Amlodipine and Benazepril Hydrochloride (Page 4 of 6)

11 DESCRIPTION

Amlodipine and benazepril hydrochloride capsules USP are a combination of amlodipine besylate and benazepril hydrochloride.

Benazepril hydrochloride USP is a white to off-white, crystalline powder, soluble (greater than 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 C₂₄ H₂₈ N₂ O₅ •HCl, and its molecular weight is 460.96.

Benazeprilat, the active metabolite of benazepril, is a nonsulfhydryl ACE inhibitor. Benazepril is converted to benazeprilat by hepatic cleavage of the ester group.

Amlodipine besylate USP is a white or almost white 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 C₂₀ H₂₅ ClN₂ O₅ •C₆ H₆ O₃ S, and its molecular weight is 567.1.

Amlodipine besylate is the besylate salt of amlodipine, a dihydropyridine calcium channel blocker.
Amlodipine and benazepril hydrochloride is available as capsules containing amlodipine besylate USP (3.5 mg, 6.9 mg or 13.9 mg, equivalent to 2.5 mg, 5 mg or 10 mg of amlodipine respectively), with 10 mg, 20 mg, or 40 mg of benazepril hydrochloride USP providing for the following available combinations: 2.5 mg/10 mg, 5 mg/10 mg, 5 mg/20 mg, 5 mg/40 mg, 10 mg/20 mg, and 10 mg/40 mg.
The inactive ingredients of the capsules are colloidal silicon dioxide, crospovidone, gelatin, magnesium stearate, microcrystalline cellulose, povidone, sodium lauryl sulfate, and titanium dioxide. In addition, the hard gelatin capsule shells of 5 mg/10 mg contains iron oxide black, iron oxide red, and iron oxide yellow, 5 mg/20 mg contains iron oxide red, 5 mg/40 mg and 10 mg/40 mg contains FD&C Blue 1, FD&C Red 3, and 10 mg/20 mg contains D&C Red 28, FD&C Blue 1, FD&C Red 40, and FD&C Yellow 5. The capsules are printed with edible ink containing black iron oxide and shellac.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Benazepril

Benazepril and benazeprilat inhibit 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 (5.6)].

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 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.

12.2 Pharmacodynamics

Benazepril

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 [see Warnings and Precautions (5.4)].

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.

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 to 114 mmHg) had about 50% greater response than patients with mild hypertension (diastolic pressure 90 to 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.

12.3 Pharmacokinetics

The rate and extent of absorption of benazepril and amlodipine from amlodipine and benazepril hydrochloride 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 amlodipine and benazepril hydrochloride have not been studied.

Absorption: Following oral administration of amlodipine and benazepril hydrochloride, 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 amlodipine and benazepril hydrochloride, 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.

Specific 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 [see Use in Specific Populations (8.5)].

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 [see Use in Specific Populations (8.6)].

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 [see Dosage and Administration (2.2), Use in Specific Populations (8.7) and Warnings and Precautions (5.7)].

Drug Interactions

Amlodipine

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.

Benazepril

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.