Lotrel
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Questions & Answers
Side Effects & Adverse Reactions
Presumably because angiotensin-converting enzyme inhibitors affect the metabolism of eicosanoids and polypeptides, including endogenous bradykinin, patients receiving ACE inhibitors (including Lotrel) may be subject to a variety of adverse reactions, some of them serious. These reactions usually occur after one of the first few doses of the ACE inhibitor, but they sometimes do not appear until after months of therapy.
Head and Neck Angioedema: Angioedema of the face, extremities, lips, tongue, glottis, and larynx has been reported in patients treated with ACE inhibitors. In U.S. clinical trials, symptoms consistent with angioedema were seen in none of the subjects who received placebo and in about 0.5% of the subjects who received benazepril. Angioedema associated with laryngeal edema can be fatal. If laryngeal stridor or angioedema of the face, tongue, or glottis occurs, treatment with Lotrel should be discontinued and appropriate therapy instituted immediately. When involvement of the tongue, glottis, or larynx appears likely to cause airway obstruction, appropriate therapy, e.g., subcutaneous epinephrine injection 1:1000 (0.3-0.5 mL), should be promptly administered (see ADVERSE REACTIONS).
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); in some cases there was no prior history of facial angioedema and C-1 esterase levels were normal. The angioedema was diagnosed by procedures including abdominal CT scan or ultrasound, or at surgery, and 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.
Anaphylactoid Reactions During Desensitization: Two patients undergoing desensitizing treatment with hymenoptera venom while receiving ACE inhibitors sustained life-threatening anaphylactoid reactions. In the same patients, these reactions were avoided when ACE inhibitors were temporarily withheld, but they reappeared upon inadvertent rechallenge.
Anaphylactoid Reactions During Membrane Exposure: Anaphylactoid reactions have been reported in patients dialyzed with high-flux membranes and treated concomitantly with an ACE inhibitor. Anaphylactoid reactions have also been reported in patients undergoing low-density lipoprotein apheresis with dextran sulfate absorption.
Increased Angina and/or Myocardial Infarction: Rarely, patients, particularly those with severe obstructive coronary artery disease, have developed documented increased frequency, duration, and/or severity of angina or acute myocardial infarction on starting calcium channel blocker therapy or at the time of dosage increase. The mechanism of this effect has not been elucidated.
Lotrel can cause symptomatic hypotension. Like other ACE inhibitors, benazepril has been only rarely associated with hypotension in uncomplicated hypertensive patients. Symptomatic hypotension is most likely to occur in patients who have been volume and/or salt depleted as a result of prolonged diuretic therapy, dietary salt restriction, dialysis, diarrhea, or vomiting. Volume and/or salt depletion should be corrected before initiating therapy with Lotrel.
Since the vasodilation induced by amlodipine is gradual in onset, acute hypotension has rarely been reported after oral administration of amlodipine. Nonetheless, caution should be exercised when administering Lotrel as with any other peripheral vasodilator, particularly in patients with severe aortic stenosis.
In patients with congestive heart failure, with or without associated renal insufficiency, ACE inhibitor therapy may cause excessive hypotension, which may be associated with oliguria, azotemia, and (rarely) with acute renal failure and death. In such patients, Lotrel therapy should be started under close medical supervision; they should be followed closely for the first 2 weeks of treatment and whenever the dose of the benazepril component is increased or a diuretic is added or its dose increased.
If hypotension occurs, the patient should be placed in a supine position, and if necessary, treated with intravenous infusion of physiologic saline. Lotrel treatment usually can be continued following restoration of blood pressure and volume.
Another ACE inhibitor, captopril, has been shown to cause agranulocytosis and bone marrow depression, rarely in uncomplicated patients (incidence probably less than once per 10,000 exposures) but more frequently (incidence possibly as great as once per 1000 exposures) in patients with renal impairment, especially those who also have collagen-vascular diseases such as systemic lupus erythematosus or scleroderma. Available data from clinical trials of benazepril are insufficient to show that benazepril does not cause agranulocytosis at similar rates. Monitoring of white blood cell counts should be considered in patients with collagen-vascular disease, especially if the disease is associated with impaired renal function.
ACE inhibitors can cause fetal and neonatal morbidity and death when administered to pregnant women. Several dozen cases have been reported in the world literature. When pregnancy is detected, Lotrel should be discontinued as soon as possible and monitoring of the fetal development should be performed on a regular basis.
The use of ACE inhibitors during the second and third trimesters of pregnancy has been associated with fetal and neonatal injury, including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death. Oligohydramnios has also been reported, presumably resulting from decreased fetal renal function; oligohydramnios in this setting has been associated with fetal limb contractures, craniofacial deformation, and hypoplastic lung development. Prematurity, intrauterine growth retardation, and patent ductus arteriosus have also been reported, although it is not clear whether these occurrences were due to the ACE inhibitor exposure.
In addition, use of ACE inhibitors during the first trimester of pregnancy has been associated with a potentially increased risk of birth defects. In women planning to become pregnant, ACE inhibitors (including Lotrel) should not be used. Women of child-bearing age should be made aware of the potential risk and ACE inhibitors (including Lotrel) should only be given after careful counseling and consideration of individual risks and benefits.
Rarely (probably less often than once in every thousand pregnancies), no alternative to ACE inhibitors will be found. In these rare cases, the mothers should be apprised of the potential hazards to their fetuses, and serial ultrasound examinations should be performed to assess the intra-amniotic environment.
If oligohydramnios is observed, benazepril should be discontinued unless it is considered life-saving for the mother. Contraction stress testing (CST), a nonstress test (NST), or biophysical profiling (BPP) may be appropriate, depending upon the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury.
Infants with histories of in utero exposure to ACE inhibitors should be closely observed for hypotension, oliguria, and hyperkalemia. If oliguria occurs, attention should be directed toward support of blood pressure and renal perfusion. Exchange transfusion or peritoneal dialysis may be required as means of reversing hypotension and/or substituting for disordered renal function. Benazepril, which crosses the placenta, can theoretically be removed from the neonatal circulation by these means; there are occasional reports of benefit from these maneuvers, but experience is limited.
Lotrel has not been adequately studied in pregnant women. When rats received benazepril:amlodipine at doses ranging from 5:2.5 to 50:25 mg/kg/day, dystocia was observed with increasing dose-related incidence at all doses tested. On a mg/m2 basis, the 2.5 mg/kg/day dose of amlodipine is 3.6 times the amlodipine dose delivered when the maximum recommended dose of Lotrel is given to a 50-kg woman. Similarly, the 5 mg/kg/day dose of benazepril is approximately 2 times the benazepril dose delivered when the maximum recommended dose of Lotrel is given to a 50-kg woman.
No teratogenic effects were seen when benazepril and amlodipine were administered in combination to pregnant rats or rabbits. Rats received dose ratios up to 50:25 mg/kg/day (benazepril:amlodipine) (24 times the maximum recommended human dose on a mg/m2 basis, assuming a 50-kg woman). Rabbits received doses of up to 1.5:0.75 (benazepril:amlodipine) mg/kg/day; on a mg/m2 basis, this is 0.97 times the size of a maximum recommended dose of Lotrel given to a 50-kg woman.
Similar results were seen in animal studies involving benazepril alone and amlodipine alone.
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.
Legal Issues
There is currently no legal information available for this drug.
FDA Safety Alerts
There are currently no FDA safety alerts available for this drug.
Manufacturer Warnings
There is currently no manufacturer warning information available for this drug.
FDA Labeling Changes
There are currently no FDA labeling changes available for this drug.
Uses
Lotrel is indicated for the treatment of hypertension.
This fixed combination drug is not indicated for the initial therapy of hypertension (see DOSAGE AND ADMINISTRATION).
In using Lotrel, consideration should be given to the fact that an ACE inhibitor, captopril, has caused agranulocytosis, particularly in patients with renal impairment or collagen-vascular disease. Available data are insufficient to show that benazepril does not have a similar risk (see WARNINGS, Neutropenia/Agranulocytosis).
Black patients receiving ACE inhibitors have been reported to have a higher incidence of angioedema compared to nonblacks.
History
There is currently no drug history available for this drug.
Other Information
Benazepril hydrochloride is a white to off-white crystalline powder, soluble (>100 mg/mL) in water, in ethanol, and in methanol. Benazepril hydrochloride’s chemical name is 3-[[1-(ethoxycarbonyl)-3-phenyl-(1S)-propyl]amino]-2,3,4,5-tetrahydro-2-oxo-1H-1-(3S)-benzazepine-1-acetic acid monohydrochloride; its structural formula is
Its empirical formula is C24H28N2O5•HCl, and its molecular weight is 460.96.
Benazeprilat, the active metabolite of benazepril, is a nonsulfhydryl angiotensin-converting enzyme (ACE) inhibitor. Benazepril is converted to benazeprilat by hepatic cleavage of the ester group.
Amlodipine besylate is a white to pale yellow crystalline powder, slightly soluble in water and sparingly soluble in ethanol. Its chemical name is (R,S)3-ethyl-5-methyl-2-(2-aminoethoxymethyl)-4-(2-chlorophenyl)-1,4-dihydro-6-methyl-3,5-pyridinedicarboxylate benzenesulfonate; its structural formula is
Its empirical formula is C20H25ClN2O5•C6H6O3S, and its molecular weight is 567.1.
Amlodipine besylate is the besylate salt of amlodipine, a dihydropyridine calcium channel blocker.
Lotrel is a combination of amlodipine besylate and benazepril hydrochloride. The capsules are formulated in six different strengths for oral administration with a combination of amlodipine besylate equivalent to 2.5 mg, 5 mg or 10 mg of amlodipine, with 10 mg, 20 mg or 40 mg of benazepril hydrochloride providing for the following available combinations: 2.5/10 mg, 5/10 mg, 5/20 mg, 5/40 mg, 10/20 mg and 10/40 mg. The inactive ingredients of the capsules are calcium phosphate, cellulose compounds, colloidal silicon dioxide, crospovidone, gelatin, hydrogenated castor oil (not present in 5/40 mg or 10/40 mg strengths), iron oxides, lactose, magnesium stearate, polysorbate 80, silicon dioxide, sodium lauryl sulfate, sodium starch (potato) glycolate, starch (corn), talc, and titanium dioxide.
Sources
Lotrel Manufacturers
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Cardinal Health
![Lotrel (Amlodipine Besylate And Benazepril Hydrochloride) Capsule [Cardinal Health]](/wp-content/themes/bootstrap/assets/img/loading2.gif)
Lotrel | Cardinal Health
Amlodipine is an effective treatment of hypertension in once-daily doses of 2.5-10 mg while benazepril is effective in doses of 10-80 mg. In clinical trials of amlodipine/benazepril combination therapy using amlodipine doses of 2.5-10 mg and benazepril doses of 10-40 mg, the antihypertensive effects increased with increasing dose of amlodipine in all patient groups, and the effects increased with increasing dose of benazepril in nonblack groups. All patient groups benefited from the reduction in amlodipine-induced edema (see below).
The hazards (see WARNINGS) of benazepril are generally independent of dose; those of amlodipine are a mixture of dose-dependent phenomena (primarily peripheral edema) and dose-independent phenomena, the former much more common than the latter. When benazepril is added to a regimen of amlodipine, the incidence of edema is substantially reduced. Therapy with any combination of amlodipine and benazepril will thus be associated with both sets of dose-independent hazards, but the incidence of edema will generally be less than that seen with similar (or higher) doses of amlodipine monotherapy.
Rarely, the dose-independent hazards of benazepril are serious. To minimize dose-independent hazards, it is usually appropriate to begin therapy with Lotrel only after a patient has either (a) failed to achieve the desired antihypertensive effect with one or the other monotherapy, or (b) demonstrated inability to achieve adequate antihypertensive effect with amlodipine therapy without developing edema.
Dose Titration Guided by Clinical Effect: A patient whose blood pressure is not adequately controlled with amlodipine (or another dihydropyridine) alone or with benazepril (or another ACE inhibitor) alone may be switched to combination therapy with Lotrel. The addition of benazepril to a regimen of amlodipine should not be expected to provide additional antihypertensive effect in African-Americans. However, all patient groups benefit from the reduction in amlodipine-induced edema. Dosage must be guided by clinical response; steady-state levels of benazepril and amlodipine will be reached after approximately 2 and 7 days of dosing, respectively.
In patients whose blood pressures are adequately controlled with amlodipine but who experience unacceptable edema, combination therapy may achieve similar (or better) blood pressure control without edema. Especially in nonblacks, it may be prudent to minimize the risk of excessive response by reducing the dose of amlodipine as benazepril is added to the regimen.
Replacement Therapy: For convenience, patients receiving amlodipine and benazepril from separate tablets may instead wish to receive capsules of Lotrel containing the same component doses.
Use in Patients With Metabolic Impairments: Regimens of therapy with Lotrel need not take account of renal function as long as the patient’s creatinine clearance is >30 mL/min/1.73m2 (serum creatinine roughly ≤3 mg/dL or 265 µmol/L). In patients with more severe renal impairment, the recommended initial dose of benazepril is 5 mg. Lotrel is not recommended in these patients.
In small, elderly, frail, or hepatically impaired patients, the recommended initial dose of amlodipine, as monotherapy or as a component of combination therapy, is 2.5 mg.
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Pd-rx Pharmaceuticals, Inc.
Lotrel | Pd-rx Pharmaceuticals, Inc.
Amlodipine is an effective treatment of hypertension in once-daily doses of 2.5-10 mg while benazepril is effective in doses of 10-80 mg. In clinical trials of amlodipine/benazepril combination therapy using amlodipine doses of 2.5-10 mg and benazepril doses of 10-40 mg, the antihypertensive effects increased with increasing dose of amlodipine in all patient groups, and the effects increased with increasing dose of benazepril in nonblack groups.
The antihypertensive effect of Lotrel is largely attained within 2 weeks.
It is usually appropriate to begin therapy with Lotrel only after a patient has either (a) failed to achieve the desired antihypertensive effect with one or the other monotherapy, or (b) demonstrated inability to achieve adequate antihypertensive effect with amlodipine therapy without developing edema.
Renal Impairment: Regimens of therapy with Lotrel need not take account of renal function as long as the patient’s creatinine clearance is >30 mL/min/1.73m2 (serum creatinine roughly ≤3 mg/dL or 265 µmol/L). Lotrel is not recommended in patients with more severe renal impairment.
Hepatic Impairment and Elderly Patients: The recommended initial dose of amlodipine, as monotherapy or as a component of combination therapy, is 2.5 mg.
2.2 Add-on TherapyA patient whose blood pressure is not adequately controlled with amlodipine (or another dihydropyridine) alone or with benazepril (or another ACE inhibitor) alone may be switched to combination therapy with Lotrel.
In patients whose blood pressure is adequately controlled with amlodipine but who experience unacceptable edema, combination therapy may achieve similar (or better) blood pressure control with less edema.
2.3 Replacement TherapyLotrel may be substituted for the titrated components.
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Pd-rx Pharmaceuticals, Inc.
Lotrel | Pd-rx Pharmaceuticals, Inc.
Amlodipine is an effective treatment of hypertension in once-daily doses of 2.5-10 mg while benazepril is effective in doses of 10-80 mg. In clinical trials of amlodipine/benazepril combination therapy using amlodipine doses of 2.5-10 mg and benazepril doses of 10-40 mg, the antihypertensive effects increased with increasing dose of amlodipine in all patient groups, and the effects increased with increasing dose of benazepril in nonblack groups.
The antihypertensive effect of Lotrel is largely attained within 2 weeks.
It is usually appropriate to begin therapy with Lotrel only after a patient has either (a) failed to achieve the desired antihypertensive effect with one or the other monotherapy, or (b) demonstrated inability to achieve adequate antihypertensive effect with amlodipine therapy without developing edema.
Renal Impairment: Regimens of therapy with Lotrel need not take account of renal function as long as the patient’s creatinine clearance is >30 mL/min/1.73m2 (serum creatinine roughly ≤3 mg/dL or 265 µmol/L). Lotrel is not recommended in patients with more severe renal impairment.
Hepatic Impairment and Elderly Patients: The recommended initial dose of amlodipine, as monotherapy or as a component of combination therapy, is 2.5 mg.
2.2 Add-on TherapyA patient whose blood pressure is not adequately controlled with amlodipine (or another dihydropyridine) alone or with benazepril (or another ACE inhibitor) alone may be switched to combination therapy with Lotrel.
In patients whose blood pressure is adequately controlled with amlodipine but who experience unacceptable edema, combination therapy may achieve similar (or better) blood pressure control with less edema.
2.3 Replacement TherapyLotrel may be substituted for the titrated components.
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Physicians Total Care, Inc.
Lotrel | Physicians Total Care, Inc.
Amlodipine is an effective treatment of hypertension in once-daily doses of 2.5-10 mg while benazepril is effective in doses of 10-80 mg. In clinical trials of amlodipine/benazepril combination therapy using amlodipine doses of 2.5-10 mg and benazepril doses of 10-40 mg, the antihypertensive effects increased with increasing dose of amlodipine in all patient groups, and the effects increased with increasing dose of benazepril in nonblack groups.
The antihypertensive effect of Lotrel is largely attained within 2 weeks.
It is usually appropriate to begin therapy with Lotrel only after a patient has either (a) failed to achieve the desired antihypertensive effect with one or the other monotherapy, or (b) demonstrated inability to achieve adequate antihypertensive effect with amlodipine therapy without developing edema.
Renal Impairment: Regimens of therapy with Lotrel need not take account of renal function as long as the patient’s creatinine clearance is >30 mL/min/1.73m2 (serum creatinine roughly ≤3 mg/dL or 265 µmol/L). Lotrel is not recommended in patients with more severe renal impairment.
Hepatic Impairment and Elderly Patients: The recommended initial dose of amlodipine, as monotherapy or as a component of combination therapy, is 2.5 mg.
2.2 Add-on TherapyA patient whose blood pressure is not adequately controlled with amlodipine (or another dihydropyridine) alone or with benazepril (or another ACE inhibitor) alone may be switched to combination therapy with Lotrel.
In patients whose blood pressure is adequately controlled with amlodipine but who experience unacceptable edema, combination therapy may achieve similar (or better) blood pressure control with less edema.
2.3 Replacement TherapyLotrel may be substituted for the titrated components.
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Novartis Pharmaceuticals Corporation
Lotrel | Novartis Pharmaceuticals Corporation
2.1 General ConsiderationsThe recommended initial dose of Lotrel is 1 capsule of amlodipine 2.5 mg/benazepril 10 mg orally once-daily.
It is usually appropriate to begin therapy with Lotrel only after a patient has either (a) failed to achieve the desired antihypertensive effect with amlodipine or benazepril monotherapy, or (b) demonstrated inability to achieve adequate antihypertensive effect with amlodipine therapy without developing edema.
The antihypertensive effect of Lotrel is largely attained within 2 weeks. If blood pressure remains uncontrolled, the dose may be titrated up to amlodipine 10 mg/benazepril 40 mg once-daily. The dosing should be individualized and adjusted according to the patient’s clinical response.
Amlodipine is an effective treatment of hypertension in once-daily doses of 2.5 to 10 mg while benazepril is effective in doses of 10 to 80 mg. In clinical trials of amlodipine/benazepril combination therapy using amlodipine doses of 2.5 to 10 mg and benazepril doses of 10 to 40 mg, the antihypertensive effects increased with increasing dose of amlodipine in all patient groups, and the effects increased with increasing dose of benazepril in nonblack groups.
2.2 Dosage Adjustment in Renal ImpairmentRenal Impairment: Lotrel is not recommended in patients with creatinine clearance (CrCl) less than or equal to 30 mL/min. No dose adjustment of Lotrel is required in patients with CrCl greater than 30 mL/min/1.73m2 (serum creatinine roughly less than or equal to 3 mg/dL or 265 micromol/L) [see Warnings and Precautions (5.7), Use in Specific Populations (8.7), and Clinical Pharmacology (12.3)].
2.3 Replacement TherapyLotrel may be substituted for the titrated components.
![Lotrel (Amlodipine Besylate And Benazepril Hydrochloride) Capsule [Pd-rx Pharmaceuticals, Inc.]](http://dailymed.nlm.nih.gov/dailymed/image.cfm?setid=1dd4f8bf-51cc-468f-a1cb-2427a8c71ad7&name=55289039.jpg)
![Lotrel (Amlodipine Besylate And Benazepril Hydrochloride) Capsule [Pd-rx Pharmaceuticals, Inc.]](http://dailymed.nlm.nih.gov/dailymed/image.cfm?setid=2bd2b07b-0da6-47a2-858b-e18851d566fb&name=55289096.jpg)
![Lotrel (Amlodipine Besylate And Benazepril Hydrochloride) Capsule [Physicians Total Care, Inc.]](http://dailymed.nlm.nih.gov/dailymed/image.cfm?setid=4653cabc-f249-4b4e-95b6-5fb4ddc0ad5d&name=4066.jpg)
![Lotrel (Amlodipine Besylate And Benazepril Hydrochloride) Capsule [Novartis Pharmaceuticals Corporation]](http://dailymed.nlm.nih.gov/dailymed/image.cfm?setid=94ae6054-b7ae-4212-a567-4f803af8f2c7&name=lotrel-04.jpg)
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