell membranes selectively, with a greater effect on vascular smooth muscle cells than on cardiac muscle cells. Negative inotropic effects can be detected in vitro but such effects have not been seen in intact animals at therapeutic doses.


Serum calcium concentration is not affected by [[amlodipine]]. Within the physiologic pH range, [[amlodipine]] is an ionized compound (pKa=8.6), and its kinetic interaction with the [[calcium channel]] receptor is characterized by a gradual rate of association and dissociation with the receptor binding site, resulting in a gradual onset of effect.
Serum calcium concentration is not affected by [[amlodipine]]. Within the physiologic pH range, [[amlodipine]] is an ionized compound (pKa=8.6), and its kinetic interaction with the [[calcium channel]] receptor is characterized by a gradual rate of association and dissociation with the receptor binding site, resulting in a gradual onset of effect.


Amlodipine is a peripheral arterial vasodilator that acts directly on vascular smooth muscle to cause a reduction in peripheral vascular resistance and reduction in [[blood pressure]].
Amlodipine is a peripheral arterial [[vasodilator]] that acts directly on vascular [[smooth muscle]] to cause a reduction in peripheral vascular resistance and reduction in [[blood pressure]].
|structure=[[Perindopril]] arginine and [[amlodipine besylate]] is a combination of [[perindopril]] arginine and [[amlodipine]] besylate.
|structure=[[Perindopril]] arginine and [[amlodipine besylate]] is a combination of [[perindopril]] arginine and [[amlodipine]] besylate.


Perindopril arginine is the L-arginine salt of [[perindopril]], the ethyl ester of a non-sulfhydryl [[angiotensin converting enzyme inhibitor]]. [[Perindopril]] arginine is chemically described as L-arginine (2S,3aS,7aS)-1-[(2S)-2-[(1S)-1-(ethoxycarbonyl)butyl]amino]propanoyl] octahydro-1H-indole-2-carboxylate. Its empirical formula is C19H32N2O5•C6H14N4O2 and its structural formula is:
[[Perindopril]] arginine is the L-arginine salt of [[perindopril]], the ethyl ester of a non-sulfhydryl [[angiotensin converting enzyme inhibitor]]. [[Perindopril]] arginine is chemically described as L-arginine (2S,3aS,7aS)-1-[(2S)-2-[(1S)-1-(ethoxycarbonyl)butyl]amino]propanoyl] octahydro-1H-indole-2-carboxylate. Its empirical formula is C19H32N2O5•C6H14N4O2 and its structural formula is:
STRUCTURE 1
[[File:Perindopril arginine and amlodipine besylate structure1.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]]
Perindopril arginine is a white, crystalline powder with a molecular weight 542.7. The free acid has the molecular weight of 368.5. It is readily soluble in purified water, slightly soluble in 95% ethanol, and practically insoluble in chloroform.
[[Perindopril]] arginine is a white, crystalline powder with a molecular weight 542.7. The free acid has the molecular weight of 368.5. It is readily soluble in purified water, slightly soluble in 95% [[ethanol]], and practically insoluble in [[chloroform]].


Perindopril is the free-acid form of [[perindopril]] arginine. [[Perindopril]] is a pro-drug and is metabolized in vivo by hydrolysis of the ester group to form [[perindopril|perindoprilat]], the biologically active metabolite.
[[Perindopril]] is the free-acid form of [[perindopril]] arginine. [[Perindopril]] is a pro-drug and is metabolized in vivo by [[hydrolysis]] of the ester group to form [[perindopril|perindoprilat]], the biologically active [[metabolite]].


[[Amlodipine besylate]] is the benzene sulphonic acid salt of [[amlodipine]], a long-acting [[dihydropyridine]] [[calcium channel blocker]]. [[Amlodipine besylate]] is chemically described as 3-ethyl-5-methyl (±)-2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-1,4-dihydro-6-methyl-3,5-pyridinedicarboxylate monobenzenesulphonate. Its empirical formula is C20H25ClN2O5•C6H6O3S and its structural formula is:
[[Amlodipine besylate]] is the benzene sulphonic acid salt of [[amlodipine]], a long-acting [[dihydropyridine]] [[calcium channel blocker]]. [[Amlodipine besylate]] is chemically described as 3-ethyl-5-methyl (±)-2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-1,4-dihydro-6-methyl-3,5-pyridinedicarboxylate monobenzenesulphonate. Its empirical formula is C20H25ClN2O5•C6H6O3S and its structural formula is:
STRUCTURE 2
[[File:Perindopril arginine and amlodipine besylate structure2.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]]
Amlodipine besylate is a white crystalline powder with a molecular weight of 567.1. It is slightly soluble in water and sparingly soluble in ethanol. The content of the tablets is expressed as [[amlodipine]] (free base) which has a molecular weight of 409.1.
Amlodipine besylate is a white crystalline powder with a molecular weight of 567.1. It is slightly soluble in water and sparingly soluble in [[ethanol]]. The content of the tablets is expressed as [[amlodipine]] (free base) which has a molecular weight of 409.1.


[[Perindopril]] arginine and [[amlodipine besylate]] tablets are formulated in three different strengths for oral administration. Tablets contain [[perindopril]] arginine 3.5 mg, 7 mg, or 14 mg and [[amlodipine]] 2.5 mg, 5 mg, or 10 mg for the following available [[perindopril]] arginine/amlodipine combinations: 3.5/2.5 mg, 7/5 mg, and 14/10 mg.
[[Perindopril]] arginine and [[amlodipine besylate]] tablets are formulated in three different strengths for oral administration. Tablets contain [[perindopril]] arginine 3.5 mg, 7 mg, or 14 mg and [[amlodipine]] 2.5 mg, 5 mg, or 10 mg for the following available [[perindopril]] arginine/amlodipine combinations: 3.5/2.5 mg, 7/5 mg, and 14/10 mg.


Inactive ingredients are lactose, microcrystalline cellulose, colloidal silicon dioxide, and magnesium stearate.
Inactive ingredients are [[lactose]], [[microcrystalline cellulose]], colloidal [[silicon dioxide]], and [[magnesium stearate]].
|PD=Perindopril:
|PD=[[Perindopril]]:
After administration of [[perindopril]], ACE is inhibited in a dose and blood concentration-related fashion. The degree of [[ACE inhibitor|ACE inhibition]] achieved by a given dose appears to diminish over time (the ID50 increases). The pressor response to an angiotensin I infusion is reduced by [[perindopril]], but this is not as persistent as the effect on ACE.


Amlodipine:
After administration of [[perindopril]], [[ACE]] is inhibited in a dose and blood concentration-related fashion. The degree of [[ACE inhibitor|ACE inhibition]] achieved by a given dose appears to diminish over time (the ID50 increases). The pressor response to an [[angiotensin I]] infusion is reduced by [[perindopril]], but this is not as persistent as the effect on [[ACE]].
Following administration of therapeutic doses to patients with [[hypertension]], [[amlodipine]] produces vasodilation resulting in a reduction of supine and standing [[blood pressure|blood pressures]]. These decreases in [[blood pressure]] are not accompanied by a significant change in heart rate or plasma catecholamine levels with chronic dosing. Although the acute intravenous administration of [[amlodipine]] decreases arterial [[blood pressure]] and increases heart rate in hemodynamic studies of patients with [[chronic stable angina]], chronic oral administration of [[amlodipine]] in clinical trials did not lead to clinically significant changes in heart rate or [[blood pressure|blood pressures]] in normotensive patients with [[angina]].


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 did patients with mild [[hypertension]] (diastolic pressure 90-104 mmHg). Normotensive subjects experienced no clinically significant change in [[blood pressure|blood pressures]] (+1/-2 mmHg).
[[Amlodipine]]:


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.
Following administration of therapeutic doses to patients with [[hypertension]], [[amlodipine]] produces [[vasodilation]] resulting in a reduction of [[supine]] and standing [[blood pressure|blood pressures]]. These decreases in [[blood pressure]] are not accompanied by a significant change in heart rate or plasma [[catecholamine]] levels with [[chronic]] dosing. Although the acute [[intravenous]] administration of [[amlodipine]] decreases arterial [[blood pressure]] and increases heart rate in [[hemodynamic]] studies of patients with [[chronic stable angina]], [[chronic]] oral administration of [[amlodipine]] in clinical trials did not lead to clinically significant changes in heart rate or [[blood pressure|blood pressures]] in normotensive patients with [[angina]].


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 humans, even when co-administered with β-blockers to humans. Similar findings, however, have been observed in normal or well-compensated patients with heart failure with agents possessing significant negative inotropic effects.
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 did patients with mild [[hypertension]] ([[diastolic pressure]] 90-104 mmHg). Normotensive subjects experienced no clinically significant change in [[blood pressure|blood pressures]] (+1/-2 mmHg).


Electrophysiologic Effects: [[Amlodipine]] does not change sinoatrial (SA) nodal function or atrioventricular (AV) conduction in intact animals or humans. In clinical studies in which [[amlodipine]] was administered in combination with β-blockers to patients with either [[hypertension]] or [[angina]], no adverse effects on electrocardiographic parameters were observed.
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 humans, even when co-administered with [[β-blockers]] to humans. Similar findings, however, have been observed in normal or well-compensated patients with heart failure with agents possessing significant negative [[inotropic]] effects.
 
Electrophysiologic Effects: [[Amlodipine]] does not change [[sinoatrial]] (SA) nodal function or [[AV node|atrioventricular]] (AV) conduction in intact animals or humans. In clinical studies in which [[amlodipine]] was administered in combination with [[β-blockers]] to patients with either [[hypertension]] or [[angina]], no adverse effects on electrocardiographic parameters were observed.
|PK=[[Perindopril]] arginine and [[amlodipine besylate]]:
|PK=[[Perindopril]] arginine and [[amlodipine besylate]]:
Following administration of [[perindopril]] arginine and [[amlodipine besylate]], peak plasma concentration of [[perindopril]], [[perindopril|perindoprilat]] and [[amlodipine]] occur at approximately 1 hour, 4 hours and 6-12 hours, respectively. The mean half-life of [[perindopril]] is approximately 1.3 hours. The decline in the plasma concentration of [[perindopril|perindoprilat]] is multiphasic and shows a terminal elimination half-life of approximately 100 hours, resulting from slow dissociation of [[perindopril|perindoprilat]] from plasma/tissue ACE binding sites. [[Amlodipine]] elimination from plasma is biphasic with a terminal elimination half-life of approximately 30 to 50 hours.
Following administration of [[perindopril]] arginine and [[amlodipine besylate]], peak plasma concentration of [[perindopril]], [[perindopril|perindoprilat]] and [[amlodipine]] occur at approximately 1 hour, 4 hours and 6-12 hours, respectively. The mean half-life of [[perindopril]] is approximately 1.3 hours. The decline in the plasma concentration of [[perindopril|perindoprilat]] is multiphasic and shows a terminal elimination half-life of approximately 100 hours, resulting from slow dissociation of [[perindopril|perindoprilat]] from plasma/tissue [[ACE]] binding sites. [[Amlodipine]] elimination from plasma is biphasic with a terminal elimination half-life of approximately 30 to 50 hours.


When [[perindopril]] arginine and [[amlodipine besylate]] is administered with food, the exposure to [[perindopril]], [[perindopril|perindoprilat]] and [[amlodipine]] is not impacted.
When [[perindopril]] arginine and [[amlodipine besylate]] is administered with food, the exposure to [[perindopril]], [[perindopril|perindoprilat]] and [[amlodipine]] is not impacted.


Perindopril:
[[Perindopril]]:
Following administration of [[perindopril]] arginine and [[amlodipine besylate]], [[perindopril]] is rapidly absorbed, with peak plasma concentrations occurring at approximately 1 hour. The absolute oral bioavailability of [[perindopril]] is approximately 75%. Following absorption, approximately 30% to 50% of systemically available [[perindopril]] is hydrolyzed to its active metabolite, [[perindopril|perindoprilat]], which has a mean bioavailability of approximately 25%. Peak plasma concentrations of [[perindopril|perindoprilat]] are attained approximately 4 hours after [[perindopril]] arginine and [[amlodipine besylate]] administration. Food had no effect on the extent of absorption of [[perindopril]] or [[perindopril|perindoprilat]], but slightly reduced the rate of absorption of [[perindopril]] and [[perindopril|perindoprilat]] by 18% and 14%, respectively.


The Cmax and AUC of [[perindopril]] and [[perindopril|perindoprilat]] increase in a linear and dose proportional manner following both single oral dosing and at steady state during an once-a-day multiple dosing regimen. [[Perindopril]] exhibits multiexponential pharmacokinetics following oral administration. The mean half-life of [[perindopril]] associated with most of its elimination is approximately 0.8 to 1 hours.
Following administration of [[perindopril]] arginine and [[amlodipine besylate]], [[perindopril]] is rapidly absorbed, with peak plasma concentrations occurring at approximately 1 hour. The absolute oral bioavailability of [[perindopril]] is approximately 75%. Following absorption, approximately 30% to 50% of systemically available [[perindopril]] is hydrolyzed to its active [[metabolite]], [[perindopril|perindoprilat]], which has a mean bioavailability of approximately 25%. Peak plasma concentrations of [[perindopril|perindoprilat]] are attained approximately 4 hours after [[perindopril]] arginine and [[amlodipine besylate]] administration. Food had no effect on the extent of absorption of [[perindopril]] or [[perindopril|perindoprilat]], but slightly reduced the rate of absorption of [[perindopril]] and [[perindopril|perindoprilat]] by 18% and 14%, respectively.


Perindopril is extensively metabolized following oral administration, with only 4% to 12% of the dose recovered unchanged in the urine. Six metabolites resulting from hydrolysis, glucuronidation, and cyclization via dehydration have been identified. These include the active [[ACE inhibitor]] [[perindopril|perindoprilat]]
The [[Cmax]] and AUC of [[perindopril]] and [[perindopril|perindoprilat]] increase in a linear and dose proportional manner following both single oral dosing and at steady state during an once-a-day multiple dosing regimen. [[Perindopril]] exhibits multiexponential pharmacokinetics following oral administration. The mean half-life of [[perindopril]] associated with most of its elimination is approximately 0.8 to 1 hours.
(hydrolyzed [[perindopril]]), [[perindopril]], and [[perindopril|perindoprilat]] glucuronides, dehydrated [[perindopril]], and the diastereoisomers of dehydrated [[perindopril|perindoprilat]]. In humans, hepatic esterase appears to be responsible for the hydrolysis of [[perindopril]].


The active metabolite, [[perindopril|perindoprilat]], also exhibits multiexponential pharmacokinetics following the oral administration of [[perindopril]]. Formation of perindoprilat is gradual with peak plasma concentrations occurring between 3 and 7 hours. The subsequent decline in plasma concentration shows a prolonged terminal elimination half-life of 120 hours resulting from slow dissociation of [[perindopril|perindoprilat]] from plasma/tissue ACE binding sites. During repeated oral once-daily dosing with [[perindopril]], [[perindopril|perindoprilat]] accumulates about 1.5- to 2-fold and attains steady state plasma levels in 3 to 6 days. The clearance of [[perindopril|perindoprilat]] and its metabolites is almost exclusively renal.
[[Perindopril]] is extensively metabolized following oral administration, with only 4% to 12% of the dose recovered unchanged in the urine. Six [[metabolites]] resulting from [[hydrolysis]], [[glucuronidation]], and cyclization via dehydration have been identified. These include the active [[ACE inhibitor]] [[perindopril|perindoprilat]], (hydrolyzed [[perindopril]]), [[perindopril]], and [[perindopril|perindoprilat]] glucuronides, dehydrated [[perindopril]], and the diastereoisomers of dehydrated [[perindopril|perindoprilat]]. In humans, hepatic esterase appears to be responsible for the [[hydrolysis]] of [[perindopril]].
 
The active [[metabolite]], [[perindopril|perindoprilat]], also exhibits multiexponential pharmacokinetics following the oral administration of [[perindopril]]. Formation of [[perindopril|perindoprilat]] is gradual with peak plasma concentrations occurring between 3 and 7 hours. The subsequent decline in plasma concentration shows a prolonged terminal elimination half-life of 120 hours resulting from slow dissociation of [[perindopril|perindoprilat]] from plasma/tissue [[ACE]] binding sites. During repeated oral once-daily dosing with [[perindopril]], [[perindopril|perindoprilat]] accumulates about 1.5- to 2-fold and attains steady state plasma levels in 3 to 6 days. The clearance of [[perindopril|perindoprilat]] and its [[metabolites]] is almost exclusively renal.


Approximately 60% of circulating [[perindopril]] is bound to plasma proteins, and only 10% to 20% of [[perindopril|perindoprilat]] is bound. Therefore, drug interactions mediated through effects on protein binding are not anticipated.
Approximately 60% of circulating [[perindopril]] is bound to plasma proteins, and only 10% to 20% of [[perindopril|perindoprilat]] is bound. Therefore, drug interactions mediated through effects on protein binding are not anticipated.


Amlodipine:
[[Amlodipine]]:
 
Absolute bioavailability of [[amlodipine]] has been estimated between 64% and 90%. Ex vivo studies indicate that approximately 93% of circulating [[amlodipine]] is bound to plasma proteins in hypertensive patients.
Absolute bioavailability of [[amlodipine]] has been estimated between 64% and 90%. Ex vivo studies indicate that approximately 93% of circulating [[amlodipine]] is bound to plasma proteins in hypertensive patients.


Amlodipine is extensively (approximately 90%) metabolized in the liver to inactive metabolites. Steady-state plasma levels are reached after once-daily dosing for 7 to 8 days. 10% of unchanged drug and 60% of [[amlodipine]] metabolites are excreted in urine.
[[Amlodipine]] is extensively (approximately 90%) metabolized in the liver to inactive [[metabolites]]. Steady-state plasma levels are reached after once-daily dosing for 7 to 8 days. 10% of unchanged drug and 60% of [[amlodipine]] [[metabolites]] are excreted in [[urine]].


Drug Interactions:
Drug Interactions:
Perindopril: Co-administered [[perindopril]] does not impact the exposure to [[amlodipine]] or digoxin.
 
[[Amlodipine]]: Co-administered cimetidine, magnesium- and aluminum hydroxide antacids, sildenalfil, and grapefruit juice have no impact on the exposure to [[amlodipine]]. Co-administered [[amlodipine]] does not affect the exposure to [[perindopril]], [[perindopril|perindoprilat]], atorvastatin, ethanol and the warfarin prothrombin response time
[[Perindopril]]: Co-administered [[perindopril]] does not impact the exposure to [[amlodipine]] or [[digoxin]].
[[Amlodipine]]: Co-administered [[Cimetidine (injection)|cimetidine]], magnesium- and aluminum hydroxide [[antacids]], [[sildenalfil]], and [[grapefruit juice]] have no impact on the exposure to [[amlodipine]]. Co-administered [[amlodipine]] does not affect the exposure to [[perindopril]], [[perindopril|perindoprilat]], [[atorvastatin]], [[ethanol]] and the [[warfarin]] [[prothrombin]] response time


'''Use in Specific Populations:'''
'''Use in Specific Populations:'''
*Elderly:
*Elderly:
**Perindopril: Plasma concentrations of both [[perindopril]] and [[perindopril|perindoprilat]] in elderly patients (>65 years) are approximately twice those observed in younger patients, reflecting both increased conversion of [[perindopril]] to [[perindopril|perindoprilat]] and decreased renal excretion of [[perindopril|perindoprilat]].
**[[Perindopril]]: Plasma concentrations of both [[perindopril]] and [[perindopril|perindoprilat]] in elderly patients (>65 years) are approximately twice those observed in younger patients, reflecting both increased conversion of [[perindopril]] to [[perindopril|perindoprilat]] and decreased renal excretion of [[perindopril|perindoprilat]].
**Amlodipine: Clearance of [[amlodipine]] is decreased in elderly patients, resulting in an increased area under the plasma concentration curve (AUC) of approximately 40% to 60%.
**[[Amlodipine]]: Clearance of [[amlodipine]] is decreased in elderly patients, resulting in an increased area under the plasma concentration curve (AUC) of approximately 40% to 60%.
*[[renal impairment|Renal Impairment]]:
*[[renal impairment|Renal Impairment]]:
**Perindopril: [[perindopril|Perindoprilat]] elimination is decreased in renally impaired patients. At creatinine clearances of 30 mL/min to 80 mL/min, AUC is about double that at 100 mL/min. When creatinine clearance drops below 30 mL/min, AUC increases more markedly.
**[[Perindopril]]: [[perindopril|Perindoprilat]] elimination is decreased in renally impaired patients. At [[creatinine clearance|creatinine clearances]] of 30 mL/min to 80 mL/min, AUC is about double that at 100 mL/min. When [[creatinine clearance]] drops below 30 mL/min, AUC increases more markedly.
**During dialysis, [[perindopril]] is removed with the same clearance as in patients with normal [[renal function]]. In a limited number of patients studied, [[perindopril]] clearance by dialysis ranged from about 40 to 80 mL/min. [[perindopril|Perindoprilat]] clearance by dialysis ranged from about 40 to 90 mL/min.
**During [[dialysis]], [[perindopril]] is removed with the same clearance as in patients with normal [[renal function]]. In a limited number of patients studied, [[perindopril]] clearance by [[dialysis]] ranged from about 40 to 80 mL/min. [[perindopril|Perindoprilat]] clearance by [[dialysis]] ranged from about 40 to 90 mL/min.
**Amlodipine: The pharmacokinetics of [[amlodipine]] is not significantly influenced by [[renal impairment]].
**[[Amlodipine]]: The pharmacokinetics of [[amlodipine]] is not significantly influenced by [[renal impairment]].
*Hepatic Impairment:
*[[hepatic impairment|Hepatic Impairment]]:
**Perindopril: The bioavailability of [[perindopril|perindoprilat]] is increased in patients with impaired hepatic function. Plasma concentrations of [[perindopril|perindoprilat]] in patients with impaired liver function were about 50% higher than those observed in healthy subjects or hypertensive patients with normal liver function.
**[[Perindopril]]: The bioavailability of [[perindopril|perindoprilat]] is increased in patients with impaired hepatic function. Plasma concentrations of [[perindopril|perindoprilat]] in patients with impaired liver function were about 50% higher than those observed in healthy subjects or hypertensive patients with normal liver function.
**Amlodipine: Patients with hepatic insufficiency have decreased clearance of [[amlodipine]] with a resulting increase in AUC of approximately 40–60%.
**[[Amlodipine]]: Patients with hepatic insufficiency have decreased clearance of [[amlodipine]] with a resulting increase in AUC of approximately 40–60%.
*Heart Failure:
*[[heart failure|Heart Failure]]:
**[[Perindopril]]: [[perindopril|Perindoprilat]] clearance is reduced in congestive heart failure patients, resulting in a 40% higher dose interval AUC.
**[[Perindopril]]: [[perindopril|Perindoprilat]] clearance is reduced in [[congestive heart failure]] patients, resulting in a 40% higher dose interval AUC.
**[[Amlodipine]]: Patients with hepatic insufficiency have decreased clearance of [[amlodipine]] with a resulting increase in AUC of approximately 40–60%.
**[[Amlodipine]]: Patients with hepatic insufficiency have decreased clearance of [[amlodipine]] with a resulting increase in AUC of approximately 40–60%.
|nonClinToxic='''Carcinogenesis, Mutagenesis, Impairment of Fertility'''
|nonClinToxic='''Carcinogenesis, Mutagenesis, Impairment of Fertility'''
No carcinogenicity, mutagenicity or fertility studies have been conducted with the combination of [[perindopril]] and [[amlodipine]]. However, these studies have been conducted for [[perindopril]] and [[amlodipine]] alone.


Perindopril:
No [[carcinogenicity]]. mutagenicity or [[fertility]] studies have been conducted with the combination of [[perindopril]] and [[amlodipine]]. However, these studies have been conducted for [[perindopril]] and [[amlodipine]] alone.
*Carcinogenicity: No evidence of carcinogenicity was observed in studies in rats and mice when [[perindopril]] was administered at dosages up to 5 times (mg/m2) the maximum recommended human dose (MRHD) of 14 mg/day for 104 weeks.
 
*Mutagenesis: No genotoxic potential was detected for [[perindopril]], [[perindopril|perindoprilat]], and other metabolites in various in vitro and in vivo investigations, including the Ames test, the Saccharomyces cerevisiae D4 test, cultured human lymphocytes, thymidine kinase ± mouse lymphoma assay, mouse and rat micronucleus tests, the in vivo micronucleus and chromosomal aberration tests, and Chinese hamster bone marrow assay.
[[Perindopril]]:
*Impairment of Fertility: There was no meaningful effect on reproductive performance or fertility in rats given up to 7 times (mg/m2) the MRHD during the period of spermatogenesis in males or oogenesis and gestation in females.
*[[Carcinogenicity]]: No evidence of [[carcinogenicity]] was observed in studies in rats and mice when [[perindopril]] was administered at dosages up to 5 times (mg/m2) the maximum recommended human dose (MRHD) of 14 mg/day for 104 weeks.
*[[Mutagenesis]]: No genotoxic potential was detected for [[perindopril]], [[perindopril|perindoprilat]], and other [[metabolites]] in various in vitro and in vivo investigations, including the [[Ames test]], the [[Saccharomyces cerevisiae]] D4 test, cultured human [[lymphocytes]], [[thymidine kinase]] ± mouse [[lymphoma]] assay, mouse and rat [[micronucleus]] tests, the in vivo [[micronucleus]] and [[chromosomal aberration]] tests, and Chinese hamster bone marrow assay.
*Impairment of Fertility: There was no meaningful effect on reproductive performance or [[fertility]] in rats given up to 7 times (mg/m2) the MRHD during the period of [[spermatogenesis]] in males or [[oogenesis]] and gestation in females.


Amlodipine:
[[Amlodipine]]:
*Carcinogenicity: Rats and mice treated with [[amlodipine]] maleate in the diet for up to 2 years, at concentrations calculated to provide daily [[amlodipine]] dosage levels of 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 body surface area basis, similar to the [[amlodipine]] MRHD of 10 mg/day. For the rat, the highest dose was, on a body surface area basis, approximately 2.5 times the MRHD, assuming a patient weight of 60 kg.
*[[Carcinogenicity]]: Rats and mice treated with [[amlodipine]] maleate in the diet for up to 2 years, at concentrations calculated to provide daily [[amlodipine]] dosage levels of 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 body surface area basis, similar to the [[amlodipine]] MRHD of 10 mg/day. For the rat, the highest dose was, on a body surface area basis, approximately 2.5 times the MRHD, assuming a patient weight of 60 kg.
*Mutagenesis: Mutagenicity studies conducted with [[amlodipine]] maleate revealed no drug-related effects at either the gene or chromosome level.
*[[Mutagenesis]]: Mutagenicity studies conducted with [[amlodipine]] maleate revealed no drug-related effects at either the gene or chromosome level.
*Impairment of Fertility: 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 [[amlodipine]] doses of up to 10 mg/kg/day, about 10 times the MRHD of 10 mg/day on a body surface area basis.
*Impairment of Fertility: 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 [[amlodipine]] doses of up to 10 mg/kg/day, about 10 times the MRHD of 10 mg/day on a body surface area basis.
'''Reproductive Toxicity'''
'''Reproductive Toxicity'''
Reproductive toxicity studies have not been conducted with this combination. However, these studies have been conducted for [[amlodipine]] alone.
Reproductive toxicity studies have not been conducted with this combination. However, these studies have been conducted for [[amlodipine]] alone.
Amlodipine:
 
No evidence of teratogenicity or other embryo/fetal toxicity was found when pregnant rats and rabbits were treated orally with [[amlodipine]] maleate at [[amlodipine]] doses of up to 10 mg/kg/day (respectively, about 8 and 23 times the maximum recommended human dose of 10 mg on a mg/m2 basis, assuming a patient weight of 50 kg) during their periods of major organogenesis. However, litter size was significantly decreased (by about 50%) and the number of intrauterine deaths was significantly increased (about 5-fold) for rats receiving [[amlodipine]] maleate at an [[amlodipine]] dose equivalent to 10 mg/kg/day for 14 days before mating and throughout mating and gestation. [[Amlodipine]] maleate has been shown to prolong both the gestation period and the duration of labor in rats at this dose.
[[Amlodipine]]:
 
No evidence of [[teratogenicity]] or other embryo/fetal toxicity was found when pregnant rats and rabbits were treated orally with [[amlodipine]] maleate at [[amlodipine]] doses of up to 10 mg/kg/day (respectively, about 8 and 23 times the maximum recommended human dose of 10 mg on a mg/m2 basis, assuming a patient weight of 50 kg) during their periods of major [[organogenesis]]. However, litter size was significantly decreased (by about 50%) and the number of intrauterine deaths was significantly increased (about 5-fold) for rats receiving [[amlodipine]] maleate at an [[amlodipine]] dose equivalent to 10 mg/kg/day for 14 days before mating and throughout mating and gestation. [[Amlodipine]] maleate has been shown to prolong both the gestation period and the duration of labor in rats at this dose.
|clinicalStudies=The [[antihypertensive]] effects of [[perindopril]] arginine and [[amlodipine besylate]] have been demonstrated in two randomized controlled trials.
|clinicalStudies=The [[antihypertensive]] effects of [[perindopril]] arginine and [[amlodipine besylate]] have been demonstrated in two randomized controlled trials.


The highest strength of [[perindopril]] arginine and [[amlodipine besylate]] (14/10 mg) was studied in a double-blind, active controlled study in hypertensive patients. A total of 837 patients with seated diastolic pressure 95 to 115 mmHg (mean baseline systolic/[[diastolic blood pressure]] was 158/101 mmHg) received treatments of [[perindopril]] arginine and [[amlodipine besylate]] 14/10 mg, [[perindopril]] erbumine 16 mg, or [[amlodipine]] 10 mg once daily for 6 weeks. The mean age of the population was 51 years, 51% of patients were male, and 34% were black. Overall, 20% of the population had type 2 [[diabetes]].
The highest strength of [[perindopril]] arginine and [[amlodipine besylate]] (14/10 mg) was studied in a double-blind, active controlled study in hypertensive patients. A total of 837 patients with seated [[diastolic]] pressure 95 to 115 mmHg (mean baseline [[systolic]]/[[diastolic blood pressure]] was 158/101 mmHg) received treatments of [[perindopril]] arginine and [[amlodipine besylate]] 14/10 mg, [[perindopril]] erbumine 16 mg, or [[amlodipine]] 10 mg once daily for 6 weeks. The mean age of the population was 51 years, 51% of patients were male, and 34% were black. Overall, 20% of the population had type 2 [[diabetes]].


At Week 6, [[perindopril]] arginine and [[amlodipine besylate]] 14/10 mg produced statistically significantly greater reductions in [[blood pressure]] than each of the monotherapies. The reductions in systolic/[[diastolic blood pressure]] with [[perindopril]] arginine and [[amlodipine besylate]] 14/10 mg were 10.1/6.3 mmHg greater than with [[perindopril]] erbumine 16 mg and 3.9/2.5 mmHg greater than with [[amlodipine]] 10 mg. In black patients and in diabetic patients, treatment with [[perindopril]] arginine and [[amlodipine besylate]] 14/10 mg did not provide additional [[antihypertensive]] effect beyond that achieved with use of [[amlodipine]] 10 mg.
At Week 6, [[perindopril]] arginine and [[amlodipine besylate]] 14/10 mg produced statistically significantly greater reductions in [[blood pressure]] than each of the monotherapies. The reductions in [[systolic]]/[[diastolic blood pressure]] with [[perindopril]] arginine and [[amlodipine besylate]] 14/10 mg were 10.1/6.3 mmHg greater than with [[perindopril]] erbumine 16 mg and 3.9/2.5 mmHg greater than with [[amlodipine]] 10 mg. In black patients and in diabetic patients, treatment with [[perindopril]] arginine and [[amlodipine besylate]] 14/10 mg did not provide additional [[antihypertensive]] effect beyond that achieved with use of [[amlodipine]] 10 mg.


The lowest strength of [[perindopril]] arginine/amlodipine (3.5/2.5 mg) was studied in 246 hypertensive patients. A total of 1581 patients with supine diastolic pressure 95-110 mmHg (mean baseline systolic/[[diastolic blood pressure]] was 161/101 mmHg) received treatment with [[perindopril]] arginine/amlodipine 3.5/2.5 mg, [[perindopril]] arginine 3.5 mg, [[perindopril]] arginine 5 mg, [[amlodipine]] 2.5 mg, [[amlodipine]] 5 mg, or placebo. The mean age of the population was 52 years, 47% were male, and 1% were black. No included patients had a history of [[diabetes]].
The lowest strength of [[perindopril]] arginine/amlodipine (3.5/2.5 mg) was studied in 246 hypertensive patients. A total of 1581 patients with supine [[diastolic]] pressure 95-110 mmHg (mean baseline [[systolic]]/[[diastolic blood pressure]] was 161/101 mmHg) received treatment with [[perindopril]] arginine/amlodipine 3.5/2.5 mg, [[perindopril]] arginine 3.5 mg, [[perindopril]] arginine 5 mg, [[amlodipine]] 2.5 mg, [[amlodipine]] 5 mg, or placebo. The mean age of the population was 52 years, 47% were male, and 1% were black. No included patients had a history of [[diabetes]].


At Week 8, [[perindopril]] arginine and [[amlodipine besylate]] 3.5/2.5 mg produced statistically significantly greater reductions in [[blood pressure]] than [[perindopril]] arginine 3.5 mg and [[amlodipine]] 2.5 mg. The reduction in systolic/[[diastolic blood pressure]] with [[perindopril]] arginine/amlodipine 3.5/2.5 mg was 7.2/4.1 mmHg greater than with placebo.
At Week 8, [[perindopril]] arginine and [[amlodipine besylate]] 3.5/2.5 mg produced statistically significantly greater reductions in [[blood pressure]] than [[perindopril]] arginine 3.5 mg and [[amlodipine]] 2.5 mg. The reduction in [[systolic]]/[[diastolic blood pressure]] with [[perindopril]] arginine/amlodipine 3.5/2.5 mg was 7.2/4.1 mmHg greater than with placebo.
|howSupplied=[[Perindopril]] arginine and [[amlodipine besylate]] is available as white, uncoated tablets containing [[perindopril]] arginine 3.5 mg, 7 mg, or 14 mg and [[amlodipine]] 2.5 mg, 5 mg, or 10 mg for the following three combinations of [[perindopril]] arginine/amlodipine: 3.5/2.5 mg, 7/5 mg, and 14/10 mg. All three strengths are packaged in bottles of 90 tablets. Each tablet is debossed with the tablet strength.
|howSupplied=[[Perindopril]] arginine and [[amlodipine besylate]] is available as white, uncoated tablets containing [[perindopril]] arginine 3.5 mg, 7 mg, or 14 mg and [[amlodipine]] 2.5 mg, 5 mg, or 10 mg for the following three combinations of [[perindopril]] arginine/amlodipine: 3.5/2.5 mg, 7/5 mg, and 14/10 mg. All three strengths are packaged in bottles of 90 tablets. Each tablet is debossed with the tablet strength.
TABLE 2
[[File:Perindopril arginine and amlodipine besylate T2.JPG|thumb|none|400px|This image is provided by the National Library of Medicine.]]
|storage=Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F). Protect from moisture. Dispense in tight container (USP).
|storage=Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F). Protect from moisture. Dispense in tight container (USP).
|packLabel=LABEL 1
|packLabel=[[File:Perindopril arginine and amlodipine besylate label1.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]]
LABEL 2
[[File:Perindopril arginine and amlodipine besylate label2.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]]
LABEL 3
[[File:Perindopril arginine and amlodipine besylate label3.jpg|thumb|none|400px|This image is provided by the National Library of Medicine.]]
INGREDIENTS 1
[[File:Perindopril arginine and amlodipine besylate ingredient1.JPG|thumb|none|400px|This image is provided by the National Library of Medicine.]]
INGREDIENTS 2
[[File:Perindopril arginine and amlodipine besylate ingredient2.JPG|thumb|none|400px|This image is provided by the National Library of Medicine.]]
INGREDIENTS 3
[[File:Perindopril arginine and amlodipine besylate ingredient3.JPG|thumb|none|400px|This image is provided by the National Library of Medicine.]]
|fdaPatientInfo=Advise the patient to read the FDA-approved patient labeling (Patient Information).
|fdaPatientInfo=Advise the patient to read the FDA-approved patient labeling (Patient Information).


Tell female patients of childbearing age that use of drugs like [[perindopril]] that act on the [[renin-angiotensin system]] can cause serious problems in the fetus and infant, including [[low blood pressure]], poor development of skull bones, kidney failure, and death. Discuss other treatment options with female patients planning to become pregnant. Tell women using [[perindopril]] arginine and [[amlodipine besylate]] who become pregnant to notify their physician as soon as possible.
Tell female patients of childbearing age that use of drugs like [[perindopril]] that act on the [[renin-angiotensin system]] can cause serious problems in the fetus and infant, including [[low blood pressure]], poor development of [[skull bones]], [[kidney failure]], and death. Discuss other treatment options with female patients planning to become pregnant. Tell women using [[perindopril]] arginine and [[amlodipine besylate]] who become pregnant to notify their physician as soon as possible.


In case of a missed dose, have patients resume the usual dose at the next scheduled time.
In case of a missed dose, have patients resume the usual dose at the next scheduled time.
|alcohol=Alcohol-Perindopril arginine, [[amlodipine besylate]] interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
|alcohol=Alcohol-[[Perindopril]] arginine and [[amlodipine besylate]] interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
|brandNames=PRESTALIA
|brandNames=PRESTALIA
}}
}}

Latest revision as of 20:40, 24 July 2017

Perindopril arginine, amlodipine besylate
Black Box Warning
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Allison Tu [2]

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Black Box Warning

FETAL TOXICITY
See full prescribing information for complete Boxed Warning.
  • When pregnancy is detected, discontinue perindopril arginine and amlodipine besylate as soon as possible
  • Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus

Overview

Perindopril arginine, amlodipine besylate is a combination of an angiotensin converting enzyme inhibitor and a dihydropyridine calcium channel blocker that is FDA approved for the treatment of hypertension to lower blood pressure in patients not adequately controlled with monotherapy, or as initial therapy in patients likely to need multiple drugs to achieve their blood pressure goals. There is a Black Box Warning for this drug as shown here. Common adverse reactions include headache, cough, peripheral edema, and pulmonary edema.

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

Perindopril arginine and amlodipine besylate contains perindopril arginine, an angiotensin converting enzyme inhibitor, and amlodipine, a dihydropyridine calcium channel blocker, and is indicated for the treatment of hypertension, to lower blood pressure. Perindopril arginine and amlodipine besylate may be used in patients whose blood pressure is not adequately controlled on monotherapy or as initial therapy in patients likely to need multiple drugs to achieve blood pressure goals.

Dosing Information

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Perindopril arginine, amlodipine besylate in adult patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Perindopril arginine, amlodipine besylate in adult patients.

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

There is limited information regarding Perindopril arginine, amlodipine besylate FDA-Labeled Indications and Dosage (Pediatric) in the drug label.

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Perindopril arginine, amlodipine besylate in pediatric patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Perindopril arginine, amlodipine besylate in pediatric patients.

Contraindications

Warnings

FETAL TOXICITY
See full prescribing information for complete Boxed Warning.
  • When pregnancy is detected, discontinue perindopril arginine and amlodipine besylate as soon as possible
  • Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus

Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue perindopril arginine and amlodipine besylate as soon as possible.

Adverse Reactions

Clinical Trials Experience

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

This image is provided by the National Library of Medicine.

Monotherapy with perindopril or amlodipine has been evaluated for safety in clinical trials in over 3,000 and 11,000 patients, respectively, as summarized below.

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of the individual components of perindopril arginine and amlodipine besylate. 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.

Drug Interactions

Perindopril arginine and amlodipine besylate:

Perindopril:

Amlodipine

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA): 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 perindopril arginine and amlodipine besylate 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 therapy with drugs affecting the renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus. Perform serial ultra-sound examinations to assess the intra-amniotic environment. If oligohydramnios is observed, discontinue perindopril arginine and amlodipine besylate, 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 perindopril arginine and amlodipine besylate for hypotension, oliguria, and hyperkalemia. Radioactivity was detectable in fetuses after administration of 14C-perindopril to pregnant rats.
Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Perindopril arginine, amlodipine besylate in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of Perindopril arginine, amlodipine besylate during labor and delivery.

Nursing Mothers

It is not known whether perindopril or amlodipine is excreted in human milk, but radioactivity was detected in the milk of lactating rats following administration of 14C-perindopril. Because of the potential for adverse effects on the nursing infant, decide whether to discontinue nursing or discontinue perindopril arginine and amlodipine besylate.

Pediatric Use

Neonates with a history of in utero exposure to perindopril arginine and amlodipine besylate: 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 perindopril arginine and amlodipine besylate in pediatric patients have not been established.

Geriatic Use

The mean blood pressure effect of perindopril was somewhat smaller in patients over 60 years of age than in younger patients, although the difference was not significant. Plasma concentrations of both perindopril and perindoprilat in elderly patients (>65 years) are approximately twice those observed in younger patients. No adverse effects were clearly increased in older patients with the exception of dizziness and rash.

Amlodipine is extensively metabolized in the liver. In the elderly, clearance of amlodipine is decreased with resulting increases in peak plasma levels, elimination half-life, and AUC.

Experience with perindopril arginine and amlodipine besylate is limited in the elderly at doses exceeding 7/5 mg. If doses above 7/5 mg are required, monitor blood pressure up to two weeks following up titration.

Gender

There is no FDA guidance on the use of Perindopril arginine, amlodipine besylate with respect to specific gender populations.

Race

There is no FDA guidance on the use of Perindopril arginine, amlodipine besylate with respect to specific racial populations.

Renal Impairment

Pharmacokinetic data indicate that perindoprilat elimination is decreased in renally impaired patients, with a marked increase in accumulation when creatinine clearance drops below 30 mL/min. Perindopril arginine and amlodipine besylate is not recommended in patients with creatinine clearances <30 mL/min. For patients with creatinine clearance between 30 and 80 mL/min (mild or moderate renal impairment), do not exceed 7/5 mg.

Hepatic Impairment

There is no FDA guidance on the use of Perindopril arginine, amlodipine besylate in patients with hepatic impairment.

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Perindopril arginine, amlodipine besylate in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Perindopril arginine, amlodipine besylate in patients who are immunocompromised.

Administration and Monitoring

Administration

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 amlodipine and the ACE inhibitor class to which perindopril principally belongs. There are no controlled trials demonstrating risk reduction with perindopril arginine and amlodipine besylate.

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. In a clinical trial of perindopril arginine and amlodipine besylate, treatment with perindopril arginine and amlodipine besylate 14/10 mg did not provide additional antihypertensive effect beyond that achieved with use of amlodipine 10 mg in black and diabetic patients. The choice of perindopril arginine and amlodipine besylate as initial therapy for hypertension should be based on an assessment of potential benefits and risks including whether the patient is likely to tolerate the starting dose of perindopril arginine and amlodipine besylate.

Patients with moderate-to-severe hypertension are at a relatively high risk of cardiovascular events (e.g., stroke, heart attack, and heart failure), kidney failure, and vision problems, so prompt treatment is clinically relevant. Consider the patient's baseline blood pressure, target goal and the incremental likelihood of achieving the goal with a combination product, such as perindopril arginine and amlodipine besylate, versus a monotherapy product when deciding upon initial therapy. Individual blood pressure goals may vary based on the patient's risk.

Data from an 6-week, active-controlled trial provide estimates of the probability of reaching a target blood pressure with perindopril arginine and amlodipine besylate compared with perindopril erbumine or amlodipine monotherapy.

FIGURES 1.A-1.D provide estimates of the likelihood of achieving target clinic systolic and diastolic blood pressure control with perindopril arginine and amlodipine besylate 14/10 mg tablets after 6 weeks, based on baseline systolic and diastolic blood pressure. The curve for each treatment group was estimated by logistic regression modeling and is less well defined in the tails.

This image is provided by the National Library of Medicine.
This image is provided by the National Library of Medicine.
This image is provided by the National Library of Medicine.
This image is provided by the National Library of Medicine.

For example, a patient with a baseline blood pressure of 170/105 mmHg has approximately a 26% likelihood of achieving a goal of <140 mmHg (systolic) and 31% likelihood of achieving <90 mmHg (diastolic) on perindopril erbumine 16 mg. The likelihood of achieving these same goals on amlodipine 10 mg is approximately 40% (systolic) and 46% (diastolic). These likelihoods rise to 50% (systolic) and 65% (diastolic) with perindopril arginine and amlodipine besylate 14/10 mg.

Monitoring

Monitoring in Elderly Patients (Over 65 Years of Age): Monitor blood pressure for up to two weeks following titrations at dosages above 7/5 mg in patients over 65 years of age.

IV Compatibility

There is limited information regarding the compatibility of Perindopril arginine, amlodipine besylate and IV administrations.

Overdosage

Perindopril:

In animals, doses of perindopril up to 2,500 mg/kg in mice, 3,000 mg/kg in rats and 1,600 mg/kg in dogs were non-lethal. Past experiences were scant but suggested that overdosage with other ACE inhibitors was also fairly well tolerated by humans. The most likely manifestation is hypotension, and treatment should be symptomatic and supportive. Therapy with the ACE inhibitor should be discontinued, and the patient should be observed. Dehydration, electrolyte imbalance and hypotension should be treated by established procedures.

Among the reported cases of perindopril overdosage, patients who were known to have ingested a dose of 80 mg to 120 mg required assisted ventilation and circulatory support. One additional patient developed hypothermia, circulatory arrest and died following ingestion of up to 180 mg of perindopril. The intervention for perindopril overdose may require vigorous support.

Laboratory determinations of serum levels of perindopril and its metabolites are not widely available, and such determinations have, in any event, no established role in the management of perindopril overdose. No data are available to suggest physiological maneuvers (e.g., maneuvers to change the pH of the urine) that might accelerate elimination of perindopril and its metabolites.

Angiotensin II could presumably serve as a specific antagonist-antidote in the setting of perindopril overdose, but angiotensin II is essentially unavailable outside of scattered research facilities. Because the hypotensive effect of perindopril is achieved through vasodilation and effective hypovolemia, it is reasonable to treat perindopril overdose by infusion of normal saline solution.

Amlodipine:

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.

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.

If massive overdose should occur, initiate active cardiac and respiratory monitoring. Frequent blood pressure measurements are essential. Should hypotension occur, provide cardiovascular support including elevation of the extremities and the judicious administration of fluids. If hypotension remains unresponsive to these conservative measures, consider administration of vasopressors (such as phenylephrine) with attention to circulating volume and urine output. As amlodipine is highly protein bound, hemodialysis is not likely to be of benefit.

Pharmacology

Mechanism of Action

Perindopril:

Perindopril, a pro-drug, is hydrolyzed to perindoprilat, which inhibits ACE in humans and in animals. ACE is a peptidyl dipeptidase that catalyzes the conversion of the inactive decapeptide, angiotensin I, to the vasoconstrictor substance angiotensin II. Angiotensin II is a potent peripheral vasoconstrictor, which stimulates aldosterone secretion by the adrenal cortex, and provides negative feedback on renin secretion. Inhibition of ACE results in decreased plasma angiotensin II, leading to decreased vasoconstriction, increased plasma renin activity and decreased aldosterone secretion. The latter results in diuresis and natriuresis and may be associated with an increase in serum potassium. ACE is identical to kininase II, an enzyme that degrades bradykinin. Whether increased levels of bradykinin, a potent vasodepressor peptide, play a role in the therapeutic effects of perindopril remains to be elucidated.

While the principal mechanism of perindopril in blood pressure reduction is believed to be through the renin-angiotensin-aldosterone system, ACE inhibitors have some effect even in apparent low-renin hypertension. Perindopril has been studied in relatively few black patients, usually a low-renin population, and the average response of diastolic blood pressure to perindopril was about half the response seen in nonblack patients, a finding consistent with previous experience of other ACE inhibitors.

Amlodipine:

Amlodipine is a dihydropyridine calcium antagonist (calcium ion antagonist or slow channel blocker) that inhibits the transmembrane influx of calcium ions into vascular smooth muscle and cardiac muscle. Experimental data suggest that amlodipine binds to both dihydropyridine and nondihydropyridine binding sites. The contractile processes of cardiac muscle and vascular smooth muscle are dependent upon the movement of extracellular calcium ions into these cells through specific ion channels. Amlodipine inhibits calcium ion influx across cell membranes selectively, with a greater effect on vascular smooth muscle cells than on cardiac muscle cells. Negative inotropic effects can be detected in vitro but such effects have not been seen in intact animals at therapeutic doses.

Serum calcium concentration is not affected by amlodipine. Within the physiologic pH range, amlodipine is an ionized compound (pKa=8.6), and its kinetic interaction with the calcium channel receptor is characterized by a gradual rate of association and dissociation with the receptor binding site, resulting in a gradual onset of effect.

Amlodipine is a peripheral arterial vasodilator that acts directly on vascular smooth muscle to cause a reduction in peripheral vascular resistance and reduction in blood pressure.

Structure

Perindopril arginine and amlodipine besylate is a combination of perindopril arginine and amlodipine besylate.

Perindopril arginine is the L-arginine salt of perindopril, the ethyl ester of a non-sulfhydryl angiotensin converting enzyme inhibitor. Perindopril arginine is chemically described as L-arginine (2S,3aS,7aS)-1-[(2S)-2-[(1S)-1-(ethoxycarbonyl)butyl]amino]propanoyl] octahydro-1H-indole-2-carboxylate. Its empirical formula is C19H32N2O5•C6H14N4O2 and its structural formula is:

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Perindopril arginine is a white, crystalline powder with a molecular weight 542.7. The free acid has the molecular weight of 368.5. It is readily soluble in purified water, slightly soluble in 95% ethanol, and practically insoluble in chloroform.

Perindopril is the free-acid form of perindopril arginine. Perindopril is a pro-drug and is metabolized in vivo by hydrolysis of the ester group to form perindoprilat, the biologically active metabolite.

Amlodipine besylate is the benzene sulphonic acid salt of amlodipine, a long-acting dihydropyridine calcium channel blocker. Amlodipine besylate is chemically described as 3-ethyl-5-methyl (±)-2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-1,4-dihydro-6-methyl-3,5-pyridinedicarboxylate monobenzenesulphonate. Its empirical formula is C20H25ClN2O5•C6H6O3S and its structural formula is:

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Amlodipine besylate is a white crystalline powder with a molecular weight of 567.1. It is slightly soluble in water and sparingly soluble in ethanol. The content of the tablets is expressed as amlodipine (free base) which has a molecular weight of 409.1.

Perindopril arginine and amlodipine besylate tablets are formulated in three different strengths for oral administration. Tablets contain perindopril arginine 3.5 mg, 7 mg, or 14 mg and amlodipine 2.5 mg, 5 mg, or 10 mg for the following available perindopril arginine/amlodipine combinations: 3.5/2.5 mg, 7/5 mg, and 14/10 mg.

Inactive ingredients are lactose, microcrystalline cellulose, colloidal silicon dioxide, and magnesium stearate.

Pharmacodynamics

Perindopril:

After administration of perindopril, ACE is inhibited in a dose and blood concentration-related fashion. The degree of ACE inhibition achieved by a given dose appears to diminish over time (the ID50 increases). The pressor response to an angiotensin I infusion is reduced by perindopril, but this is not as persistent as the effect on ACE.

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. Although the acute intravenous administration of amlodipine decreases arterial blood pressure and increases heart rate in hemodynamic studies of patients with chronic stable angina, chronic oral administration of amlodipine in clinical trials did not lead to clinically significant changes in heart rate or blood pressures in normotensive patients with angina.

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 did 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 humans, even when co-administered with β-blockers to humans. Similar findings, however, have been observed in normal or well-compensated patients with heart failure with agents possessing significant negative inotropic effects.

Electrophysiologic Effects: Amlodipine does not change sinoatrial (SA) nodal function or atrioventricular (AV) conduction in intact animals or humans. In clinical studies in which amlodipine was administered in combination with β-blockers to patients with either hypertension or angina, no adverse effects on electrocardiographic parameters were observed.

Pharmacokinetics

Perindopril arginine and amlodipine besylate: Following administration of perindopril arginine and amlodipine besylate, peak plasma concentration of perindopril, perindoprilat and amlodipine occur at approximately 1 hour, 4 hours and 6-12 hours, respectively. The mean half-life of perindopril is approximately 1.3 hours. The decline in the plasma concentration of perindoprilat is multiphasic and shows a terminal elimination half-life of approximately 100 hours, resulting from slow dissociation of perindoprilat from plasma/tissue ACE binding sites. Amlodipine elimination from plasma is biphasic with a terminal elimination half-life of approximately 30 to 50 hours.

When perindopril arginine and amlodipine besylate is administered with food, the exposure to perindopril, perindoprilat and amlodipine is not impacted.

Perindopril:

Following administration of perindopril arginine and amlodipine besylate, perindopril is rapidly absorbed, with peak plasma concentrations occurring at approximately 1 hour. The absolute oral bioavailability of perindopril is approximately 75%. Following absorption, approximately 30% to 50% of systemically available perindopril is hydrolyzed to its active metabolite, perindoprilat, which has a mean bioavailability of approximately 25%. Peak plasma concentrations of perindoprilat are attained approximately 4 hours after perindopril arginine and amlodipine besylate administration. Food had no effect on the extent of absorption of perindopril or perindoprilat, but slightly reduced the rate of absorption of perindopril and perindoprilat by 18% and 14%, respectively.

The Cmax and AUC of perindopril and perindoprilat increase in a linear and dose proportional manner following both single oral dosing and at steady state during an once-a-day multiple dosing regimen. Perindopril exhibits multiexponential pharmacokinetics following oral administration. The mean half-life of perindopril associated with most of its elimination is approximately 0.8 to 1 hours.

Perindopril is extensively metabolized following oral administration, with only 4% to 12% of the dose recovered unchanged in the urine. Six metabolites resulting from hydrolysis, glucuronidation, and cyclization via dehydration have been identified. These include the active ACE inhibitor perindoprilat, (hydrolyzed perindopril), perindopril, and perindoprilat glucuronides, dehydrated perindopril, and the diastereoisomers of dehydrated perindoprilat. In humans, hepatic esterase appears to be responsible for the hydrolysis of perindopril.

The active metabolite, perindoprilat, also exhibits multiexponential pharmacokinetics following the oral administration of perindopril. Formation of perindoprilat is gradual with peak plasma concentrations occurring between 3 and 7 hours. The subsequent decline in plasma concentration shows a prolonged terminal elimination half-life of 120 hours resulting from slow dissociation of perindoprilat from plasma/tissue ACE binding sites. During repeated oral once-daily dosing with perindopril, perindoprilat accumulates about 1.5- to 2-fold and attains steady state plasma levels in 3 to 6 days. The clearance of perindoprilat and its metabolites is almost exclusively renal.

Approximately 60% of circulating perindopril is bound to plasma proteins, and only 10% to 20% of perindoprilat is bound. Therefore, drug interactions mediated through effects on protein binding are not anticipated.

Amlodipine:

Absolute bioavailability of amlodipine has been estimated between 64% and 90%. Ex vivo studies indicate that approximately 93% of circulating amlodipine is bound to plasma proteins in hypertensive patients.

Amlodipine is extensively (approximately 90%) metabolized in the liver to inactive metabolites. Steady-state plasma levels are reached after once-daily dosing for 7 to 8 days. 10% of unchanged drug and 60% of amlodipine metabolites are excreted in urine.

Drug Interactions:

Perindopril: Co-administered perindopril does not impact the exposure to amlodipine or digoxin. Amlodipine: Co-administered cimetidine, magnesium- and aluminum hydroxide antacids, sildenalfil, and grapefruit juice have no impact on the exposure to amlodipine. Co-administered amlodipine does not affect the exposure to perindopril, perindoprilat, atorvastatin, ethanol and the warfarin prothrombin response time

Use in Specific Populations:

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

No carcinogenicity. mutagenicity or fertility studies have been conducted with the combination of perindopril and amlodipine. However, these studies have been conducted for perindopril and amlodipine alone.

Perindopril:

Amlodipine:

  • Carcinogenicity: Rats and mice treated with amlodipine maleate in the diet for up to 2 years, at concentrations calculated to provide daily amlodipine dosage levels of 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 body surface area basis, similar to the amlodipine MRHD of 10 mg/day. For the rat, the highest dose was, on a body surface area basis, approximately 2.5 times the MRHD, assuming a patient weight of 60 kg.
  • Mutagenesis: Mutagenicity studies conducted with amlodipine maleate revealed no drug-related effects at either the gene or chromosome level.
  • Impairment of Fertility: 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 amlodipine doses of up to 10 mg/kg/day, about 10 times the MRHD of 10 mg/day on a body surface area basis.

Reproductive Toxicity

Reproductive toxicity studies have not been conducted with this combination. However, these studies have been conducted for amlodipine alone.

Amlodipine:

No evidence of teratogenicity or other embryo/fetal toxicity was found when pregnant rats and rabbits were treated orally with amlodipine maleate at amlodipine doses of up to 10 mg/kg/day (respectively, about 8 and 23 times the maximum recommended human dose of 10 mg on a mg/m2 basis, assuming a patient weight of 50 kg) during their periods of major organogenesis. However, litter size was significantly decreased (by about 50%) and the number of intrauterine deaths was significantly increased (about 5-fold) for rats receiving amlodipine maleate at an amlodipine dose equivalent to 10 mg/kg/day for 14 days before mating and throughout mating and gestation. Amlodipine maleate has been shown to prolong both the gestation period and the duration of labor in rats at this dose.

Clinical Studies

The antihypertensive effects of perindopril arginine and amlodipine besylate have been demonstrated in two randomized controlled trials.

The highest strength of perindopril arginine and amlodipine besylate (14/10 mg) was studied in a double-blind, active controlled study in hypertensive patients. A total of 837 patients with seated diastolic pressure 95 to 115 mmHg (mean baseline systolic/diastolic blood pressure was 158/101 mmHg) received treatments of perindopril arginine and amlodipine besylate 14/10 mg, perindopril erbumine 16 mg, or amlodipine 10 mg once daily for 6 weeks. The mean age of the population was 51 years, 51% of patients were male, and 34% were black. Overall, 20% of the population had type 2 diabetes.

At Week 6, perindopril arginine and amlodipine besylate 14/10 mg produced statistically significantly greater reductions in blood pressure than each of the monotherapies. The reductions in systolic/diastolic blood pressure with perindopril arginine and amlodipine besylate 14/10 mg were 10.1/6.3 mmHg greater than with perindopril erbumine 16 mg and 3.9/2.5 mmHg greater than with amlodipine 10 mg. In black patients and in diabetic patients, treatment with perindopril arginine and amlodipine besylate 14/10 mg did not provide additional antihypertensive effect beyond that achieved with use of amlodipine 10 mg.

The lowest strength of perindopril arginine/amlodipine (3.5/2.5 mg) was studied in 246 hypertensive patients. A total of 1581 patients with supine diastolic pressure 95-110 mmHg (mean baseline systolic/diastolic blood pressure was 161/101 mmHg) received treatment with perindopril arginine/amlodipine 3.5/2.5 mg, perindopril arginine 3.5 mg, perindopril arginine 5 mg, amlodipine 2.5 mg, amlodipine 5 mg, or placebo. The mean age of the population was 52 years, 47% were male, and 1% were black. No included patients had a history of diabetes.

At Week 8, perindopril arginine and amlodipine besylate 3.5/2.5 mg produced statistically significantly greater reductions in blood pressure than perindopril arginine 3.5 mg and amlodipine 2.5 mg. The reduction in systolic/diastolic blood pressure with perindopril arginine/amlodipine 3.5/2.5 mg was 7.2/4.1 mmHg greater than with placebo.

How Supplied

Perindopril arginine and amlodipine besylate is available as white, uncoated tablets containing perindopril arginine 3.5 mg, 7 mg, or 14 mg and amlodipine 2.5 mg, 5 mg, or 10 mg for the following three combinations of perindopril arginine/amlodipine: 3.5/2.5 mg, 7/5 mg, and 14/10 mg. All three strengths are packaged in bottles of 90 tablets. Each tablet is debossed with the tablet strength.

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Storage

Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F). Protect from moisture. Dispense in tight container (USP).

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Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (Patient Information).

Tell female patients of childbearing age that use of drugs like perindopril that act on the renin-angiotensin system can cause serious problems in the fetus and infant, including low blood pressure, poor development of skull bones, kidney failure, and death. Discuss other treatment options with female patients planning to become pregnant. Tell women using perindopril arginine and amlodipine besylate who become pregnant to notify their physician as soon as possible.

In case of a missed dose, have patients resume the usual dose at the next scheduled time.

Precautions with Alcohol

Alcohol-Perindopril arginine and amlodipine besylate interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

Brand Names

PRESTALIA

Look-Alike Drug Names

There is limited information regarding Perindopril arginine, amlodipine besylate Look-Alike Drug Names in the drug label.

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.

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