LOTREL amlodipine besylate and benazepril hydrochloride capsule
WARNING: FETAL TOXICITY
When pregnancy is detected, discontinue Lotrel as soon as possible. Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus.
DESCRIPTION
Lotrel is combination of amlodipine besylate and benazepril hydrochloride.
Benazepril hydrochloride is 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 empirical formula is C24 H28 N2 O5 ?HCl, and its molecular weight is 460.96.
Benazeprilat, the active metabolite of benazepril, is nonsulfhydryl angiotensin-converting enzyme (ACE) inhibitor. Benazepril is converted to benazeprilat by hepatic cleavage of the ester group.
Amlodipine besylate is 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 empirical formula is C20 H25 ClN2 O5 ?C6 H6 O3 S, and its molecular weight is 567.1
INDICATIONS AND USAGE
1.1 Hypertension
Lotrel is indicated for the treatment of hypertension in patients not adequately controlled on monotherapy with either agent.
2 DOSAGE AND ADMINISTRATION
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.
The antihypertensive effect of Lotrel is largely attained within weeks.
DOSAGE FORMS AND STRENGTHS
Lotrel (amlodipine/benazepril) capsules are available as follows:
2.5/10 mg, 5/10 mg, 5/20 mg, 5/40 mg, 10/20 mg, and 10/40 mg.
Fetal Toxicity
Pregnancy Category D
Amlodipine besylate is the besylate salt of amlodipine, dihydropyridine calcium channel blocker.
Lotrel capsules are formulated in six different strengths for oral administration with combination of amlodipine besylate equivalent to 2.5 mg, mg or 10 mg of amlodipine, with 10 mg, 20 mg or 40 mg of benazepril hydrochloride providing for the following available combinations: 2.5/10 mg, 5/10 mg, 5/20 mg, 5/40 mg, 10/20 mg and 10/40 mg.
The inactive ingredients of the capsules are calcium phosphate, cellulose compounds, colloidal silicon dioxide, crospovidone, gelatin, hydrogenated castor oil (not present in 5/40 mg or 10/40 mg strengths), iron oxides, lactose, magnesium stearate, polysorbate 80, silicon dioxide, sodium lauryl sulfate, sodium starch (potato) glycolate, starch (corn), talc, and titanium dioxide.
Mechanism of Action
Benazepril
Benazepril and benazeprilat inhibit angiotensin-converting enzyme (ACE) in human subjects and in animals. ACE is peptidyl dipeptidase that catalyzes the conversion of angiotensin 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 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
Amlodipine
Amlodipine is 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 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 gradual rate of association and dissociation with the receptor binding site, resulting in gradual onset of effect.
Amlodipine is peripheral arterial vasodilator that acts directly on vascular smooth muscle to cause reduction in peripheral vascular resistance and reduction in blood pressure.
