Side Effects of Lotrel (amlodipine and benazepril)

Lotrel (amlodipine and benazepril) is a combination of an ACE inhibitor a and calcium channel blocker (CCB) used to treat high blood pressure (hypertension) when blood pressure is not adequately controlled with either of its constituent drugs alone. 

ACE is an enzyme in the body that causes the formation of angiotensin II. Angiotensin II causes contraction of the muscles surrounding arteries and constriction of arteries in the body, thereby elevating blood pressure. 

ACE inhibitors such as benazepril lower blood pressure by inhibiting the formation of angiotensin II, thus relaxing the arteries. Relaxing the arteries not only lowers blood pressure, but also improves the pumping efficiency of a failing heart and thereby benefits patients with heart failure. 

Chest pain or heart pain (angina) occurs because of insufficient oxygen delivered to the heart muscles. Insufficient oxygen may be a result of coronary artery blockage or spasm, or because of exertion which increases the need of the heart for oxygen in patients with coronary artery narrowing (coronary artery disease or atherosclerosis). 

Amlodipine is used for the treatment and prevention of angina resulting from coronary spasm as well as from exertion. Amlodipine also is used in the treatment of high blood pressure.

Common side effects of Lotrel include

• water retention (edema) in legs and arms,
• edema in the lungs stomach pain,
• nausea,
• dizziness,
• fatigue,
• headache,
• muscle cramps,
• sexual problems, and
• drowsiness.

Serious side effects of Lotrel include

• kidney failure,
• indigestion,
• blood disorders,
• overgrowth of gums,
• heart palpitations,
• anemia,
• reduced platelets in the blood, and
• serious skin reactions.

Drug interactions of Lotrel include potassium supplements, potassium containing salt substitutes, and potassium conserving diuretics such as amiloride, spironolactone, and triamterene, because combining benazepril with these drugs can lead to dangerously high blood levels of potassium. 

• There have been reports of increased lithium levels when lithium is used in combination with ACE inhibitors, which may lead to toxicity from lithium. Aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen, indomethacin, and naproxen may reduce the effects of ACE inhibitors. 
• Combining ACE inhibitors with NSAIDs in patients who are elderly, volume-depleted (including those on diuretic therapy), or with poor kidney function may result in reduced kidney function, including kidney failure. These effects usually are reversible. 
• Nitritoid reactions (symptoms include facial flushing, nausea, vomiting and low blood pressure or hypotension) may occur when injectable gold (sodium aurothiomalate), used in the treatment of rheumatoid arthritis, is combined with ACE inhibitors. 
• Amlodipine increases blood levels of simvastatin. 
• The dose of simvastatin should be limited to 20 mg daily when combined with amlodipine. 

ACE inhibitors, including benazepril, can be harmful to a fetus and should not be taken by pregnant women. 

Small amounts of benazepril are excreted in breast milk. It is unknown if amlodipine is excreted in breast milk. Lotrel or breastfeeding should be discontinued.

Lotrel causes the same side effects as benazepril and amlodipine.

Common side of Lotrel include

• water retention (edema) in legs and arms,
• edema in the lungs
• stomach pain,
• nausea,
• dizziness,
• fatigue,
• headache,
• muscle cramps,
• sexual problems, and
• drowsiness.

Other side effects of Lotrel include

• kidney failure,
• indigestion,
• blood disorders,
• overgrowth of gums,
• heart palpitations,
• anemia,
• reduced number of platelets in the blood, and
• serious skin reactions also may occur.

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The adverse reaction information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates.

• Lotrel has been evaluated for safety in over 2,991 patients with hypertension; over 500 of these patients were treated for at least 6 months, and over 400 were treated for more than 1 year.
• In a pooled analysis of 5 placebo-controlled trials involving Lotrel doses up to 5/20, the reported side effects were generally mild and transient, and there was no relationship between side effects and age, sex, race, or duration of therapy. Discontinuation of therapy due to side effects was required in approximately 4% of patients treated with Lotrel and in 3% of patients treated with placebo.
• The most common reasons for discontinuation of therapy with Lotrel in these studies were cough and edema (including angioedema).
• The peripheral edema associated with amlodipine use is dose-dependent. When benazepril is added to a regimen of amlodipine, the incidence of edema is substantially reduced.
• 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.
• The side effects considered possibly or probably related to study drug that occurred in these trials in more than 1% of patients treated with Lotrel are shown in the table below.
• Cough was the only adverse event with at least possible relationship to treatment that was more common on Lotrel (3.3%) than on placebo (0.2%).

Percent Incidence in U. S. Placebo-controlled Trials

The incidence of edema was greater in patients treated with amlodipine monotherapy (5.1%) than in patients treated with Lotrel (2.1%) or placebo (2.2%). Other side effects considered possibly or probably related to study drug that occurred in U.S. placebo-controlled trials of patients treated with Lotrel or in postmarketing experience were the following:

Body as a Whole: Asthenia and fatigue.

CNS: Insomnia, nervousness, anxiety, tremor, and decreased libido.

Dermatologic: Flushing, hot flashes, rash, skin nodule, and dermatitis.

Digestive: Dry mouth, nausea, abdominal pain, dyspepsia, and esophagitis.

Hematologic: Neutropenia

Musculoskeletal: cramps, and muscle cramps.

Urogenital: Sexual problems such as impotence, and polyuria.

Monotherapies of benazepril and amlodipine have been evaluated for safety in clinical trials in over 6,000 and 11,000 patients, respectively. The observed adverse reactions to the monotherapies in these trials were similar to those seen in trials of Lotrel.

Postmarketing Experience

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

In postmarketing experience with benazepril, there have been rare reports of

• Stevens-Johnson syndrome,
• pancreatitis,
• hemolytic anemia,
• pemphigus,
• thrombocytopenia,
• paresthesia,
• dysgeusia,
• orthostatic symptoms and hypotension,
• angina pectoris and arrhythmia,
• pruritus,
• photosensitivity reaction,
• arthralgia,
• arthritis,
• myalgia,
•  blood urea nitrogen (BUN) increase,
• serum creatinine increase,
• renal impairment,
• vision impairment,
• agranulocytosis,
• neutropenia.

Rare reports in association with use of amlodipine:

• gingival hyperplasia,
•  tachycardia,
• jaundice, and hepatic enzyme elevations (mostly consistent with cholestasis severe enough to require hospitalization),
• leukocytopenia,
• allergic reaction,
• hyperglycemia,
• dysgeusia,
• hypoesthesia,
• paresthesia,
• syncope,
• peripheral neuropathy,
• hypertonia,
• visual impairment,
• diplopia,
• hypotension,
• vasculitis,
• rhinitis,
• gastritis,
• hyperhidrosis,
• pruritus,
• skin discoloration,
• urticaria,
• erythema multiform,
• muscle spasms,
• arthralgia,
• micturition disorder,
• nocturia,
• erectile dysfunction,
• malaise,
• weight decrease or
• gain.

Other potentially important adverse experiences attributed to other ACE inhibitors and calcium channel blockers include:

•  eosinophilic pneumonitis (ACE inhibitors) and
• gynecomastia (CCBs).

Drug/Drug Interactions

Amlodipine

Simvastatin

• Coadministration of simvastatin with amlodipine increases the systemic exposure of simvastatin. Limit the dose of simvastatin in patients on amlodipine to 20 mg daily.

CYP3A4 Inhibitors

• Coadministration with CYP3A inhibitors (moderate and strong) results in increased systemic exposure to amlodipine and may require dose reduction. Monitor for symptoms of hypotension and edema when amlodipine is coadministered with CYP3A4 inhibitors to determine the need for dose adjustment.

CYP3A4 Inducers

• No information is available on the quantitative effects of CYP3A4 inducers on amlodipine. Blood pressure should be monitored when amlodipine is coadministered with CYP3A4 inducers (e.g. rifampicin, St. John’s Wort).

Benazepril

Potassium Supplements and Potassium-Sparing Diuretics

• Benazepril can attenuate potassium loss caused by thiazide diuretics. Potassium-sparing diuretics (spironolactone, amiloride, triamterene, and others) or potassium supplements can increase the risk of hyperkalemia. If concomitant use of such agents is indicated, the patient’s serum potassium should be monitored frequently.

Lithium

• Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving ACE inhibitors during therapy with lithium. When coadministering Lotrel and lithium, frequent monitoring of serum lithium levels is recommended.

Gold

• Nitritoid reactions (symptoms include facial flushing, nausea, vomiting and hypotension) have been reported rarely in patients on therapy with injectable gold (sodium aurothiomalate) and concomitant ACE inhibitor therapy.

Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) including Selective Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors)

• In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, coadministration of NSAIDs, including selective COX-2 inhibitors, with ACE inhibitors, including benazepril, may result in deterioration of renal function, including possible acute renal failure.
• These effects are usually reversible. Monitor renal function periodically in patients receiving benazepril and NSAID therapy.

The antihypertensive effect of ACE inhibitors, including benazepril, may be attenuated by NSAIDs.

Antidiabetic Agents

• In rare cases, diabetic patients receiving an ACE inhibitor (including benazepril) concomitantly with insulin or oral antidiabetics may develop hypoglycemia. Such patients should therefore be advised about the possibility of hypoglycemic reactions and should be monitored accordingly.

Mammalian Target of Rapamycin (mTOR) Inhibitors

• The risk of angioedema may be increased in patients receiving coadministration of ACE inhibitors and mTOR inhibitors (e.g., temsirolimus, sirolimus, everolimus).

Dual Blockade of the Renin-Angiotensin System (RAS)

• Dual blockade of the RAS with angiotensin receptor blockers, ACE inhibitors, or aliskiren is associated with increased risks of hypotension, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy.
• Most patients receiving the combination of two RAS inhibitors do not obtain any additional benefit compared to monotherapy.
• In general, avoid combined use of RAS inhibitors.
• Closely monitor blood pressure, renal function and electrolytes in patients on Lotrel and other agents that block the RAS

Do not coadminister aliskiren with Lotrel in patients with diabetes. Avoid use of aliskiren with Lotrel in patients with renal impairment [glomerular filtration rate (GFR) < 60 mL/min].

Neprilysin Inhibitor

Patients taking concomitant neprilysin inhibitors may be at increased risk for angioedema.