benazepril/amlodipine (Lotrel)

Dosing and uses of Lotrel (benazepril/amlodipine)

• Adult
• Pediatric
• Geriatric

 

Adult dosage forms and strengths

benazepril/amlodipine

capsule

• 10mg/2.5mg
• 10mg/5mg
• 20mg/5mg
• 20mg/10mg
• 40mg/5mg
• 40mg/10mg

 

Hypertension

1 tablet (2.5-10 mg amlodipine; 10-40mg benazepril) PO qDay; titrate with appropriate dosage combination to control BP; not to exceed 10 mg/day amlodipine, 80 mg/day benazepriL

 

Dosing Modifications

Renal impairment: Decrease dose if CrCl <30 mL/min, severe liver impairment, or coadministered with diuretic

Hepatic impairment: 2.5 mg based on amlodipine initially

 

Pediatric dosage forms and strengths

Safety and efficacy not established

 

Geriatric dosage forms and strengths

The recommended initial dose of amlodipine in elderly patients is 2.5 mg

 

Lotrel (benazepril/amlodipine) adverse (side) effects

>10%

Amlodipine

• Peripheral edema (2-15%)
• Pulmonary edema (7-15%)

BenazepriL

• None indicated

 

1-10%

Amlodipine

• Abdominal pain (1.6%)
• Dizziness (1.1-3.4%)
• Dyspepsia (1-2%)
• Fatigue (4.5%)
• Flushing (0.7-2.6%)
• Headache (7.3%)
• Male sexual dysfunction (1-2%)
• Muscle cramps (1-2%)
• Nausea (2.9%)
• Palpitation (0.7-4.5%)
• Rash (1-2%)
• Somnolence (1-2%)
• Weakness (1-2%)

BenazepriL

• ARF if renal artery stenosis
• Cough (1-10%)
• Dizziness (4%)
• Fatigue (2%)
• Headache (6%)
• Nausea (1%)
• Postural dizziness (2%)
• Serum creatinine increased (2%)
• Somnolence (2%)

 

Postmarketing Reports

Amlodipine

• Gingival hyperplasia
• Tachycardia
• Jaundice
• Hepatic enzyme elevations
• Diplopia
• Gynecomastia
• Cholestasis
• Acute interstitial nephritis
• Depression
• Leukopenia

BenazepriL

• Stevens-Johnson syndrome
• Pancreatitis
• Hemolytic anemia
• Pemphigus
• Thrombocytopenia
• Arthralgia
• ECG changes
• Gastritis
• Flushing
• Hemolytic anemia
• Neutropenia

 

Warnings

Black box warnings

Discontinue as soon as possible when pregnancy is detected; affects renin-angiotensin system, causing oligohydramnios, which may result in fetal injury and/or death

 

Contraindications

Hypersensitivity

History of angioedema with or without previous ACE inhibitor therapy

Hereditary or idiopathic angioedema

Concomitant use with Aliskiren in patients with diabetes mellitus

Pregnancy (2nd and 3rd trimesters): Significant risk of fetal/neonatal morbidity and mortality; discontinue as soon as pregnancy detected

 

Cautions

Use with caution in CHF

Use with caution in patients with aortic stenosis, ischemic heart disease or cerebrovascular disease

Use with caution in patients with unstented unilateral/bilateral renal artery stenosis; avoid use due to elevated risk of deterioration in renal function

Persistent, progressive dermatologic reactions

Exacerbation of angina (during initiation of treatment, after dose increase, or withdrawal of beta blocker)

Use caution in hepatic impairment (may require lower starting dose)

Excessive hypotension if concomitant diuretics, hypovolemia, hyponatremia

Risk of hyperkalemia, especially with renal impairment or DM or in patients taking concomitant K+-elevating drugs; assess for hypotension and hyperkalemia

Dual blockade of the renin-angiotensin system with ARBs, ACE inhibitors, or aliskiren associated with increased risk for hypotension, hyperkalemia, and renal function changes (including acute renal failure), compared with monotherapy; most patients receiving combination of two renin-angiotensin system (RAS) inhibitors do not obtain additional benefit compared to monotherapy; in general, avoid combined use of RAS inhibitors

Black patients receiving ACE inhibitors have higher incidence of angioedema compared with nonblacks

Titrate slowly with hepatic impairment; amlodipine extensively metabolized by liver (half-life is 56 hr with hepatic impairment)

Rare reports of cholestatic hepatitis and acute liver failure (some fatal)

Patients receiving coadministration of ACE inhibitor and mTOR (mammalian target of rapamycin) inhibitor (e.g., temsirolimus, sirolimus, everolimus) therapy may be at increased risk for angioedema

Myocardial infarction or increased angina in patients with obstructive coronary artery disease may occur

Avoid with severe renal impairment (ie, CrCl <30 mL/min); avoid in patients with severe heart failure, whose renal function may depend on the activity of the renin-angiotensin-aldosterone system; treatment with ACE inhibitor causes oliguria or progressive azotemia and (rarely) with acute renal failure and/or death

 

Pregnancy and lactation

Pregnancy category: d

Lactation: Minimal amounts of benazepril enters milk, but excretion of amlodipine is not known; not recommended

 

Pregnancy categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

 

Pharmacology of Lotrel (benazepril/amlodipine)

Mechanism of action

Amlodipine: Ca channel blocker; inhibits the transmembrane influx of extracellular Ca ions across the membranes of myocardial cells and vascular smooth muscle cells without changing serum calcium concentrations, resulting in inhibition of cardiac and vascular smooth muscle contraction, thereby dilating the main coronary and systemic arteries

Benazepril: Competitively inhibits angiotensin-converting enzymes, resulting in decreased plasma angiotensin II concentrations; consequently, blood pressure may be reduced in part through decreased vasoconstriction, increased renin activity, and decreased aldosterone secretion

 

Absorption

Bioavailability: Benazepril (37%); amlodipine (64-90%)

Peak plasma time: Benazepril (0.5-2 hr); amlodipine (6-12 hr)

 

Distribution

Protein bound: >90% for each component

Vd: Benazepril (0.7 L/kg); amlodipine (21 L/kg)

 

Metabolism

Benazepril by hepatic metabolism to active metabolite (benazeprilat)

Amlodipine is extensively metabolized in liver

 

Elimination

Half-life, elimination: Benazeprilat (10-11 hr); amlodipine (~48 hr)