Lotrel 10 20

Lotrel

SIDE EFFECTS

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

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, constipation, diarrhea, dyspepsia, and esophagitis.

Hematologic: Neutropenia

Metabolic and Nutritional: Hypokalemia.

Musculoskeletal: Back pain, musculoskeletal pain, cramps, and muscle cramps.

Respiratory: Pharyngitis.

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). Other infrequently reported events included chest pain, ventricular extrasystole, gout, neuritis, tinnitus, alopecia, upper respiratory tract infection, palpitations and somnolence.

Read the entire FDA prescribing information for Lotrel (Amlodipine Besylate and Benazepril HCl)

Lotrel is the brand name of a prescription medicine containing the drugs amlodipine and benazepril. It’s used to treat high blood pressure.

Amlodipine is a calcium channel blocker that works by relaxing blood vessels and improving blood flow.

Benazepril is an angiotensin-converting enzyme (ACE) inhibitor that widens blood vessels and prevents water retention.

The Food and Drug Administration (FDA) approved Lotrel in 1995. It’s manufactured by Novartis Pharmaceuticals.

Lotrel Warnings

Before taking Lotrel, tell your doctor if you have, or have ever had:

  • Kidney disease
  • Liver disease
  • Heart disease or congestive heart failure
  • Diabetes
  • A connective tissue disease (such as Marfan syndrome, Sjogren’s syndrome, scleroderma, lupus, or rheumatoid arthritis)
  • Allergies to medications
  • Angioedema (swelling under the skin surface that’s sometimes caused by an allergic reaction)

If you’re African-American, you may be more likely to have an allergic reaction to Lotrel. Talk to your doctor about this risk.

If you have diabetes, don’t take Lotrel with any medicine that contains aliskiren (Amturnide, Tekturna, Tekamlo, or Valturna).

Lotrel can cause you to become easily dehydrated. Tell your doctor if you’ve recently experienced severe diarrhea or vomiting.

Also, let your health care provider know if you’re on a low-salt diet or take any salt substitutes that contain potassium before starting on Lotrel.

Lotrel can help control high blood pressure, but it won’t cure the condition.

Continue to take Lotrel even if you feel well. Don’t stop taking the drug without first talking to your doctor.

Tell your doctor you’re taking Lotrel before having any type of surgery, including a dental procedure.

Your doctor will probably want to monitor your blood pressure often while you take this drug. Be sure to keep all appointments with your healthcare provider and laboratory while on Lotrel.

Pregnancy and Lotrel

Lotrel contains a black-box warning because it can harm an unborn baby.

Don’t take this drug if you’re pregnant, and let your doctor know if you’re planning on getting pregnant before taking Lotrel.

Be sure to use an effective method of birth control while taking this medicine.

If you become pregnant while taking Lotrel, stop taking it immediately, and call your doctor right away.

Lotrel is passed into breast milk and may hurt a breastfeeding baby.

Don’t breastfeed while taking this medicine.

Generic Name: amlodipine and benazepril (am LOE di peen and ben AY ze pril)
Brand Names: Lotrel

Medically reviewed by Sophia Entringer, PharmD Last updated on Jun 23, 2019.

  • Overview
  • Side Effects
  • Dosage
  • Professional
  • Interactions
  • More

What is Lotrel?

Lotrel contains a combination of amlodipine and benazepril. Amlodipine is a calcium channel blocker. Amlodipine relaxes (widens) blood vessels and improves blood flow.

Benazepril is an ACE inhibitor. ACE stands for angiotensin converting enzyme. Benazepril also widens blood vessels and also prevents the body from retaining water.

Lotrel is used to treat high blood pressure (hypertension).

Lotrel may also be used for purposes not listed in this medication guide.

Important Information

Do not use Lotrel if you are pregnant. If you become pregnant, stop taking this medicine and tell your doctor right away.

You should not use this medicine if you have ever had angioedema. Do not take this medicine within 36 hours before or after taking medicine that contains sacubitril (such as Entresto).

If you have diabetes, do not use Lotrel together with any medication that contains aliskiren (a blood pressure medicine).

Call your doctor if you have ongoing vomiting or diarrhea, or if you are sweating more than usual. You can easily become dehydrated while taking Lotrel, which can lead to severely low blood pressure or a serious electrolyte imbalance.

Before taking this medicine

You should not use Lotrel if you are allergic to amlodipine or benazepril, or if:

  • you have had angioedema (hives or severe swelling of deep skin tissues sometimes caused by allergic reaction);

  • you have diabetes and are taking a medication called aliskiren;

  • you recently took a heart medicine called sacubitril; or

  • you are allergic to any other ACE inhibitor, such as captopril, enalapril, lisinopril, moexipril, benazepril, quinapril, ramipril, Accupril, Prinivil, Mavik, Vasotec, and many others.

Do not take Lotrel within 36 hours before or after taking medicine that contains sacubitril (such as Entresto).

If you have diabetes, do not use Lotrel together with any medication that contains aliskiren (a blood pressure medicine).

You may also need to avoid taking Lotrel with aliskiren if you have kidney disease.

Tell your doctor if you have ever had:

  • heart disease or congestive heart failure;

  • high levels of potassium in your blood (hyperkalemia);

  • kidney disease (or if you are on dialysis);

  • liver disease; or

  • if you are on a low-salt diet.

Do not use Lotrel if you are pregnant. If you become pregnant, stop taking this medicine and tell your doctor right away. Benazepril can cause injury or death to the unborn baby if you take the medicine during your second or third trimester.

You should not breast-feed while you are using Lotrel unless instructed by your doctor.

How should I take Lotrel?

Take Lotrel exactly as prescribed by your doctor. Follow all directions on your prescription label and read all medication guides or instruction sheets. Your doctor may occasionally change your dose. Use the medicine exactly as directed.

You may take Lotrel with or without food. Take the medicine at the same time each day.

Vomiting, diarrhea, or heavy sweating can cause you to become dehydrated. Drink plenty of water each day while you are taking this medicine.

Your blood pressure will need to be checked often, and you may also need frequent blood tests.

If you need surgery, tell your surgeon you currently use this medicine. You may need to stop for a short time.

Call your doctor if you have ongoing vomiting or diarrhea, or if you are sweating more than usual. You can easily become dehydrated while taking Lotrel. This can lead to very low blood pressure, electrolyte disorders, or kidney failure.

Keep using Lotrel as directed, even if you feel well. High blood pressure often has no symptoms. You may need to use blood pressure medicine for the rest of your life.

Store at room temperature away from moisture and heat.

Lotrel dosing information

Usual Adult Dose for Hypertension:

Initial dose: amlodipine 2.5 mg-benazepril 10 mg orally once a day
Maintenance dose: amlodipine 2.5 to 10 mg-benazepril 10 to 40 mg orally once a day
Maximum dose: Amlodipine: 10 mg/day; Benazepril 80 mg/day

-May increase dose after 2 weeks as needed to achieve blood pressure goal.
-Adding benazepril to amlodipine should not be expected to provide additional blood pressure reduction in African Americans.

What happens if I miss a dose?

Take the medicine as soon as you can, but skip the missed dose if you are more than 12 hours late for the dose. Do not use two doses at one time.

What happens if I overdose?

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

What should I avoid while taking Lotrel?

Drinking alcohol with this medicine can cause side effects.

Avoid driving or hazardous activity until you know how this medicine will affect you. Your reactions could be impaired.

Do not use salt substitutes or potassium supplements while taking Lotrel, unless your doctor has told you to.

Lotrel side effects

Get emergency medical help if you have signs of an allergic reaction: hives; severe stomach pain; difficulty breathing; swelling of your face, lips, tongue, or throat. You may be more likely to have an allergic reaction if you are African-American.

Some side effects may not occur until after you have used the medicine for several months.

Call your doctor at once if you have:

  • a light-headed feeling, like you might pass out;

  • swelling in your hands or feet, rapid weight gain;

  • new or worsened chest pain;

  • fever, chills, sore throat, body aches, flu symptoms;

  • high potassium–nausea, weakness, tingly feeling, chest pain, irregular heartbeats, loss of movement; or

  • liver problems–nausea, stomach pain (upper right side), itching, unusual tiredness, flu-like symptoms, dark urine, jaundice (yellowing of the skin or eyes).

Common Lotrel side effects may include:

  • cough;

  • dizziness; or

  • swelling in your hands or feet.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

What other drugs will affect Lotrel?

Sometimes it is not safe to use certain medications at the same time. Some drugs can affect your blood levels of other drugs you take, which may increase side effects or make the medications less effective.

Tell your doctor about all your current medicines. Many drugs can affect Lotrel, especially:

  • lithium;

  • probenecid;

  • simvastatin;

  • a diuretic or “water pill”;

  • gold injections to treat arthritis;

  • heart or blood pressure medication;

  • insulin or oral diabetes medicine;

  • an antibiotic–clarithromycin, telithromycin;

  • antifungal medicine–itraconazole, ketoconazole;

  • antiviral medicine to treat HIV/AIDS–indinavir, ritonavir, and others;

  • medicine to prevent organ transplant rejection–cyclosporine, everolimus, sirolimus, tacrolimus, temsirolimus; or

  • NSAIDs (nonsteroidal anti-inflammatory drugs)–aspirin, ibuprofen (Advil, Motrin), naproxen (Aleve), celecoxib, diclofenac, indomethacin, meloxicam, and others.

This list is not complete and many other drugs can interact with amlodipine and benazepril. This includes prescription and over-the-counter medicines, vitamins, and herbal products. Not all possible drug interactions are listed here.

Further information

Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use Lotrel only for the indication prescribed.

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.

Copyright 1996-2020 Cerner Multum, Inc. Version: 10.02.

Medical Disclaimer

More about Lotrel (amlodipine / benazepril)

  • Side Effects
  • During Pregnancy
  • Dosage Information
  • Drug Images
  • Drug Interactions
  • Pricing & Coupons
  • En Español
  • 27 Reviews
  • Generic Availability
  • Drug class: ACE inhibitors with calcium channel blocking agents

Consumer resources

  • Lotrel
  • Lotrel (Advanced Reading)

Professional resources

  • Lotrel (FDA)

Related treatment guides

  • High Blood Pressure

Amlodipine and benazepril

Generic Name: amlodipine and benazepril (am LOE di peen and ben AY ze pril)
Brand Name: Lotrel

Medically reviewed by Drugs.com on Apr 15, 2019 – Written by Cerner Multum

  • Overview
  • Side Effects
  • Dosage
  • Professional
  • Interactions
  • More

What is amlodipine and benazepril?

Amlodipine is a calcium channel blocker. Amlodipine relaxes (widens) blood vessels and improves blood flow.

Benazepril is an ACE inhibitor. ACE stands for angiotensin converting enzyme. Benazepril also widens blood vessels and also prevents the body from retaining water.

Amlodipine and benazepril is a combination medicine used to treat high blood pressure (hypertension).

Amlodipine and benazepril may also be used for purposes not listed in this medication guide.

Do not use if you are pregnant. If you become pregnant, stop taking amlodipine and benazepril and tell your doctor right away.

You should not use this medicine if you have ever had angioedema. Do not take this medicine within 36 hours before or after taking medicine that contains sacubitril (such as Entresto).

If you have diabetes, do not use amlodipine and benazepril together with any medication that contains aliskiren (a blood pressure medicine).

You should not use this medicine if you are allergic to amlodipine or benazepril, or if:

  • you have had angioedema (hives or severe swelling of deep skin tissues sometimes caused by allergic reaction);

  • you recently took a heart medicine called sacubitril; or

  • you are allergic to any other ACE inhibitor, such as captopril, enalapril, lisinopril, moexipril, benazepril, quinapril, ramipril, Accupril, Prinivil, Mavik, Vasotec, and many others.

Do not take amlodipine and benazepril within 36 hours before or after taking medicine that contains sacubitril (such as Entresto).

If you have diabetes, do not use amlodipine and benazepril together with any medication that contains aliskiren (a blood pressure medicine).

You may also need to avoid taking amlodipine and benazepril with aliskiren if you have kidney disease.

Tell your doctor if you have ever had:

  • heart disease or congestive heart failure;

  • high levels of potassium in your blood (hyperkalemia);

  • kidney disease (or if you are on dialysis);

  • liver disease; or

  • if you are on a low-salt diet.

Do not use if you are pregnant. If you become pregnant, stop taking this medicine and tell your doctor right away. Benazepril can cause injury or death to the unborn baby if you take the medicine during your second or third trimester.

You should not breast-feed while you are using this medicine.

How should I take amlodipine and benazepril?

Follow all directions on your prescription label and read all medication guides or instruction sheets. Your doctor may occasionally change your dose. Use the medicine exactly as directed.

You may take amlodipine and benazepril with or without food. Take the medicine at the same time each day.

Vomiting, diarrhea, or heavy sweating can cause you to become dehydrated. Drink plenty of water each day while you are taking amlodipine and benazepril.

Your blood pressure will need to be checked often, and you may also need frequent blood tests.

If you need surgery, tell your surgeon you currently use this medicine. You may need to stop for a short time.

Call your doctor if you have ongoing vomiting or diarrhea, or if you are sweating more than usual. You can easily become dehydrated while taking amlodipine and benazepril. This can lead to very low blood pressure, electrolyte disorders, or kidney failure.

Keep using this medicine as directed, even if you feel well. High blood pressure often has no symptoms. You may need to use blood pressure medicine for the rest of your life.

Store at room temperature away from moisture and heat.

Take the medicine as soon as you can, but skip the missed dose if you are more than 12 hours late for the dose. Do not use two doses at one time.

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

What should I avoid while taking amlodipine and benazepril?

Drinking alcohol with amlodipine and benazepril can cause side effects.

Avoid driving or hazardous activity until you know how this medicine will affect you. Your reactions could be impaired.

Do not use salt substitutes or potassium supplements while taking amlodipine and benazepril, unless your doctor has told you to.

More about amlodipine / benazepril

  • Side Effects
  • During Pregnancy
  • Dosage Information
  • Drug Images
  • Drug Interactions
  • Pricing & Coupons
  • En Español
  • 46 Reviews
  • Drug class: ACE inhibitors with calcium channel blocking agents
  • Amlodipine and Benazepril
  • Amlodipine and benazepril (Advanced Reading)

Other brands: Lotrel

  • Amlodipine and Benazepril (Wolters Kluwer)
  • … +1 more
  • High Blood Pressure

Lotrel Side Effects

Visit your doctor or health care professional for regular checks on your progress. Check your blood pressure as directed. Ask your doctor or health care professional what your blood pressure should be and when you should contact him or her. Call your doctor or health care professional if you notice an irregular or fast heart beat.

You may get drowsy or dizzy. Do not drive, use machinery, or do anything that needs mental alertness until you know how this drug affects you. Do not stand or sit up quickly, especially if you are an older patient. This reduces the risk of dizzy or fainting spells. Alcohol can make you more drowsy and dizzy. Avoid alcoholic drinks.

If you are going to have surgery, tell your doctor or health care professional that you are taking this medicine.

Women should inform their doctor if they wish to become pregnant or think they might be pregnant. There is a potential for serious side effects to an unborn child. Talk to your health care professional or pharmacist for more information.

Check with your doctor or health care professional if you get an attack of severe diarrhea, nausea and vomiting, or if you sweat a lot. The loss of body fluid can make it dangerous to take this medicine.

A few patients have had strong allergic reactions during desensitization treatment with hymenoptera venom and during some kinds of dialysis. Talk to your doctor if you are going to have either of these procedures.

Avoid salt substitutes unless you are told otherwise by your doctor or health care professional.

Do not treat yourself for coughs, colds, or pain while you are taking this medicine without asking your doctor or health care professional for advice. Some ingredients may increase your blood pressure.

CLINICAL PHARMACOLOGY

Mechanism Of Action

Benazepril

Benazepril and benazeprilat inhibit angiotensin-converting enzyme (ACE) in human subjects and in animals. ACE is 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. The latter decrease may result in a small increase of serum potassium. Hypertensive patients treated with benazepril and amlodipine for up to 56 weeks had elevations of serum potassium up to 0.2 mEq/L .

Removal of angiotensin II negative feedback on renin secretion leads to increased plasma renin activity. In animal studies, benazepril had no inhibitory effect on the vasopressor response to angiotensin II and did not interfere with the hemodynamic effects of the autonomic neurotransmitters acetylcholine, epinephrine, and norepinephrine.

ACE is identical to kininase, an enzyme that degrades bradykinin. Whether increased levels of bradykinin, a potent vasodepressor peptide, play a role in the therapeutic effects of Lotrel remains to be elucidated.

While the mechanism through which benazepril lowers blood pressure is believed to be primarily suppression of the renin-angiotensin aldosterone system, benazepril has an antihypertensive effect even in patients with low-renin hypertension.

Amlodipine

Amlodipine is a dihydropyridine calcium antagonist (calcium ion antagonist or slow channel blocker) that inhibits the transmembrane influx of calcium ions into vascular smooth muscle and cardiac muscle. Experimental data suggest that amlodipine binds to both dihydropyridine and nondihydropyridine binding sites. The contractile processes of cardiac muscle and vascular smooth muscle are dependent upon the movement of extracellular calcium ions into these cells through specific ion channels. Amlodipine inhibits calcium ion influx across cell membranes selectively, with a greater effect on vascular smooth muscle cells than on cardiac muscle cells. Negative inotropic effects can be detected in vitro but such effects have not been seen in intact animals at therapeutic doses. Serum calcium concentration is not affected by amlodipine. Within the physiologic pH range, amlodipine is an ionized compound (pKa=8.6), and its kinetic interaction with the calcium channel receptor is characterized by a gradual rate of association and dissociation with the receptor binding site, resulting in a gradual onset of effect.

Amlodipine 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.

Pharmacodynamics

Single and multiple doses of 10 mg or more of benazepril cause inhibition of plasma ACE activity by at least 80% to 90% for at least 24 hours after dosing. For up to 4 hours after a 10 mg dose, pressor responses to exogenous angiotensin I were inhibited by 60% to 90%.

Administration of benazepril to patients with mild-to-moderate hypertension results in a reduction of both supine and standing blood pressure to about the same extent, with no compensatory tachycardia. Symptomatic postural hypotension is infrequent, although it can occur in patients who are salt and/or volume depleted .

The antihypertensive effects of benazepril were not appreciably different in patients receiving high- or low-sodium diets.

In normal human volunteers, single doses of benazepril caused an increase in renal blood flow but had no effect on glomerular filtration rate.

Following administration of therapeutic doses to patients with hypertension, amlodipine produces vasodilation resulting in a reduction of supine and standing blood pressures. These decreases in blood pressure are not accompanied by a significant change in heart rate or plasma catecholamine levels with chronic dosing.

With chronic once-daily administration, antihypertensive effectiveness is maintained for at least 24 hours. Plasma concentrations correlate with effect in both young and elderly patients. The magnitude of reduction in blood pressure with amlodipine is also correlated with the height of pretreatment elevation; thus, individuals with moderate hypertension (diastolic pressure 105–114 mmHg) had about 50% greater response than patients with mild hypertension (diastolic pressure 90–104 mmHg). Normotensive subjects experienced no clinically significant change in blood pressure (+1/-2 mmHg).

In hypertensive patients with normal renal function, therapeutic doses of amlodipine resulted in a decrease in renal vascular resistance and an increase in glomerular filtration rate and effective renal plasma flow without change in filtration fraction or proteinuria.

As with other calcium channel blockers, hemodynamic measurements of cardiac function at rest and during exercise (or pacing) in patients with normal ventricular function treated with amlodipine have generally demonstrated a small increase in cardiac index without significant influence on dP/dt or on left ventricular end diastolic pressure or volume. In hemodynamic studies, amlodipine has not been associated with a negative inotropic effect when administered in the therapeutic dose range to intact animals and humans, even when coadministered with beta blockers to humans.

Amlodipine does not change sinoatrial (SA) nodal function or atrioventricular (AV) conduction in intact animals or humans. In clinical studies in which amlodipine was administered in combination with beta blockers to patients with either hypertension or angina, no adverse effects on electrocardiographic parameters were observed.

Amlodipine has demonstrated beneficial clinical effects in patients with chronic stable angina, vasospastic angina and angiographically documented coronary artery disease.

Pharmacokinetics

The rate and extent of absorption of benazepril and amlodipine from Lotrel are the same as when administered as individual tablets. Absorption from the individual tablets is not influenced by the presence of food in the gastrointestinal tract; food effects on absorption from Lotrel have not been studied.

Absorption

Following oral administration of Lotrel, peak plasma concentrations of amlodipine are reached in 6 to 12 hours. Absolute bioavailability has been calculated as between 64% and 90%. Following oral administration of Lotrel, the peak plasma concentrations of benazepril are reached in 0.5 to 2 hours. The cleavage of the ester group (primarily in the liver) converts benazepril to its active metabolite, benazeprilat, which reaches peak plasma concentrations in 1.5 to 4 hours. The extent of absorption of benazepril is at least 37%. Amlodipine and benazepril exhibit dose proportional pharmacokinetics between the therapeutic dose range of 2.5 and 10 mg and 10 and 20 mg, respectively.

Distribution

The apparent volume of distribution of amlodipine is about 21 L/kg. In vitro studies indicate that approximately 93% of circulating amlodipine is bound to plasma proteins in hypertensive patients. The apparent volume of distribution of benazeprilat is about 0.7 L/kg. Approximately 93% of circulating amlodipine is bound to plasma proteins, and the bound fraction of benazeprilat is slightly higher. On the basis of in vitro studies, benazeprilat’s degree of protein binding should be unaffected by age, by hepatic dysfunction, or—over the therapeutic concentration range—by concentration.

Metabolism

Amlodipine is extensively (approximately 90%) metabolized in the liver to inactive metabolites. Benazepril is extensively metabolized to form benazeprilat as the main metabolite, which occurs by enzymatic hydrolysis, mainly in the liver. Two minor metabolites are the acyl glucuronide conjugates of benazepril and benazeprilat.

Elimination

Amlodipine elimination from plasma is biphasic with a terminal elimination half-life of approximately 30 to 50 hours. Steady-state plasma levels are reached after once-daily dosing for 7 to 8 days. Ten percent of unchanged drug and 60% of amlodipine metabolites are excreted in urine. Effective elimination half-life of amlodipine is 2 days. Benazepril is eliminated mainly by metabolic clearance. Benazeprilat is eliminated via the kidneys and the bile; renal excretion is the main route in patients with normal renal function. In the urine, benazepril accounts for less than 1 % and benazeprilat for about 20% of an oral dose. Elimination of benazeprilat is biphasic with an initial half-life of about 3 hours and a terminal half-life of about 22 hours. Benazeprilat’s effective elimination half-life is 10 to 11 hours, while that of amlodipine is about 2 days, so steady-state levels of the 2 components are achieved after about a week of once-daily dosing.

Special Populations

Geriatric Patients

No specific clinical studies were performed to understand the impact of age on the pharmacokinetics of amlodipine and benazepril as fixed dose combination. As individual component amlodipine is extensively metabolized in the liver. In the elderly, clearance of amlodipine is decreased with resulting increases in peak plasma levels, elimination half-life and area-under-the-plasma-concentration curve .

Hepatic Impairment

Patients with hepatic insufficiency have decreased clearance of amlodipine with a resulting increase in AUC of approximately 40 to 60%. Pharmacokinetics of benazepril is not significantly influenced by hepatic impairment .

Renal Impairment

The disposition of benazepril and benazeprilat in patients with mild-to-moderate renal insufficiency (CrCl greater than 30 mL/min) is similar to that in patients with normal renal function. In patients with CrCl less than or equal to 30 mL/min, peak benazeprilat levels and the effective half-life increase, resulting in higher systemic exposures. Pharmacokinetics of amlodipine is not significantly influenced by renal impairment .

Drug Interactions

In vitro data in human plasma indicate that amlodipine has no effect on the protein binding of digoxin, phenytoin, warfarin, and indomethacin.

Cimetidine

Coadministration of amlodipine with cimetidine did not alter the pharmacokinetics of amlodipine.

Grapefruit Juice

Coadministration of 240 mL of grapefruit juice with a single oral dose of amlodipine 10 mg in 20 healthy volunteers had no significant effect on the pharmacokinetics of amlodipine.

Maalox® (antacid)

Coadministration of the antacid Maalox with a single dose of amlodipine had no significant effect on the pharmacokinetics of amlodipine.

Sildenafil

A single 100 mg dose of sildenafil in subjects with essential hypertension had no effect on the pharmacokinetic parameters of amlodipine. When amlodipine and sildenafil were used in combination, each agent independently exerted its own blood pressure lowering effect.

Atorvastatin

Coadministration of multiple 10 mg doses of amlodipine with 80 mg of atorvastatin resulted in no significant change in the steady-state pharmacokinetic parameters of atorvastatin.

Digoxin

Coadministration of amlodipine with digoxin did not change serum digoxin levels or digoxin renal clearance in normal volunteers.

Ethanol (alcohol)

Single and multiple 10 mg doses of amlodipine had no significant effect on the pharmacokinetics of ethanol.

Warfarin

Coadministration of amlodipine with warfarin did not change the warfarin prothrombin response time.

Simvastatin

Coadministration of multiple doses of 10 mg of amlodipine with 80 mg simvastatin resulted in a 77% increase in exposure to simvastatin compared to simvastatin alone.

CYP3A Inhibitors

Coadministration of a 180 mg daily dose of diltiazem with 5 mg amlodipine in elderly hypertensive patients resulted in a 60% increase in amlodipine systemic exposure. Erythromycin coadministration in healthy volunteers did not significantly change amlodipine systemic exposure. However, strong inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, ritonavir) may increase the plasma concentrations of amlodipine to a greater extent.

The pharmacokinetic properties of benazepril are not affected by hydrochlorothiazide, furosemide, chlorthalidone, digoxin, propranolol, atenolol, nifedipine, amlodipine, naproxen, acetylsalicylic acid, or cimetidine. Likewise the administration of benazepril does not substantially affect the pharmacokinetics of these medications.

Reproductive Toxicity

When rats received benazepril:amlodipine at doses ranging from 5:2.5 to 50:25 mg/kg/day, dystocia was observed at an increasing dose-related incidence at all doses tested. On a body surface area 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 twice 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 doses of up to 50:25 mg (benazepril:amlodipine)/kg/day (24 times the MRHD on a body surface area basis, assuming a 50 kg woman). Rabbits received doses of up to 1.5:0.75 mg/kg/day (equivalent to the maximum recommended dose of Lotrel given to a 50 kg woman).

No teratogenic effects of benazepril were seen in studies of pregnant rats, mice, and rabbits. On a body surface area basis, the maximum doses used in these studies were 60 times (in rats), 9 times (in mice), and about equivalent to (in rabbits) the MRHD (assuming a 50 kg woman).

No evidence of teratogenicity or other embryo/fetal toxicity was found when pregnant rats and rabbits were treated orally with amlodipine maleate at doses of up to 10 mg amlodipine/kg/day (respectively, about 10 and 20 times the MRHD of 10 mg amlodipine on a body surface area basis) during their respective periods of major organogenesis. (Calculations based on a patient weight of 60 kg.) However, litter size was significantly decreased (by about 50%) and the number of intrauterine deaths was significantly increased (about 5-fold) for rats receiving amlodipine maleate at a dose equivalent to 10 mg amlodipine/kg/day for 14 days before mating and throughout mating and gestation. Amlodipine maleate has been shown to prolong both the gestation period and the duration of labor in rats at this dose. There are no adequate and well-controlled studies in pregnant women. Amlodipine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Clinical Studies

Over 950 patients received Lotrel once-daily in 6 double-blind, placebo-controlled studies. 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.

In 2 studies in patients not adequately controlled on either benazepril 40 mg alone (n=329) or amlodipine 10 mg alone (n=812) once-daily doses of Lotrel 10/40 mg further decreased seated blood pressure compared to the respective monotherapy alone.

Combination therapy was effective in blacks and nonblacks. Both components contributed to the antihypertensive efficacy in nonblacks, but virtually all of the antihypertensive effect in blacks could be attributed to the amlodipine component. Among nonblack patients in placebo-controlled trials comparing Lotrel to the individual components, the blood pressure lowering effects of the combination were shown to be additive and in some cases synergistic.

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.

About the author

Leave a Reply

Your email address will not be published. Required fields are marked *