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Amlobenz (Amlodipine Besylate / Benazepril Hydrochloride) - Description and Clinical Pharmacology

 
 



DESCRIPTION

Amlodipine besylate and benazepril hydrochloride capsules is a combination of 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-1H-1-(3S)-benzazepine-1-acetic acid monohydrochloride; its structural formula is

Its molecular formula is C24H28N205•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 molecular formula is C20H25ClN205•C6H603S, and its molecular weight is 567.1.

Amlodipine besylate is the besylate salt of amlodipine, a dihydropyridine calcium channel blocker. Amlodipine besylate and benazepril hydrochloride 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 mg/10 mg, 5 mg/10 mg, 5 mg/20 mg and 10 mg/20 mg.The inactive ingredients of the capsules are colloidal silicon dioxide, crospovidone, hydrogenated castor oil, lactose monohydrate, magnesium stearate, microcrystalline cellulose, pregelatinized starch, sodium starch glycolate. Each hard-gelatin capsule contains gelatin, titanium dioxide and D&C yellow # 10, D&C red # 28 (5 mg/20 mg), FD&C blue # 1(5 mg/20 mg), FD&C green # 3 (2.5 mg/10 mg), FD&C red # 40 (5 mg/20 mg), iron oxide black (10 mg/20 mg) and iron oxide red (5 mg/20 mg and 10 mg/20 mg) as coloring agents.

CLINICAL PHARMACOLOGY

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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 [see Warnings and Precautions (5) ].

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 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

Benazepril

Single and multiple doses of 10 mg or more of benazepril cause inhibition of plasma ACE activity by at least 80%-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%-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 [see Warnings and Precautions (5) ].

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.

Amlodipine

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. Plasma concentrations correlate with effect in both young and elderly patients.

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.

Pharmacokinetics

The rate and extent of absorption of benazepril and amlodipine from amlodipine besylate and benazepril hydrochloride are not significantly different, respectively, from the rate and extent of absorption of benazepril and amlodipine from individual tablet formulations. Absorption from the individual tablets is not influenced by the presence of food in the gastrointestinal tract; food effects on absorption from amlodipine besylate and benazepril hydrochloride have not been studied.

Following oral administration of amlodipine besylate and benazepril hydrochloride, peak plasma concentrations of benazepril are reached in 0.5-2 hours. Cleavage of the ester group (primarily in the liver) converts benazepril to its active metabolite, benazeprilat, which reaches peak plasma concentrations in 1.5-4 hours. The extent of absorption of benazepril is at least 37%.

Peak plasma concentrations of amlodipine are reached 6-12 hours after administration of amlodipine besylate and benazepril hydrochloride; the extent of absorption is 64%-90%.

The apparent volumes of distribution of amlodipine and benazeprilat are about 21 L/kg and 0.7 L/kg, respectively. 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.

Benazeprilat has much greater ACE-inhibitory activity than benazepril, and the metabolism of benazepril to benazeprilat is almost complete. Only trace amounts of an administered dose of benazepril can be recovered unchanged in the urine; about 20% of the dose is excreted as benazeprilat, 8% as benazeprilat glucuronide, and 4% as benazepril glucuronide.

Amlodipine is extensively metabolized in the liver, with 10% of the parent compound and 60% of the metabolites excreted in the urine. In patients with hepatic dysfunction, decreased clearance of amlodipine may increase the area-under-the-plasma-concentration curve by 40%-60%, and dosage reduction may be required (see DOSAGE AND ADMINISTRATION). In patients with renal impairment, the pharmacokinetics of amlodipine are essentially unaffected.

Benazeprilat's effective elimination half-life is 10-11 hours, while that of amlodipine is about 2 days, so steady-state levels of the two components are achieved after about a week of once-daily dosing. The clearance of benazeprilat from the plasma is primarily renal, but biliary excretion accounts for 11%-12% of benazepril elimination in normal subjects. In patients with severe renal insufficiency (creatinine clearance less than 30 mL/min), peak benazeprilat levels and the time to steady state may be increased (see DOSAGE AND ADMINISTRATION). In patients with hepatic impairment, on the other hand, the pharmacokinetics of benazeprilat are essentially unaffected.

Although the pharmacokinetics of benazepril and benazeprilat are unaffected by age, clearance of amlodipine is decreased in the elderly, with resulting increases of 35%-70% in peak plasma levels, elimination half-life, and area-under-the-plasma-concentration curve. Dose adjustment may be required.

NONCLINICAL TOXICOLOGY

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Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenicity and mutagenicity studies have not been conducted with this combination. However, these studies have been conducted with amlodipine and benazepril alone (see below). No adverse effects on fertility occurred when the benazepril:amlodipine combination was given orally to rats of either sex at doses up to 15:7.5 mg (benazepril:amlodipine)/kg/day, prior to mating and throughout gestation.

Benazepril

No evidence of carcinogenicity was found when benazepril was administered to rats and mice for up to two years at doses of up to 150 mg/kg/day. When compared on the basis of body surface area, this dose is 18 and 9 times (rats and mice, respectively) the maximum recommended human dose (calculations assume a patient weight of 60 kg). No mutagenic activity was detected in the Ames test in bacteria, in an in vitro test for forward mutations in cultured mammalian cells, or in a nucleus anomaly test. At doses of 50 mg/kg/day to 500 mg/kg/day (6-60 times the maximum recommended human dose on a body surface area basis), benazepril had no adverse effect on the reproductive performance of male and female rats.

Amlodipine

Rats and mice treated with amlodipine maleate in the diet for up to two years, at concentrations calculated to provide daily dosage levels of 0.5 mg, 1.25 mg, and 2.5 mg amlodipine/kg/day, showed no evidence of a carcinogenic effect of the drug. For the mouse, the highest dose was, on a body surface area basis, similar to the maximum recommended human dose [MRHD] of 10 mg amlodipine/day. For the rat, the highest dose was, on a body surface area basis, about two and a half times the MRHD. (Calculations based on a 60 kg patient.) Mutagenicity studies conducted with amlodipine maleate revealed no drug-related effects at either the gene or chromosome level. There was no effect on the fertility of rats treated orally with amlodipine maleate (males for 64 days and females for 14 days prior to mating) at doses of up to 10 mg amlodipine/kg/day (about 10 times the MRHD of 10 mg/day on a body surface area basis).

Reproductive Toxicity

When rats received benazepril:amlodipine at doses ranging from 5:2.5 mg/kg/day 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 amlodipine besylate and benazepril hydrochloride 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 amlodipine besylate and benazepril hydrochloride 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 maximum recommended human dose 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 amlodipine besylate and benazepril hydrochloride given to a 50 kg woman).

Benazepril

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 maximum recommended human dose (assuming a 50 kg woman).

Amlodipine

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 maximum recommended human dose [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 amlodipine besylate and benazepril hydrochloride once daily in six double-blind, placebo-controlled studies. The antihypertensive effect of a single dose persisted for 24 hours, with peak reductions achieved 2-8 hours after dosing.

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

In two 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 amlodipine besylate and benazepril hydrochloride 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 amlodipine besylate and benazepril hydrochloride 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 amlodipine besylate and benazepril hydrochloride, the maximum reduction in blood pressure with any given dose is generally achieved after 1-2 weeks. The antihypertensive effects of amlodipine besylate and benazepril hydrochloride have continued during therapy for at least 1 year. Abrupt withdrawal of amlodipine besylate and benazepril hydrochloride has not been associated with a rapid increase in blood pressure.

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