Perindopril arginine, amlodipine besylate
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Black Box Warning
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FETAL TOXICITY
See full prescribing information for complete Boxed Warning.
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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)
PRESTALIA 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. PRESTALIA 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
- The recommended starting dose of PRESTALIA is 3.5/2.5 mg once daily.
- Adjust dosage according to blood pressure goals. In general, wait 7 to 14 days between titration steps.
- The maximum recommended dose is 14/10 mg once daily.
- 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
- PRESTALIA 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.
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
- PRESTALIA tablets are contraindicated in patients 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.
- Do not co-administer aliskiren with ACE inhibitors, including PRESTALIA, in patients with diabetes
Warnings
|
FETAL TOXICITY
See full prescribing information for complete Boxed Warning.
|
- 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.
Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue PRESTALIA as soon as possible.
- Anaphylactoid and Possibly Related Reactions
- Angiotensin converting enzyme inhibitors affect the metabolism of eicosanoids and polypeptides, including endogenous bradykinin. Patients taking ACE inhibitors (including the one in PRESTALIA) may, therefore, be subject to a variety of bradykinin- or prostaglandin-mediated adverse reactions, some of them serious. Black patients receiving 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 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.
- Intestinal Angioedema: Intestinal angioedema has been reported in patients treated with 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 inhibitors presenting with abdominal pain.
- Increased Angina and/or Myocardial Infarction
- Worsening angina and acute myocardial infarction can develop after starting or increasing the dose of PRESTALIA, particularly in patients with severe obstructive coronary artery disease.
- Hypotension
- PRESTALIA 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 PRESTALIA therapy under close medical supervision. Follow patients closely for the first 2 weeks of treatment and whenever the dose of PRESTALIA 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. PRESTALIA 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.
- Surgery/Anesthesia
- In patients undergoing major surgery or during anesthesia with agents that produce hypotension, PRESTALIA 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
- Elevations of serum potassium have been observed in some patients treated with ACE inhibitors, including PRESTALIA.
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 PRESTALIA.
- Cough
- Presumably because of the inhibition of the degradation of endogenous bradykinin, persistent nonproductive cough has been reported with all ACE inhibitors, generally resolving after discontinuation of therapy. Consider ACE inhibitor-induced cough in the differential diagnosis of cough.
- Impaired Renal Function
- Monitor renal function periodically in patients receiving PRESTALIA. 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 non-steroidal anti-inflammatory agents (NSAIDS) or angiotensin receptor blockers—may be at particular risk of developing acute renal failure on PRESTALIA.
- Consider withholding or discontinuing therapy in patients who develop a clinically significant decrease in renal function on PRESTALIA.
- Hepatic Failure
- Rarely, ACE inhibitors have been associated with a syndrome that starts with cholestatic jaundice and progresses to fulminant hepatic necrosis and sometimes death. The mechanism of this syndrome is not understood. Patients receiving ACE inhibitors who develop jaundice or marked elevations of hepatic enzymes should discontinue the ACE inhibitor and receive appropriate medical follow-up.
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.
- In an active-controlled 6-week trial, the safety of the maximum dose of PRESTALIA (14/10 mg) was evaluated in 279 patients with hypertension and compared with perindopril erbumine 16 mg and amlodipine 10 mg. Adverse reactions were generally mild and transient in nature.
- Discontinuations because of adverse events occurred in 3.6% of patients treated with PRESTALIA 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 PRESTALIA was peripheral edema (1.8%).
- Common adverse events that occurred in at least 2% of patients treated with PRESTALIA in the 6-week trial are presented in TABLE 1.
TABLE 1
- 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 PRESTALIA 14/10 mg and amlodipine 10 mg arms (3%).
- Other adverse reactions in the controlled clinical trial with some plausible relationship to PRESTALIA are listed below:
- Dermatologic: Rash
- Digestive: Nausea, diarrhea
- The safety of the lowest dose of PRESTALIA (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 PRESTALIA was hyperkalemia (2.4%). Peripheral edema was reported in 1.6% of patients receiving PRESTALIA 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.
- Perindopril
- Perindopril erbumine has been evaluated for safety in approximately 3,400 patients with hypertension in U.S. and foreign clinical trials. The data presented here are based on results from the 1,417 perindopril-treated patients who participated in the U.S. clinical trials. Over 220 of these patients were treated with perindopril for at least one year.
- In placebo-controlled U.S. clinical trials, the incidence of premature discontinuation of therapy due to adverse events was 6.5% in patients treated with perindopril erbumine and 6.7% in patients treated with placebo. The most common causes were cough, headache, asthenia, and dizziness.
- Among 1,012 patients in placebo-controlled U.S. trials, the overall frequency of reported adverse events was similar in patients treated with perindopril erbumine and in those treated with placebo (approximately 75% in each group). The only adverse events whose incidence on perindopril erbumine was at least 2% greater than on placebo were cough (12% vs. 4.5%) and back pain (5.8% vs. 3.1%).
- Dizziness was not reported more frequently in the perindopril group (8.2%) than in the placebo group (8.5%), but its likelihood increased with dose, suggesting a causal relationship with perindopril.
- Amlodipine
- Amlodipine has been evaluated for safety in more than 11,000 patients in U.S. and foreign clinical trials. In controlled clinical trials comparing amlodipine (N=1730) in doses up to 10 mg with placebo (N=1250), discontinuation of amlodipine due to adverse reactions was required in about 1.5% of amlodipine-treated patients and about 1% of placebo-treated patients. The most common side effects were edema, dizziness, flushing, and palpitations.
- The following events occurred in <1% but >0.1% of patients in controlled clinical trials or under conditions of open trials or marketing experience where a causal relationship is uncertain; they are listed to alert the physician to a possible relationship:
- Cardiovascular: arrhythmia (including ventricular tachycardia and atrial fibrillation), bradycardia, chest pain, peripheral ischemia, syncope, tachycardia, vasculitis.
- Central and Peripheral Nervous System: hypoesthesia, neuropathy peripheral, paresthesia, tremor, vertigo.
- Gastrointestinal: anorexia, constipation, dysphagia, diarrhea, flatulence, pancreatitis, vomiting, gingival hyperplasia.
- General: allergic reaction, asthenia,1 back pain, hot flushes, malaise, pain, rigors, weight gain, weight decrease.
- Musculoskeletal System: arthralgia, arthrosis, muscle cramps, myalgia
- Psychiatric: sexual dysfunction (male and female), insomnia, nervousness, depression, abnormal dreams, anxiety, depersonalization.
- Respiratory System: dyspnea, epistaxis.
- Skin and Appendages: angioedema, erythema multiforme, pruritus,1 rash,1 rash erythematous, rash maculopapular.
- Special Senses: abnormal vision, conjunctivitis, diplopia, eye pain, tinnitus.
- Urinary System: micturition frequency, micturition disorder, nocturia.
- Autonomic Nervous System: dry mouth, sweating increased.
- Metabolic and Nutritional: hyperglycemia, thirst.
- Hematopoietic: leukopenia, purpura, thrombocytopenia.
- Clinical Laboratory Findings
- 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.
- 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.
- Perindopril
Postmarketing Experience
The following adverse reactions have been identified during post-approval use of the individual components of PRESTALIA. 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
- 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).
- 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.
Drug Interactions
Prestalia:
- The pharmacokinetics of perindopril and amlodipine are not altered when the drugs are co-administered.
- No drug interaction studies have been conducted with PRESTALIA, 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.
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 PRESTALIA. Provide close medical supervision with the first dose of PRESTALIA, 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.
- Lithium: Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving ACE inhibitors during therapy with lithium. When co-administering PRESTALIA 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.
- 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 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 inhibitors, including perindopril, may be attenuated by NSAIDS, including selective COX-2 inhibitors.
- Dual Blockade of the Renin-Angiotensin System (RAS): Dual blockade of the RAS with angiotensin receptor blockers, ACE inhibitors, or aliskiren is associated with increased risks of hypotension, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy. 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 PRESTALIA and other agents that affect the RAS.
- Do not co-administer aliskiren with PRESTALIA in patients with diabetes. Avoid use of aliskiren with PRESTALIA in patients with renal impairment (GFR <60 mL/min).
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.
- 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 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.
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 PRESTALIA 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 PRESTALIA, 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 PRESTALIA 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 PRESTALIA.
Pediatric Use
Neonates with a history of in utero exposure to PRESTALIA: 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 PRESTALIA 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 PRESTALIA 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. PRESTALIA 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 PRESTALIA.
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 PRESTALIA, treatment with PRESTALIA 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 PRESTALIA 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 PRESTALIA.
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 PRESTALIA, 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 PRESTALIA 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 PRESTALIA 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 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 PRESTALIA 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 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.
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
| File:Perindopril structure.svg | |
| Clinical data | |
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| Trade names | Coversyl, Coversum, Preterax, Aceon |
| AHFS/Drugs.com | Monograph |
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| Routes of administration | Oral |
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| Pharmacokinetic data | |
| Bioavailability | 24% |
| Protein binding | 20% |
| Metabolism | Renal |
| Elimination half-life | 1–17 hours for perindoprilat (active metabolite) |
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| E number | {{#property:P628}} |
| ECHA InfoCard | {{#property:P2566}}Lua error in Module:EditAtWikidata at line 36: attempt to index field 'wikibase' (a nil value). |
| Chemical and physical data | |
| Formula | C19H32N2O5 |
| Molar mass | 368.468 g/mol |
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| File:Amlodipine 3D ball.png | |
| Clinical data | |
|---|---|
| Pronunciation | /æmˈloʊdəˌpin/[1] |
| Trade names | Norvasc, others |
| AHFS/Drugs.com | Monograph |
| MedlinePlus | a692044 |
| [[Regulation of therapeutic goods |Template:Engvar data]] |
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| Pregnancy category | |
| Routes of administration | By mouth |
| ATC code | |
| Legal status | |
| Legal status |
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| Pharmacokinetic data | |
| Bioavailability | 64–90% |
| Protein binding | 93% |
| Metabolism | Liver |
| Metabolites | Various inactive pyrimidine metabolites |
| Onset of action | Highest availability 6–12 hours after oral dose |
| Elimination half-life | 30–50 hours |
| Duration of action | At least 24 hours |
| Excretion | Urine |
| Identifiers | |
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| CAS Number | |
| PubChem CID | |
| IUPHAR/BPS | |
| DrugBank | |
| ChemSpider | |
| UNII | |
| KEGG | |
| ChEBI | |
| ChEMBL | |
| PDB ligand | |
| E number | {{#property:P628}} |
| ECHA InfoCard | {{#property:P2566}}Lua error in Module:EditAtWikidata at line 36: attempt to index field 'wikibase' (a nil value). |
| Chemical and physical data | |
| Formula | C20H25ClN2O5 |
| Molar mass | 408.879 g/mol |
| 3D model (JSmol) | |
| Chirality | Racemic mixture |
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| (verify) | |
Mechanism of Action
There is limited information regarding Perindopril arginine, amlodipine besylate Mechanism of Action in the drug label.
Structure
There is limited information regarding Perindopril arginine, amlodipine besylate Structure in the drug label.
Pharmacodynamics
There is limited information regarding Perindopril arginine, amlodipine besylate Pharmacodynamics in the drug label.
Pharmacokinetics
There is limited information regarding Perindopril arginine, amlodipine besylate Pharmacokinetics in the drug label.
Nonclinical Toxicology
There is limited information regarding Perindopril arginine, amlodipine besylate Nonclinical Toxicology in the drug label.
Clinical Studies
There is limited information regarding Perindopril arginine, amlodipine besylate Clinical Studies in the drug label.
How Supplied
There is limited information regarding Perindopril arginine, amlodipine besylate How Supplied in the drug label.
Storage
There is limited information regarding Perindopril arginine, amlodipine besylate Storage in the drug label.
Images
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Patient Counseling Information
There is limited information regarding Perindopril arginine, amlodipine besylate Patient Counseling Information in the drug label.
Precautions with Alcohol
Alcohol-Perindopril arginine, amlodipine besylate interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
Brand Names
There is limited information regarding Perindopril arginine, amlodipine besylate Brand Names in the drug label.
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.
- ↑ "Medical Definition of AMLODIPINE". www.merriam-webster.com. Retrieved 5 July 2017.