Lotrel (amlodipine besylate/benazepril HCl)
Last reviewed · Source: First Databank (FDB) drug data
Overview
Benazepril is a non-sulfhydryl angiotensin-converting enzyme (ACE) inhibitor.
Amlodipine is a 1,4-dihydropyridine-derivative calcium-channel blocking agent with an intrinsically long duration of action.
Benazepril is an angiotensin-converting enzyme (ACE, bradykininase, kininase II) inhibitor, the peptidyl dipeptidase that catalyzes the conversion of angiotensin I to angiotensin II. Angiotensin II is a vasoconstrictor substance that stimulates aldosterone secretion; inhibition of ACE results in decreased plasma angiotensin II, leading to reduced vasopressor activity and aldosterone secretion. Decreased aldosterone secretion may result in a small increase in serum potassium.
Kininase, an enzyme that is identical to ACE, degrades the potent vasodepressor bradykinin. Whether increased levels of bradykinin play a role in the therapeutic effects of benazepril remains unknown. The effects of benazepril on lowering blood pressure appear to be primarily from suppression of the renin-angiotensin-aldosterone system.
However, benazepril is antihypertensive in patients with low-renin hypertension. Benazepril, the ethylester of benazeprilat, is a prodrug and has little pharmacologic activity until hydrolyzed in the liver to benazeprilat. Like enalapril, fosinopril, lisinopril, quinapril, and ramipril, but unlike captopril, benazepril does not contain a sulfhydryl group.
In adults, peak serum concentrations of benazepril and benazeprilat are reached within 0.5-1 hour and 1-2 hours, respectively, after oral administration. The bioavailability of benazepril is not affected by food; however, food delays the time to peak plasma concentration of benazeprilat to 2-4 hours. The onset of antihypertensive activity was observed within 1 hour following administration of a single dose of benazepril, with peak reductions of blood pressure achieved between 2 and 4 hours.
Single and multiple doses of benazepril 10 mg or more cause inhibition of plasma ACE activity by at least 80-90% for at least 24 hours after dosing; pressor responses to exogenous angiotensin I were inhibited by 60-90% up to 4 hours post-dose at the 10 mg dose. After a single dose, the antihypertensive effect persisted for 24 hours. In multiple dose studies, dosages of benazepril between 20-80 mg once daily decreased seated systolic blood pressure by about 6-12 mmHg and seated diastolic blood pressure by 4-7 mmHg.
The serum trough levels of benazepril represent blood pressure reductions of approximately 50% of the reductions seen at peak. Steady state concentrations of benazeprilat should be reached after 2 or 3 doses of once-daily benazepril.
Benazepril and benazeprilat are approximately 96.7 and 95.3% protein bound, respectively. Benazepril is largely metabolized by cleavage of the ester group to benazeprilat, primarily in the liver. Both benazepril and benazeprilat undergo glucuronidation, and both are excreted predominantly by the kidneys.
After oral administration, about 37% was recovered in the urine: 20% as benazeprilat, 8% as benazeprilat glucuronide, 4% as benazepril glucuronide, and as trace amounts of benazepril. About 11-12% of benazeprilat excretion occurs through nonrenal (i.e., biliary) excretion. After repeat oral administration of benazepril, the effective half-life of benazeprilat is 10-11 hours.
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.
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, amlodipine and benazepril.
Amlodipine belongs to a class of drugs known as calcium channel blockers. Benazepril belongs to a class of drugs known as ACE inhibitors. They both work by relaxing blood vessels so blood can flow more easily.
Generic name: amlodipine besylate/benazepril HCl
Pronunciation: (am-LOE-di-peen/ben-AZ-e-pril)
Reference product & biosimilars
No reference, biosimilar or interchangeable associated with this drug.
Today’s intelligence on Lotrel
Indications
The following indications are listed for Lotrel:
- Hypertension
Also known as: Elevated Blood Pressure, Essential Hypertension, Hyperpiesia, Hyperpiesis, Hypertensive Disorder, Systemic Arterial Hypertension.
Dosing
Benazepril is available as benazepril hydrochloride; dosage is expressed in terms of the salt.
Dosage of amlodipine besylate and amlodipine benzoate is expressed in terms of amlodipine.
Benazepril hydrochloride is administered orally. The drug is commercially available as single-entity 5, 10, 20, or 40 mg tablets. Benazepril hydrochloride is also commercially available as a fixed-combination capsule containing amlodipine besylate and benazepril hydrochloride and as a fixed-combination tablet containing benazepril hydrochloride and hydrochlorothiazide; see the full prescribing information for administration of these fixed-combination products.
Store benazepril tablets in a tightly closed bottle, protected from light and moisture at 20-25degreesC.
For adult or pediatric patients unable to swallow tablets or those children for whom the daily dosage does not correspond exactly to the strength of commercially available tablets, benazepril may be administered orally as an extemporaneously prepared suspension.
An extemporaneous suspension containing benazepril hydrochloride 2 mg/mL can be prepared in the following manner. First, 75 mL of suspending vehicle (Ora-Plus(R)) is added to an amber polyethylene terephthalate (PET) bottle containing fifteen 20-mg tablets of benazepril hydrochloride, and the contents are shaken for at least 2 minutes. The concentrated suspension should be allowed to stand for at least 60 minutes following reconstitution, and then should be shaken for a minimum of 1 additional minute. The concentrated suspension of benazepril hydrochloride should be diluted with 75 mL of syrup (Ora-Sweet(R)), and the container then shaken to disperse the ingredients. The suspension should be shaken before dispensing each dose. The extemporaneous suspension is stable for 30 days when stored at 2-8degreesC.
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.
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
*Known hypersensitivity to benazepril or to any other angiotensin-converting enzyme (ACE) inhibitor.
*History of angioedema with or without prior ACE inhibitor therapy.
*Concomitant use with aliskiren in patients with diabetes mellitus.
*Use in combination with a neprilysin inhibitor (e.g., sacubitril); do not administer within 36 hours of switching to or from sacubitril/valsartan.
Amlodipine is contraindicated in patients with known hypersensitivity to the drug.
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 at an incidence >=1% include headache, dizziness, somnolence, and postural dizziness.
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.
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 benazepril have not been established in children younger than 6 years of age or in pediatric patients with creatinine clearance <30 mL/minute.
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.
Benazepril can cause fetal harm when administered to pregnant females.
Use of medications that impact the RAS, such as benazepril, during the second and third trimesters of pregnancy decreases fetal renal function and increases fetal/neonatal morbidity and mortality. Oligohydramnios caused by medications that act on the RAS can result in fetal lung hypoplasia, skeletal deformations (including skull hypoplasia), anuria, hypotension, renal failure, and death.
Discontinue benazepril as soon as possible when pregnancy is detected. In the rare case that there is no appropriate alternative to therapy with drugs affecting the RAS, apprise the mother of the potential hazard to the fetus.
Perform serial ultrasound examinations to assess the intra-amniotic environment. Based on the week of pregnancy, fetal testing may be appropriate. However, patients and clinicians should be aware that oligohydramnios may not manifest until after the fetus has sustained irreversible injury. Closely observe neonates with a history of in utero exposure to benazepril for hypotension, oliguria, and hyperkalemia. If oliguria or hypotension occurs, support blood pressure and renal perfusion. Exchange transfusions or dialysis may be required.
Monitor pregnant females with hypertension carefully and manage accordingly.
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.
Benazepril and benazeprilat (active metabolite of benazepril) are distributed into human milk in minimal amounts. Because of the unknown effects of benazepril or benazeprilat in nursing infants, a decision should be made whether to discontinue nursing or benazepril, taking into account the potential risk in breast-feeding infants and the importance of the drug to the woman.
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.
The manufacturers make no specific dosage recommendations for geriatric patients.
Because of the greater frequency of decreased renal function in geriatric patients, the manufacturers state that dosage selection should be made with caution and that it may be useful to monitor renal function in geriatric patients receiving benazepril.
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.
No substantial differences in safety and efficacy have been observed in geriatric patients relative to younger adults, but increased sensitivity cannot be ruled out.
Because geriatric patients are more likely to have decreased renal function, dosage should be selected cautiously; it may be useful to monitor renal function in such patients.
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.
ICD codes
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Last reviewed · Source: First Databank (FDB) drug data
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