Prestalia (perindopril arginine/amlodipine besylate)
Last reviewed · Source: First Databank (FDB) drug data
Overview
Amlodipine is a 1,4-dihydropyridine-derivative calcium-channel blocking agent with an intrinsically long duration of action.
Perindopril erbumine is a nonsulfhydryl angiotensin-converting enzyme (ACE) inhibitor.
Amlodipine is a 1,4-dihydropyridine-derivative calcium-channel blocking agent that is structurally related to felodipine, nifedipine, and nimodipine. Unlike other currently available agents in the dihydropyridine class, amlodipine has an intrinsically long duration of action. Amlodipine inhibits transmembrane influx of extracellular calcium ions across the membranes of myocardial cells and vascular smooth muscle cells, without changing serum calcium concentrations.
Amlodipine is a peripheral arterial vasodilator; it acts directly on vascular smooth muscle causing reduction in peripheral vascular resistance and blood pressure. In patients with exertional angina, amlodipine reduces total peripheral resistance (afterload) and rate pressure product, and thus myocardial oxygen demand, at any given level of exercise. In patients with vasospastic angina, amlodipine inhibits coronary spasm; the drug blocks constriction and restores blood flow in coronary arteries in response to calcium, potassium, epinephrine, serotonin, and thromboxane A2 analog in animal studies and human vessels in vitro.
Following oral administration of amlodipine besylate tablets and solution (Norliqva(R)), peak plasma concentrations of the drug are attained within 6-12 and 6.5 hours, respectively. With chronic once-daily administration, the antihypertensive effects of amlodipine persist for at least 24 hours. Steady-state amlodipine plasma levels are reached after 7-8 days.
Absolute bioavailability ranges from 64-90%; food does not affect bioavailability of amlodipine. The peak plasma concentration and AUC of amlodipine benzoate (Katerzia(R)) suspension are similar to amlodipine besylate (Norvasc(R)) tablets. A standard high-fat, high-calorie breakfast, compared to fasted state administration, did not have a significant effect on the absorption of amlodipine benzoate suspension.
Administration of amlodipine besylate (Norliqva(R)) solution with a high-fat, high-calorie meal did not have a significant effect on peak plasma concentration and AUC. Amlodipine is approximately 93% bound to plasma proteins. Amlodipine is present in human milk (4.2% estimated median relative infant dose) and in cord blood.
Amlodipine is extensively (approximately 90%) metabolized to inactive metabolites in the liver. Amlodipine is excreted in urine as metabolites (60%) and unchanged drug (10%). The terminal elimination half-life of amlodipine is 30-50 hours; in patients with impaired hepatic function, the plasma elimination half-life is 56 hours.
Geriatric patients and patients with hepatic insufficiency or moderate to severe heart failure have decreased amlodipine clearance resulting in an approximately 40-60% higher AUC. Amlodipine pharmacokinetics are not influenced by renal impairment. In pediatric patients 6-17 years of age, weight-adjusted clearance and volume of distribution were similar to values in adults.
Perindopril erbumine is a pro-drug for perindoprilat, which inhibits angiotensin-converting enzyme (ACE) in humans and animals. The mechanism through which perindoprilat lowers blood pressure is believed to be primarily inhibition of ACE activity. ACE is a peptidyl dipeptidase that catalyzes conversion of the inactive decapeptide, angiotensin I, to the vasoconstrictor, 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 a small increase of 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 erbumine 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 non-Black patients, a finding consistent with previous experience of other ACE inhibitors.
After administration of perindopril, ACE is inhibited in a dose- and blood concentration- related fashion, with the maximal inhibition of 80-90% attained by 8 mg persisting for 10-12 hours. Twenty-four hour ACE inhibition is about 60% after these doses. The degree of ACE inhibition achieved by a given dose appears to diminish over time.
Oral administration of perindopril results in peak plasma concentrations that occur at approximately 1 hour. The absolute oral bioavailability of perindopril is about 75%. Following absorption, approximately 30-50% of systemically available perindopril is hydrolyzed to its active metabolite, perindoprilat, which has a mean bioavailability of about 25%.
Peak plasma concentrations of perindoprilat are attained 3-7 hours after perindopril administration. Oral administration of perindopril with food does not significantly lower the rate or extent of perindopril absorption relative to the fasted state; however, the extent of biotransformation of perindopril to the active metabolite, perindoprilat, is reduced approximately 43%, resulting in a reduction in the plasma ACE inhibition curve of approximately 20%, which is probably clinically insignificant. In clinical trials, perindopril was generally administered in a non-fasting state.
Approximately 60% of circulating perindopril is bound to plasma proteins; only 10-20% of perindoprilat is bound. Therefore, drug interactions mediated through effects on protein binding are not anticipated. Perindopril is extensively metabolized following oral administration into 6 metabolites, including perindoprilat (active metabolite).
Following oral administration, only 4-12% of the dose is recovered unchanged in the urine (as metabolites). Hepatic esterase appears to be responsible for the hydrolysis of perindopril. The mean half-life of perindopril associated with most of its elimination is approximately 0.8-1 hours.
The active metabolite, perindoprilat, also exhibits multicompartment pharmacokinetics following oral administration of perindopril erbumine. Formation of perindoprilat is gradual with peak plasma concentrations occurring between 3-7 hours. The subsequent decline in plasma concentration shows an apparent mean half-life of 3-10 hours for the majority of the elimination, with a prolonged terminal elimination half-life of 30-120 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 3-6 days. The clearance of perindoprilat and its metabolites is almost exclusively renal.
USES: This medication is used to treat high blood pressure. Lowering high blood pressure helps prevent strokes, heart attacks, and kidney problems. This product contains 2 medications, perindopril and amlodipine.
Perindopril belongs to a class of drugs known as ACE inhibitors. Amlodipine belongs to a class of drugs known as calcium channel blockers. They both work by relaxing blood vessels so blood can flow more easily.
Generic name: perindopril arginine/amlodipine besylate
Pronunciation: (per-IN-doe-pril/am-LOE-di-peen)
Reference product & biosimilars
No reference, biosimilar or interchangeable associated with this drug.
Today’s intelligence on Prestalia
Indications
The following indications are listed for Prestalia:
- Hypertension
Also known as: Elevated Blood Pressure, Essential Hypertension, Hyperpiesia, Hyperpiesis, Hypertensive Disorder, Systemic Arterial Hypertension.
Dosing
Dosage of amlodipine besylate and amlodipine benzoate is expressed in terms of amlodipine.
Amlodipine is administered orally (as tablets, solution, or suspension) without regard to meals, preferably at the same time each day. Amlodipine is also commercially available in fixed combination with benazepril (e.g., Lotrel(R)), olmesartan medoxomil (e.g., Azor(R)), olmesartan medoxomil and hydrochlorothiazide (e.g., Tribenzor(R)), telmisartan, valsartan (e.g., Exforge(R)), valsartan and hydrochlorothiazide (e.g., Exforge(R) HCT), and atorvastatin (e.g., Caduet(R)). See the full prescribing information for additional administration instructions for each specific combination product.
If a dose of amlodipine is missed, the missed dose may be administered as soon as possible. If the dose is missed for more than 12 hours, do not take the dose and resume treatment with the next scheduled dose.
Amlodipine besylate tablets: Store the tablets at 15-30degreesC; dispense in a tight, light-resistant container.
Amlodipine besylate oral solution (Norliqva(R)): Store the oral solution at 20-25degreesC (excursions permitted to 15-30degreesC). Store and dispense in the original packaging (amber glass bottle).
Amlodipine benzoate oral suspension (Katerzia(R)): Shake the suspension well and measure each dose with a calibrated measuring device; do not use a household teaspoon or tablespoon. Store the oral suspension at 2-8degreesC and protect from light. Avoid freezing and excessive heat.
Perindopril erbumine is commercially available as 2 mg, 4 mg, and 8 mg tablets. Perindopril is administered orally once or twice daily. In clinical studies, administration of the drug in 2 divided doses generally was only slightly more effective than once-daily dosing.
Store perindopril tablets at 20-25degreesC (excursions permitted to 15-30degreesC). Protect from moisture.
No dosing information is available for this tab.
No dosing information is available for this tab.
Drug interactions
Amlodipine is a weak inhibitor of cytochrome P-450 (CYP) 3A isoenzymes.
When amlodipine is used in fixed combination with other drugs, interactions associated with the concomitant agent(s) must be considered in addition to those associated with amlodipine.
There are no contraindication interactions for this drug.
There are no severe interactions for this drug.
There are no moderate interactions for this drug.
Contraindications
Amlodipine is contraindicated in patients with known hypersensitivity to the drug.
*Known hypersensitivity (e.g., history of angioedema) to perindopril, other angiotensin-converting enzyme (ACE) inhibitors, or any ingredient in the formulation.
*History of hereditary or idiopathic angioedema.
*Concomitant aliskiren therapy in patients with diabetes mellitus.
*Concomitant use (within 36 hours) of a neprilysin inhibitor (e.g., sacubitril).
There are no contraindication contraindications for this drug.
There are no severe contraindications for this drug.
There are no moderate contraindications for this drug.
Adverse reactions
Adverse effects reported in 1% or more of patients receiving amlodipine include dose-related edema, dizziness, flushing, and palpitations; fatigue, nausea, abdominal pain, and somnolence also reported. Adverse effects reported in the clinical trial in pediatric patients with hypertension were similar to those that have been reported in adults.
Adverse effects occurring in patients receiving perindopril for hypertension at an incidence >=5% included cough, dizziness, and back pain.
Adverse effects occurring in patients receiving perindopril for stable coronary artery disease leading to treatment discontinuation were cough, drug intolerance, and hypotension.
There are no severe adverse reactions for this drug.
There are no less severe adverse reactions for this drug.
Precautions
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Safety and efficacy of amlodipine in children younger than 6 years of age have not been established. Safety and effectiveness of amlodipine (2.5-5 mg daily) for the treatment of pediatric patients 6-17 years of age with hypertension have been established in a trial of 8 weeks' duration.
Safety and efficacy of amlodipine in fixed combination with atorvastatin, benazepril, olmesartan (with or without hydrochlorothiazide), telmisartan, or valsartan (with or without hydrochlorothiazide) have not been established in pediatric patients.
Safety and efficacy of perindopril are not established in pediatric patients.
If oliguria or hypotension occurs in neonates with a history of in utero exposure to perindopril, support blood pressure and renal function; exchange transfusions or dialysis may be required.
The manufacturers state that there are limited data on use of amlodipine in pregnant women to inform a drug-associated risk for major birth defects and miscarriage. There is some data indicating that amlodipine crosses the placenta in measurable quantities in the third trimester of pregnancy.
Hypertension in pregnancy is a major cause of maternal, fetal or neonatal morbidity and mortality. Maternal risks include pre-eclampsia, gestational diabetes, premature delivery, placental abruption, delivery complications (e.g., need for cesarean section, postpartum hemorrhage), stroke, pulmonary edema, thromboembolic events, multiple organ failure (liver, kidney) and disseminated intravascular coagulation. Fetal risks include intrauterine growth restriction, prematurity, and intrauterine death. Neonates may require prolonged high-level care and experience morbidity. Pregnant women with hypertension should be carefully monitored and managed accordingly.
Teratogenicity or other embryo-fetal toxicity was not observed when pregnant rats and rabbits were treated orally with a different salt form of amlodipine (amlodipine maleate) at doses up to 10 mg/kg per day (approximately 10 and 20 times the maximum recommended human dose (MRHD) based on body surface area, respectively) during their respective periods of major organogenesis. However, when amlodipine maleate at doses up to 10 mg amlodipine/kg per day was administered to rats for 14 days prior to mating and throughout gestation, litter size decreased approximately 50%, and a 5-fold increase in the number of intrauterine deaths was observed at this dose equivalent to 10 times the MDRD. Amlodipine maleate has also been shown to prolong both the gestation period and the duration of labor in rats at this dose.
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. Perindopril crosses the placenta. Radioactivity was detectable in fetuses after administration of 14C-perindopril to pregnant rats.
Appropriate management of maternal hypertension during pregnancy is important to optimize outcomes for both the mother and fetus. Verify pregnancy status in females of reproductive potential prior to initiation of perindopril. Discontinue perindopril as soon as possible when pregnancy is detected.
In the rare situation that use of perindopril is deemed necessary, apprise the mother of the risk to the fetus. Perform serial ultrasound examinations to assess the intraamniotic environment. Fetal testing may be appropriate, based on the week of pregnancy; however, oligohydramnios may not appear until after the fetus has sustained irreversible injury. If oligohydramnios is observed, discontinue perindopril unless it is considered lifesaving for the mother. Closely observe infants with histories of in utero exposure to perindopril for hypotension, oliguria, and hyperkalemia.
The manufacturer states limited available data from a published clinical lactation study reported that amlodipine is present in human milk at an estimated median relative infant dose of 4.2%. No adverse effects of amlodipine on the breastfed infant have been observed; there is no available information on the effects of amlodipine on milk production.
It is not known whether perindopril is secreted in human milk. Milk of lactating rats contained radioactivity following administration of 14C-perindopril.
Because many drugs are secreted in human milk, exercise caution when perindopril is given to breast-feeding mothers.
The elimination of amlodipine may be impaired substantially in geriatric patients, resulting in increased exposure to the drug (AUC increases of 40-60%). For management of hypertension, some manufacturers recommend an initial amlodipine dosage of 2.5 mg once daily for geriatric patients. For management of vasospastic (Prinzmetal variant) angina or chronic stable angina in geriatric patients, an amlodipine dosage of 5 mg daily is recommended; adequate control of angina usually requires a maintenance dosage of 10 mg once daily.
In geriatric patients with hypertension, the recommended initial daily dosage of perindopril erbumine is 4 mg daily, given in 1 or 2 divided doses. Experience is limited with daily dosages above 8 mg; dosages above 8 mg daily require careful titration and close blood pressure monitoring.
In geriatric patients (>70 years) receivingperindopril erbumine for stable coronary artery disease, the recommended dosage is 2 mg once daily in the first week,followed by 4 mg once daily in the second week and 8 mg once daily as the maintenance dosage, if tolerated.
In geriatric patients, amlodipine clearance is decreased and AUC is increased by about 40-60%. Therefore, amlodipine dosage should be selected carefully, usually initiating therapy with dosages at the lower end of the recommended range (i.e., 2.5 mg daily). The greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy observed in the elderly also should be considered.
Clinical studies of amlodipine did not include sufficient numbers of patients 65 years of age and older to determine whether geriatric patients respond differently than younger patients; however, other clinical experience has not revealed age-related differences in response or tolerance.
Perindopril has been reported to have a somewhat smaller, but not significantly different, effect on blood pressure in those 60 years of age and older than in younger patients. Increased plasma concentrations of perindopril and perindoprilat (active metabolite) have been reported in geriatric patients compared with younger patients. Dizziness and possibly rash may occur more frequently in geriatric patients; monitor for dizziness because of the potential for falls.
In geriatric patients, start perindopril at a low dose and titrate slowly as needed. Experience with perindopril in geriatric patients at daily doses exceeding 8 mg is limited.
ICD codes
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Last reviewed · Source: First Databank (FDB) drug data
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