Lotrel

— THERAPEUTIC CATEGORIES —
  • Hypertension
PAGE CONTENTS
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  • Generic Name & Formulations
  • Indications
  • Dosage and Administration
  • Contraindications
  • Boxed Warnings
  • Warnings/Precautions
  • Pharmacokinetics
  • Interactions
  • Adverse Reactions
  • Clinical Trials
  • Note
  • Patient Counseling

    • Lotrel Generic Name & Formulations

    Legal Class

    Rx

    General Description

    Amlodipine (as besylate), benazepril (as HCl); 2.5mg/10mg, 5mg/10mg, 5mg/20mg, 5mg/40mg, 10mg/20mg, 10mg/40mg; caps.

    Pharmacological Class

    Calcium channel blocker (CCB) (dihydropyridine) + ACE inhibitor.

    How Supplied

    Caps—100

    How Supplied

    Lotrel is available as capsules containing amlodipine besylate (6.9 mg or 13.9 mg, equivalent to 5 mg or 10 mg of amlodipine respectively), with 10 mg, 20 mg, or 40 mg of benazepril hydrochloride providing for the following available combinations: 5/10 mg, 5/20 mg, 10/20 mg, and 10/40 mg. All strengths are packaged in bottles of 100 capsules.

    • 5/10 mg capsule: light brown with 2 white bands/2260

    • 5/20 mg capsule: pink with 2 white bands/2265

    • 10/20 mg capsule: purple (a amethyst) with 2 white bands/0364

    • 10/40 mg capsule: dark blue with 2 white bands/0379

    Storage

    Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F). [See USP controlled room temperature]. Protect from moisture. Dispense in tight container (USP).

    Manufacturer

    Novartis Pharmaceuticals Corp

    Generic Availability

    YES

    Mechanism of Action

    Benazepril and benazeprilat inhibit ACE, a peptidyl dipeptidase that catalyzes the conversion of angiotensin I to the vasoconstrictor substance angiotensin II. Angiotensin II also stimulates aldosterone secretion by the adrenal cortex. Inhibition of ACE results in decreased plasma angiotensin II, which leads to decreased vasopressor activity and to decreased aldosterone secretion. Amlodipine inhibits calcium ion influx across cell membranes selectively, with a greater effect on vascular smooth muscle cells than on cardiac muscle cells. It is a peripheral arterial vasodilator that acts directly on vascular smooth muscle to cause a reduction in peripheral vascular resistance and reduction in blood pressure.

    Lotrel Indications

    Indications

    Hypertension (not for initial therapy).

    Lotrel Dosage and Administration

    Adult

    For patients not adequately controlled with amlodipine or benazepril monotherapy or in those who show inability to achieve BP control with amlodipine without developing edema: initially 2.5mg/10mg once daily; may titrate up to 10mg/40mg once daily if BP remains uncontrolled. Replacement therapy: may be substituted for titrated components. CrCl ≤30mL/min: not recommended. Hepatic impairment, elderly: consider lower doses.

    Children

    Not established.

    Lotrel Contraindications

    Contraindications

    History of ACEI-associated or other angioedema. Concomitant aliskiren in patients with diabetes. Concomitant neprilysin inhibitor (eg, sacubitril); do not administer amlodipine/benazepril within 36hrs of switching to or from sacubitril/valsartan.

    Lotrel Boxed Warnings

    Boxed Warning

    Fetal toxicity.

    Lotrel Warnings/Precautions

    Warnings/Precautions

    Fetal toxicity may develop; discontinue if pregnancy is detected. Correct salt/volume depletion prior to initiation. Renal or hepatic impairment. Dialysis (esp. high-flux membrane). Renal artery stenosis. CHF. Severe obstructive coronary artery disease. Severe aortic or mitral stenosis. Obstructive hypertrophic cardiomyopathy. Diabetes. Surgery. Discontinue and treat if angioedema, laryngeal edema, jaundice or marked elevation of liver enzymes develop. Monitor BP, electrolytes and renal function. Black patients may have higher rate of angioedema than non-black patients. Elderly. Neonates. Pregnancy: monitor. Nursing mothers.

    Warnings/Precautions

    Fetal Toxicity

    • Lotrel can cause fetal harm when given to a pregnant woman.

    • Use of drugs that act on the renin-angiotensin system during the 2nd and 3rd trimesters of pregnancy reduces fetal renal function and increases fetal/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 Lotrel as soon as possible.

    Angioedema and Anaphylactoid Reactions

    • Head and Neck Angioedema: Angioedema of the face, extremities, lips, tongue, glottis, and larynx has been reported. Discontinue Lotrel and treat immediately if laryngeal stridor or angioedema of the face, tongue, or glottis occurs. Increased risk for angioedema in patients with a history of angioedema, Black patients, and patients receiving coadministration of an ACE inhibitor and mTOR inhibitor or a neprilysn inhibitor.

    • Intestinal Angioedema: Intestinal angioedema has been reported. Patients presented with abdominal pain.

    Increased Angina or Myocardial Infarction

    • Worsening angina and acute myocardial infarction can develop after starting or increasing the dose of Lotrel (esp. in those with severe obstructive coronary artery disease).

    Hypotension

    • Symptomatic hypotension is possible (esp. in those with heart failure, severe aortic or mitral stenosis, obstructive hypertrophic cardiomyopathy or have been volume or salt depleted as a result of diuretic therapy, dietary salt restriction, dialysis, diarrhea, or vomiting). 

    • Correct volume and salt depletion prior to initiating therapy with benazepril. Continue treatment with benazepril once BP and volume have returned to normal.

    • For patients with CHF, initiate Lotrel therapy under close medical supervision.

    Impaired Renal Function 

    • Changes in renal function including acute renal failure can be caused by drugs that inhibit the renin-angiotensin system.

    • Patients whose renal function may depend in part on the activity of the renin-angiotensin system (eg, those with renal artery stenosis, chronic kidney disease, severe CHF, or volume depletion) may be at particular risk of developing acute renal failure on Lotrel. Monitor renal function periodically in these patients.

    • Consider withholding or discontinuing therapy in patients who develop a clinically significant decrease in renal function on Lotrel.

    Hyperkalemia

    • Monitor serum potassium periodically. Increased risk for hyperkalemia in patients with renal insufficiency, diabetes mellitus, and the concomitant use of potassium-sparing diuretics, potassium supplements, and/or potassium-containing salt substitutes.

    Hepatitis and Hepatic Failure

    • Discontinue and treat if jaundice or marked elevation of liver enzymes develop, and keep patients under medical surveillance.

    Pregnancy Considerations

    Risk Summary 

    • Lotrel can cause fetal harm when administered to a pregnant woman. Use of drugs that act on the renin-angiotensin system during the 2nd and 3rd trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. When pregnancy is detected, discontinue Lotrel as soon as possible.

    Clinical Considerations 

    • Disease-Associated Maternal and/or Embryo/Fetal Risk: Hypertension during pregnancy increases the maternal risk for pre-eclampsia, gestational diabetes, premature delivery, and delivery complications (e.g., need for cesarean section, and post-partum hemorrhage). Hypertension increases the fetal risk for intrauterine growth restriction and intrauterine death. Monitor pregnant women with hypertension carefully.

    • Fetal/Neonatal Adverse Reactions: Perform serial ultrasound examinations to assess the intra-amniotic environment. Monitor closely in neonates with histories of in utero exposure to Lotrel for hypotension, oliguria, and hyperkalemia.

    Nursing Mother Considerations

    Risk Summary

    • Minimal amounts of unchanged benazepril and of benazeprilat are excreted into the breast milk of lactating women treated with benazepril.

    • Limited available data from a published clinical lactation study reports that amlodipine is present in human milk.

    • There is no available information on the effects of amlodipine or benazepril on milk production.

    Pediatric Considerations

    The safety and efficacy of Lotrel have not been established in pediatric patients.

    Renal Impairment Considerations

    Patients with severe renal impairment have increased exposure to benazepril. Lotrel is not recommended in patients with severe renal impairment.

    No dose adjustments are needed in patients with mild or moderate renal impairment.

    Hepatic Impairment Considerations

    Patients with hepatic impairment have increased exposure to amlodipine: consider reducing doses of Lotrel.

    Lotrel Pharmacokinetics

    Absorption

    Amlodipine:

    • After oral administration, peak plasma concentrations of amlodipine are reached between 6–12 hours. Absolute bioavailability has been estimated to be between 64–90%. 

    Benazepril:

    • After oral administration, peak plasma concentrations of benazepril are reached between 0.5–2 hours. The extent of absorption is at least 37%.  

    Distribution

    Amlodipine:

    • Plasma protein bound: ~93%.

    • Apparent volume of distribution: ~21 L/kg.

    Benazepril:

    • Plasma protein bound: ≥93%.

    • Apparent volume of distribution: ~0.7 L/kg.

    Metabolism

    Hepatic. 

    Elimination

    Amlodipine: renal. Benazepril: renal (primarily), biliary. Half-life: 10–11 hours (benazepril); ~2 days (amlodipine).

    Lotrel Interactions

    Interactions

    See Contraindications. Increased risk of angioedema with concomitant neprilysin inhibitor or mTOR inhibitor (eg, temsirolimus, sirolimus, everolimus). Dual inhibition of the renin-angiotensin system with ARBs, ACEIs, or aliskiren may increase risk of hypotension, hyperkalemia, renal function changes; monitor closely, in general, avoid combined use of RAS inhibitors. Avoid aliskiren in renal impairment (CrCl <60mL/min). Hyperkalemia with K+supplements, K+ -sparing diuretics, or salt substitutes. May increase lithium levels; monitor. Potentiates simvastatin (max 20mg daily). Potentiated by diuretics, CYP3A4 inhibitors. Nitritoid reactions with concomitant injectable gold (sodium aurothiomalate); rare. May be antagonized by, and renal toxicity potentiated by, NSAIDs, including selective COX-2 inhibitors (monitor renal function periodically in elderly and/or volume depleted). Hypoglycemia with insulin and oral antidiabetics; rare.

    Lotrel Adverse Reactions

    Adverse Reactions

    Cough, edema, fatigue, dizziness, GI upset, angioedema, hypotension, hyperkalemia, palpitations, flushing, anaphylactoid reactions; rare: hepatic failure.

    Lotrel Clinical Trials

    Clinical Trials

    • The efficacy and safety of Lotrel was evaluated in 6 double-blind, placebo-controlled studies which included over 950 patients. The antihypertensive effect of a single dose persisted for 24 hours, with peak reductions achieved 2 to 8 hours after dosing.

    • Once-daily doses of benazepril/amlodipine using benazepril doses of 10 to 20 mg and amlodipine doses of 2.5 to 10 mg decreased seated pressure (systolic/diastolic) 24 hours after dosing by about 10–25/6–13 mmHg.

    • During chronic therapy with Lotrel, the maximum reduction in blood pressure with any given dose is generally achieved after 1 to 2 weeks. The antihypertensive effects of Lotrel have continued during therapy for at least 1 year. Abrupt withdrawal of Lotrel has not been associated with a rapid increase in blood pressure.

    Lotrel Note

    Not Applicable

    Lotrel Patient Counseling

    Patient Counseling

    Pregnancy

    • Advise female patients of childbearing age regarding the risks of exposure to Lotrel during pregnancy.

    Symptomatic Hypotension

    • Advise patients that lightheadedness may occur.

    • Caution all patients that inadequate fluid intake, excessive perspiration, diarrhea, or vomiting can lead to an excessive fall in blood pressure, with the same consequences of lightheadedness and possible syncope.

    Hyperkalemia

    • Advise patients not to use salt substitutes without consulting their healthcare provider.

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