1.1Hypertension

Amlodipine Besylate and Benazepril Hydrochloride Capsules are indicated for the treatment of hypertension in patients not adequately controlled on monotherapy with either agent.  

2.2 Add-on Therapy

A patient whose blood pressure is not adequately controlled with amlodipine (or another dihydropyridine) alone or with benazepril (or another ACE inhibitor) alone may be switched to combination therapy with Amlodipine Besylate and Benazepril Hydrochloride Capsules.

In patients whose blood pressure is adequately controlled with amlodipine but who experience unacceptable edema, combination therapy may achieve similar (or better) blood pressure control with less edema.

2.3 Replacement Therapy

Amlodipine Besylate and Benazepril Hydrochloride Capsules may be substituted for the titrated components.

5.1 Anaphylactoid and Possibly Related Reactions

Presumably because angiotensin-converting enzyme inhibitors affect the metabolism of eicosanoids and polypeptides, including endogenous bradykinin, patients receiving ACE inhibitors (including Amlodipine Besylate and Benazepril Hydrochloride Capsules) may be subject to a variety of adverse reactions, some of them serious. These reactions usually occur after one of the first few doses of the ACE inhibitor, but they sometimes do not appear until after months of therapy. Black patients receiving ACE inhibitors have a higher incidence of angioedema compared to nonblacks.

Head and Neck Angioedema: Angioedema of the face, extremities, lips, tongue, glottis, and larynx has been reported in patients treated with ACE inhibitors. In U.S. clinical trials, symptoms consistent with angioedema were seen in none of the subjects who received placebo and in about 0.5% of the subjects who received benazepril. Angioedema associated with laryngeal edema can be fatal. If laryngeal stridor or angioedema of the face, tongue, or glottis occurs, discontinue treatment with Amlodipine Besylate and Benazepril Hydrochloride Capsules and treat immediately. When involvement of the tongue, glottis, or larynx appears likely to cause airway obstruction, appropriate therapy, e.g., administer subcutaneous epinephrine injection 1:1000 (0.3-0.5 mL), promptly [see Adverse Reactions (6)].

Intestinal Angioedema: Intestinal angioedema has been reported in patients treated with ACE inhibitors. These patients presented with abdominal pain (with or without nausea or vomiting); in some cases there was no prior history of facial angioedema and C-1 esterase levels were normal. The angioedema was diagnosed by procedures including abdominal CT scan or ultrasound, or at surgery, and symptoms resolved after stopping the ACE inhibitor. Intestinal angioedema should be included in the differential diagnosis of patients on ACE inhibitors presenting with abdominal pain.

Anaphylactoid Reactions During Desensitization: Two patients undergoing desensitizing treatment with hymenoptera venom while receiving ACE inhibitors sustained life-threatening anaphylactoid reactions. In the same patients, these reactions were avoided when ACE inhibitors were temporarily withheld, but they reappeared upon inadvertent rechallenge.

Anaphylactoid Reactions During Membrane Exposure: Anaphylactoid reactions have been reported in patients dialyzed with high-flux membranes and treated concomitantly with an ACE inhibitor. Anaphylactoid reactions have also been reported in patients undergoing low-density lipoprotein apheresis with dextran sulfate absorption.

5.2 Increased Angina and/or Myocardial Infarction

Rarely, patients, particularly those with severe obstructive coronary artery disease, have developed documented increased frequency, duration or severity of angina or acute myocardial infarction on starting calcium channel blocker therapy or at the time of dosage increase. The mechanism of this effect has not been elucidated.

5.3 Hypotension

Amlodipine Besylate and Benazepril Hydrochloride Capsules can cause symptomatic hypotension. Symptomatic hypotension is most likely to occur in patients who have been volume or salt depleted as a result of prolonged diuretic therapy, dietary salt restriction, dialysis, diarrhea, or vomiting.

In patients with congestive heart failure, with or without associated renal insufficiency, ACE inhibitor therapy may cause excessive hypotension, which may be associated with oliguria, azotemia, and (rarely) with acute renal failure and death. In such patients, start amlodipine besylate and benazepril hydrochloride therapy under close medical supervision; follow closely for the first 2 weeks of treatment and whenever the dose of the benazepril component is increased or a diuretic is added or its dose increased.

Symptomatic hypotension is also possible in patients with severe aortic stenosis.

If hypotension occurs, place the patient in a supine position, and if necessary, treat with intravenous infusion of physiologic saline. Amlodipine Besylate and Benazepril Hydrochloride Capsules treatment usually can be continued following restoration of blood pressure and volume.

5.4 Fetal Toxicity

Pregnancy Category D

Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue Amlodipine Besylate and Benazepril Hydrochloride Capsules as soon as possible [see Use in Specific Populations (8.1)].

5.5 Hepatic Failure

Rarely, ACE inhibitors have been associated with a syndrome that starts with cholestatic jaundice and progresses to fulminant hepatic necrosis and, sometimes, death. The mechanism of this syndrome is not understood. Patients receiving ACE inhibitors who develop jaundice or marked elevations of hepatic enzymes should discontinue the ACE inhibitor and receive appropriate medical follow-up.

In patients with hepatic dysfunction due to cirrhosis, levels of benazeprilat are essentially unaltered.

However, since amlodipine is extensively metabolized by the liver and the plasma elimination half-life (t1/2) is 56 hours in patients with impaired hepatic function, titrate amlodipine besylate and benazepril hydrochloride slowly in patients with severe hepatic impairment.

5.6 Impaired Renal Function

Amlodipine Besylate and Benazepril Hydrochloride Capsules should not be used in patients with severe renal disease (Clearance creatinine < 30 mL/min) [see Dosage and Administration (2)] 

In patients with severe heart failure, whose renal function may depend on the activity of the renin-angiotensin aldosterone system, treatment with benazepril may be associated with oliguria or progressive azotemia and (rarely) with acute renal failure and/or death.

In a small study of hypertensive patients with unilateral or bilateral renal artery stenosis, 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 Capsules, monitor renal function during the first few weeks of therapy.

Some benazepril-treated hypertensive patients with no apparent preexisting renal vascular disease 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 Capsules may be required.

Renal function should be monitored periodically in patients receiving benazepril.

5.7 Hyperkalemia

In U.S. placebo-controlled trials of Amlodipine Besylate and Benazepril Hydrochloride Capsules, hyperkalemia (serum potassium at least 0.5 mEq/L greater than the upper limit of normal) not present at baseline occurred in approximately 1.5% of hypertensive patients receiving Amlodipine Besylate and Benazepril Hydrochloride Capsules. Increases in serum potassium were generally reversible. Risk factors for the development of hyperkalemia include renal insufficiency, diabetes mellitus, and the concomitant use of potassium-sparing diuretics, potassium supplements, and/or potassium-containing salt substitutes. Serum potassium should be monitored periodically in patients receiving benazepril.

5.8 Cough

Presumably due to the inhibition of the degradation of endogenous bradykinin, persistent nonproductive cough has been reported with all ACE inhibitors, generally resolving after discontinuation of therapy. Consider ACE inhibitor-induced cough in the differential diagnosis of cough.

5.9 Surgery/Anesthesia

In patients undergoing surgery or during anesthesia with agents that produce hypotension, benazepril will block the angiotensin II formation that could otherwise occur secondary to compensatory renin release. Hypotension that occurs as a result of this mechanism can be corrected by volume expansion.

6.1 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. 

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

The most common reasons for discontinuation of therapy with amlodipine besylate and benazepril hydrochloride 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 amlodipine besylate and benazepril hydrochloride are shown in the table below. Cough was the only adverse event with at least possible relationship to treatment that was more common on amlodipine besylate and benazepril hydrochloride (3.3%) than on placebo (0.2%).

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

The incidence of edema was greater in patients treated with amlodipine monotherapy (5.1%) than in patients treated with amlodipine besylate and benazepril hydrochloride (2.1%) or placebo (2.2%).

Other side effects considered possibly or probably related to study drug that occurred in U.S. placebo-controlled trials of patients treated with amlodipine besylate and benazepril hydrochloride 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 amlodipine besylate and benazepril hydrochloride.

6.2 Post-marketing 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, and thrombocytopenia. Gingival hyperplasia, tachycardia, 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 (CCBs). Other infrequently reported events included chest pain, ventricular extrasystole, gout, neuritis, tinnitus, alopecia, upper respiratory tract infection, palpitations and somnolence.

7.1 Drug/Drug interactions

Diuretics: Patients on diuretics, especially those in whom diuretic therapy was recently instituted, may occasionally experience an excessive reduction of blood pressure after initiation of therapy with amlodipine besylate and benazepril hydrochloride. The possibility of hypotensive effects with amlodipine besylate and benazepril hydrochloride can be minimized by either discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with amlodipine besylate and benazepril hydrochloride.

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

Lithium: Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving ACE inhibitors during therapy with lithium. When coadministering amlodipine besylate and benazepril hydrochloride and lithium, frequent monitoring of serum lithium levels is recommended.

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

Non-Steroidal Anti-Inflammatory Agents including Selective Cyclooxygenase-2 Inhibitors (COX-2 Inhibitors): In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, co-administration of NSAIDs, including selective COX-2 inhibitors, with ACE inhibitors, including benazepril, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving benazepril and NSAID therapy.

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

Simvastatin: Co-administration 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. Limit the dose of simvastatin in patients on amlodipine to 20 mg daily.

Other: Benazepril has been used concomitantly with oral anticoagulants, beta-adrenergic-blocking agents, calcium-blocking agents, cimetidine, diuretics, digoxin, and hydralazine without evidence of clinically important adverse interactions.

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.

7.2 Clinical Laboratory Test Findings

Serum Electrolytes: [see Warnings and Precautions (5)].

Creatinine: Minor reversible increases in serum creatinine were observed in patients with essential hypertension treated with amlodipine besylate and benazepril hydrochloride. Increases in creatinine are more likely to occur in patients with renal insufficiency or those pretreated with a diuretic and, based on experience with other ACE inhibitors, would be expected to be especially likely in patients with renal artery stenosis [see Warnings and Precautions (5)].

Other (causal relationships unknown): Clinically important changes in standard laboratory tests were rarely associated with amlodipine besylate and benazepril hydrochloride administration. Elevations of serum bilirubin and uric acid have been reported as have scattered incidents of elevations of liver enzymes.

8.1 Pregnancy

Pregnancy Category D

Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue Amlodipine Besylate and Benazepril Hydrochloride Capsules as soon as possible. These adverse outcomes are usually associated with use of these drugs in the second and third trimester of pregnancy. Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents. Appropriate management of maternal hypertension during pregnancy is important to optimize outcomes for both mother and fetus.

In the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus. Perform serial ultrasound examinations to assess the intra-amniotic environment. If oligohydramnios is observed, discontinue Amlodipine Besylate and Benazepril Hydrochloride Capsules, unless it is considered lifesaving for the mother. Fetal testing may be appropriate, based on the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury. Closely observe infants with histories of in utero exposure to Amlodipine Besylate and Benazepril Hydrochloride Capsules for hypotension, oliguria, and hyperkalemia [see Use in Specific Populations (8.4)].

8.2 Labor and Delivery

The effect of amlodipine besylate and benazepril hydrochloride on labor and delivery has not been studied.

8.3 Nursing Mothers

Minimal amounts of unchanged benazepril and of benazeprilat are excreted into the breast milk of lactating women treated with benazepril, so that a newborn child ingesting nothing but breast milk would receive less than 0.1% of the maternal doses of benazepril and benazeprilat.

It is not known whether amlodipine is excreted in human milk. Nursing or drug should be discontinued.

8.4 Pediatric Use

Neonates with a history of in utero exposure to Amlodipine Besylate and Benazepril Hydrochloride Capsules:

If oliguria or hypotension occurs, direct attention toward support of blood pressure and renal perfusion. Exchange transfusions or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function. Benazepril, which crosses the placenta, can theoretically be removed from the neonatal circulation by these means; there are occasional reports of benefit from these maneuvers, but experience is limited.

8.5 Geriatric Use

Of the total number of patients who received amlodipine besylate and benazepril hydrochloride in U.S. clinical studies of amlodipine besylate and benazepril hydrochloride, over 19% were 65 or older while about 2% were 75 or older. Overall differences in effectiveness or safety were not observed between these patients and younger patients. Clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Benazepril and benazeprilat are substantially excreted by the kidney. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

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. Thus a lower starting dose may be required in older patients [see Dosage and Administration (2)].

12.1 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.

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%-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.

12.3 Pharmacokinetics

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

Following oral administration of amlodipine besylate and benazepril hydrochloride capsules, 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 capsules; 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 (2)]. 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 (2)]. 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.

13.1 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 50-500 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, 1.25, 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).

13.3 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 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.