Amlodipine Besylate and Benazepril Hydrochloride

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Overview

What is Amlodipine Besylate and Benazepril Hydrochloride?

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-1-1-(3S)-benzazepine-1-acetic acid monohydrochloride; its structural formula is



      Its empirical formula is CHNO•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 CHClNO•CHOS, and its molecular weight is 567.1.

      Amlodipine besylate is the besylate salt of amlodipine, a dihydropyridine calcium channel blocker.

      This product is a combination of amlodipine besylate and benazepril hydrochloride. The capsules are formulated in four 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 or 20 mg of benazepril hydrochloride providing for the following available combinations: 2.5/10 mg, 5/10 mg, 5/20 mg, and 10/20 mg. The inactive ingredients of the capsules are calcium phosphate, cellulose compounds, colloidal silicon dioxide, crospovidone, gelatin, hydrogenated castor oil, iron oxides, lactose, magnesium stearate, polysorbate 80, silicon dioxide, sodium lauryl sulfate, sodium starch (potato) glycolate, starch (corn), talc, and titanium dioxide.

What does Amlodipine Besylate and Benazepril Hydrochloride look like?

What are the available doses of Amlodipine Besylate and Benazepril Hydrochloride?

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What should I talk to my health care provider before I take Amlodipine Besylate and Benazepril Hydrochloride?

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How should I use Amlodipine Besylate and Benazepril Hydrochloride?

Amlodipine besylate and benazepril hydrochloride combination capsules 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 amlodipine besylate and benazepril hydrochloride combination capsules, 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.

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 amlodipine besylate and benazepril hydrochloride combination capsules 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:

      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:

Use in Patients With Metabolic Impairments:

      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.

What interacts with Amlodipine Besylate and Benazepril Hydrochloride?

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What are the warnings of Amlodipine Besylate and Benazepril Hydrochloride?

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What are the precautions of Amlodipine Besylate and Benazepril Hydrochloride?

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What are the side effects of Amlodipine Besylate and Benazepril Hydrochloride?

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What should I look out for while using Amlodipine Besylate and Benazepril Hydrochloride?

Amlodipine besylate and benazepril hydrochloride combination capsules is contraindicated in patients with a history of angioedema, with or without previous ACE inhibitor treatment, or patients who are hypersensitive to benazepril, to any other ACE inhibitor, or to amlodipine.

What might happen if I take too much Amlodipine Besylate and Benazepril Hydrochloride?

Only a few cases of human overdose with amlodipine have been reported. One patient was asymptomatic after a 250-mg ingestion; another, who combined 70 mg of amlodipine with an unknown large quantity of a benzodiazepine, developed refractory shock and died.

      Human overdoses with any combination of amlodipine and benazepril have not been reported. In scattered reports of human overdoses with benazepril and other ACE inhibitors, there are no reports of death.

      When mice were given single oral doses of benazepril/amlodipine, mortality was 20% at 50:25 mg/kg, 10% at 100:50 mg/kg, and 100% at 500:250 mg/kg. In rats, mortality was 25% (pooling two studies) at 500:250 mg/kg and 100% at 900:450 mg/kg.

Treatment:

      The most likely effect of overdose with amlodipine besylate and benazepril hydrochloride combination capsules is vasodilation, with consequent hypotension and tachycardia. Simple repletion of central fluid volume (Trendelenburg positioning, infusion of crystalloids) may be sufficient therapy, but pressor agents (norepinephrine or high-dose dopamine) may be required. Overdoses of other dihydropyridine calcium channel blockers are reported to have been treated with calcium chloride and glucagon, but evidence of a dose-response relation has not been seen, and these interventions must be regarded as unproven. With abrupt return of peripheral vascular tone, overdoses of other dihydropyridine calcium channel blockers have sometimes progressed to pulmonary edema, and patients must be monitored for this complication.

      Analyses of bodily fluids for concentrations of amlodipine, benazepril, or their metabolites are not widely available. Such analyses are, in any event, not known to be of value in therapy or prognosis.

      No data are available to suggest physiologic maneuvers (e.g., maneuvers to change the pH of the urine) that might accelerate elimination of amlodipine, benazepril, or their metabolites. Benazeprilat is only slightly dialyzable; attempted clearance of amlodipine by hemodialysis or hemo-perfusion has not been reported, but amlodipine’s high protein binding makes it unlikely that these interventions will be of value.

      Angiotensin II could presumably serve as a specific antagonist-antidote to benazepril, but angiotensin II is essentially unavailable outside of scattered research laboratories.

How should I store and handle Amlodipine Besylate and Benazepril Hydrochloride?

Amlodipine besylate and benazepril hydrochloride combination capsules are available as capsules containing amlodipine besylate equivalent to 2.5 mg, 5 mg or 10 mg of amlodipine, with 10 mg or 20 mg of benazepril hydrochloride providing for the following available combinations: 2.5/10 mg, 5/10 mg, 5/20 mg, and 10/20 mg . All capsules are imprinted with “S” in a triangle, SANDOZ and appropriate code. The capsule color and code is as follows: 2.5/10 mg is white with 2 gold bands/571, 5/10 mg is light brown with 2 white bands/572, 5/20 mg is pink with 2 white bands/573 and 10/20 mg is purple with 2 white bands/574. All four strengths are packaged in bottles or blisters as follows:Storage: Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F).[See USP controlled room temperature.]Protect from moisture. Dispense in tight container (USP).** Trademark of Thomson Healthcare, Inc.T2009-86 Amlodipine besylate and benazepril hydrochloride combination capsules are available as capsules containing amlodipine besylate equivalent to 2.5 mg, 5 mg or 10 mg of amlodipine, with 10 mg or 20 mg of benazepril hydrochloride providing for the following available combinations: 2.5/10 mg, 5/10 mg, 5/20 mg, and 10/20 mg . All capsules are imprinted with “S” in a triangle, SANDOZ and appropriate code. The capsule color and code is as follows: 2.5/10 mg is white with 2 gold bands/571, 5/10 mg is light brown with 2 white bands/572, 5/20 mg is pink with 2 white bands/573 and 10/20 mg is purple with 2 white bands/574. All four strengths are packaged in bottles or blisters as follows:Storage: Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F).[See USP controlled room temperature.]Protect from moisture. Dispense in tight container (USP).** Trademark of Thomson Healthcare, Inc.T2009-86 Amlodipine besylate and benazepril hydrochloride combination capsules are available as capsules containing amlodipine besylate equivalent to 2.5 mg, 5 mg or 10 mg of amlodipine, with 10 mg or 20 mg of benazepril hydrochloride providing for the following available combinations: 2.5/10 mg, 5/10 mg, 5/20 mg, and 10/20 mg . All capsules are imprinted with “S” in a triangle, SANDOZ and appropriate code. The capsule color and code is as follows: 2.5/10 mg is white with 2 gold bands/571, 5/10 mg is light brown with 2 white bands/572, 5/20 mg is pink with 2 white bands/573 and 10/20 mg is purple with 2 white bands/574. All four strengths are packaged in bottles or blisters as follows:Storage: Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F).[See USP controlled room temperature.]Protect from moisture. Dispense in tight container (USP).** Trademark of Thomson Healthcare, Inc.T2009-86 Amlodipine besylate and benazepril hydrochloride combination capsules are available as capsules containing amlodipine besylate equivalent to 2.5 mg, 5 mg or 10 mg of amlodipine, with 10 mg or 20 mg of benazepril hydrochloride providing for the following available combinations: 2.5/10 mg, 5/10 mg, 5/20 mg, and 10/20 mg . All capsules are imprinted with “S” in a triangle, SANDOZ and appropriate code. The capsule color and code is as follows: 2.5/10 mg is white with 2 gold bands/571, 5/10 mg is light brown with 2 white bands/572, 5/20 mg is pink with 2 white bands/573 and 10/20 mg is purple with 2 white bands/574. All four strengths are packaged in bottles or blisters as follows:Storage: Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F).[See USP controlled room temperature.]Protect from moisture. Dispense in tight container (USP).** Trademark of Thomson Healthcare, Inc.T2009-86 Amlodipine besylate and benazepril hydrochloride combination capsules are available as capsules containing amlodipine besylate equivalent to 2.5 mg, 5 mg or 10 mg of amlodipine, with 10 mg or 20 mg of benazepril hydrochloride providing for the following available combinations: 2.5/10 mg, 5/10 mg, 5/20 mg, and 10/20 mg . All capsules are imprinted with “S” in a triangle, SANDOZ and appropriate code. The capsule color and code is as follows: 2.5/10 mg is white with 2 gold bands/571, 5/10 mg is light brown with 2 white bands/572, 5/20 mg is pink with 2 white bands/573 and 10/20 mg is purple with 2 white bands/574. All four strengths are packaged in bottles or blisters as follows:Storage: Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F).[See USP controlled room temperature.]Protect from moisture. Dispense in tight container (USP).** Trademark of Thomson Healthcare, Inc.T2009-86 Amlodipine besylate and benazepril hydrochloride combination capsules are available as capsules containing amlodipine besylate equivalent to 2.5 mg, 5 mg or 10 mg of amlodipine, with 10 mg or 20 mg of benazepril hydrochloride providing for the following available combinations: 2.5/10 mg, 5/10 mg, 5/20 mg, and 10/20 mg . All capsules are imprinted with “S” in a triangle, SANDOZ and appropriate code. The capsule color and code is as follows: 2.5/10 mg is white with 2 gold bands/571, 5/10 mg is light brown with 2 white bands/572, 5/20 mg is pink with 2 white bands/573 and 10/20 mg is purple with 2 white bands/574. All four strengths are packaged in bottles or blisters as follows:Storage: Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F).[See USP controlled room temperature.]Protect from moisture. Dispense in tight container (USP).** Trademark of Thomson Healthcare, Inc.T2009-86 Amlodipine besylate and benazepril hydrochloride combination capsules are available as capsules containing amlodipine besylate equivalent to 2.5 mg, 5 mg or 10 mg of amlodipine, with 10 mg or 20 mg of benazepril hydrochloride providing for the following available combinations: 2.5/10 mg, 5/10 mg, 5/20 mg, and 10/20 mg . All capsules are imprinted with “S” in a triangle, SANDOZ and appropriate code. The capsule color and code is as follows: 2.5/10 mg is white with 2 gold bands/571, 5/10 mg is light brown with 2 white bands/572, 5/20 mg is pink with 2 white bands/573 and 10/20 mg is purple with 2 white bands/574. All four strengths are packaged in bottles or blisters as follows:Storage: Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F).[See USP controlled room temperature.]Protect from moisture. Dispense in tight container (USP).** Trademark of Thomson Healthcare, Inc.T2009-86

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Clinical Information

Chemical Structure

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Clinical Pharmacology

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 (see PRECAUTIONS).

      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 amlodipine besylate and benazepril hydrochloride combination capsules 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 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.

Non-Clinical Toxicology

Amlodipine besylate and benazepril hydrochloride combination capsules is contraindicated in patients with a history of angioedema, with or without previous ACE inhibitor treatment, or patients who are hypersensitive to benazepril, to any other ACE inhibitor, or to amlodipine.

Diuretics:

Potassium Supplements and Potassium-Sparing Diuretics:

Lithium:

Gold

Other:

      In clinical trials, amlodipine has been safely administered with thiazide diuretics, beta blockers, ACE inhibitors, long-acting nitrates, sublingual nitroglycerin, digoxin, warfarin, nonsteroidal anti-inflammatory drugs, antibiotics, and oral hypoglycemic drugs.

      In vitro data in human plasma indicate that amlodipine has no effect on the protein binding of drugs tested (digoxin, phenytoin, warfarin, and indomethacin). Special studies have indicated that the coadministration of amlodipine with digoxin did not change serum digoxin levels or digoxin renal clearance in normal volunteers; that coadministration with cimetidine did not alter the pharmacokinetics of amlodipine; and that coadministration with warfarin did not change the warfarin-induced prothrombin response time.

Impaired Renal Function:

      When the renin-angiotensin-aldosterone system is inhibited by benazepril, changes in renal function may be anticipated in susceptible individuals. In patients with , whose renal function may depend on the activity of the renin-angiotensin-aldosterone system, treatment with ACE inhibitors (including benazepril) may be associated with oliguria and/or progressive azotemia and (rarely) with acute renal failure and/or death.

      In a small study of hypertensive patients with , treatment with benazepril was associated with increases in blood urea nitrogen and serum creatinine; these increases were reversible upon discontinuation of benazepril therapy, concomitant diuretic therapy, or both. When such patients are treated with amlodipine besylate and benazepril hydrochloride combination capsules, renal function should be monitored during the first few weeks of therapy.

      Some benazepril-treated hypertensive patients with have developed increases in blood urea nitrogen and serum creatinine, usually minor and transient, especially when benazepril has been given concomitantly with a diuretic. Dosage reduction of amlodipine besylate and benazepril hydrochloride combination capsules may be required. (see DOSAGE AND ADMINISTRATION).

Hyperkalemia:

Patients With Congestive Heart Failure:

Patients With Hepatic Failure:

Cough:

Surgery/Anesthesia:

Amlodipine besylate and benazepril hydrochloride combination capsules 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 amlodipine besylate and benazepril hydrochloride combination capsules 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 amlodipine besylate and benazepril hydrochloride combination capsules and in 3% of patients treated with placebo.

      The most common reasons for discontinuation of therapy with amlodipine besylate and benazepril hydrochloride combination capsules in these studies were cough and 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 amlodipine besylate and benazepril hydrochloride combination capsules are shown in the table below.

*Edema refers to all edema, such as dependent edema, angioedema, facial edema.

      The incidence of edema was statistically greater in patients treated with amlodipine monotherapy than in patients treated with the combination. Edema and certain other side effects are associated with amlodipine monotherapy in a dose-dependent manner, and appear to affect women more than men. The addition of benazepril resulted in lower incidences as shown in the following table; the protective effect of benazepril was independent of race and (within the range of doses tested) of dose.

      In a trial (n=386) comparing placebo, amlodipine besylate and benazepril hydrochloride combination capsules 5/20, and amlodipine besylate and benazepril hydrochloride combination capsules 10/20, edema and dizziness were most commonly reported in the amlodipine besylate and benazepril hydrochloride combination capsules 10/20 group.

      There were no appreciable differences in the safety profile of the 5/40 mg or 10/40 mg doses of amlodipine besylate and benazepril hydrochloride combination capsules when studied in two trials (n=329 and n=812) conducted to establish the effectiveness of these doses vs. benazepril monotherapy and amlodipine monotherapy, respectively.

      Other side effects considered possibly or probably related to study drug that occurred in U.S. placebo-controlled trials of patients treated with amlodipine besylate and benazepril hydrochloride combination capsules or in postmarketing experience were the following:

Angioedema:

Body as a Whole:

CNS:

Dermatologic:

Digestive:

Metabolic and Nutritional:

Musculoskeletal:

Respiratory:

Urogenital:

      Other infrequently reported events were seen in clinical trials (causal relationship unlikely) or in postmarketing experience. These included chest pain, ventricular extrasystole, gout, neuritis, tinnitus, alopecia and upper respiratory tract infection.

Fetal/Neonatal Morbidity and Mortality:

      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 amlodipine besylate and benazepril hydrochloride combination capsules. In postmarketing experience with benazepril, there have been rare reports of Stevens-Johnson syndrome, pancreatitis, hemolytic anemia, pemphigus, and thrombocytopenia. Jaundice and hepatic enzyme elevations (mostly consistent with cholestasis) severe enough to require hospitalization have been reported in association with use of amlodipine. Other potentially important adverse experiences attributed to other ACE inhibitors and calcium channel blockers include: eosinophilic pneumonitis (ACE inhibitors) and gynecomastia (CCB’s).

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Reference

This information is obtained from the National Institute of Health's Standard Packaging Label drug database.
"https://dailymed.nlm.nih.gov/dailymed/"

While we update our database periodically, we cannot guarantee it is always updated to the latest version.

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