FOSINOPRIL SODIUM- fosinopril sodium tablet
Dispensing Solutions, Inc.
USE IN PREGNANCY
When used in pregnancy during the second and third trimesters, ACE inhibitors can cause injury and even death to the developing fetus. When pregnancy is detected, fosinopril sodium should be discontinued as soon as possible. See WARNINGS, Fetal/Neonatal Morbidity and Mortality .
Fosinopril sodium tablets are the sodium salt of fosinopril, the ester prodrug of an angiotensin- converting enzyme (ACE) inhibitor, fosinoprilat. It contains a phosphinate group capable of specific binding to the active site of angiotensin-converting enzyme. Fosinopril sodium is designated chemically as: L-proline, 4-cyclohexyl-1-[[[2-methyl-1-(1-oxopropoxy)propoxy](4-phenylbutyl)phosphinyl]acetyl]-, sodium salt, trans-.
Fosinopril sodium USP is a white to off-white crystalline powder. It is soluble in water (100 mg/mL), methanol, and ethanol and slightly soluble in hexane.
Its structural formula is:
Empirical formula: C30 H45 NNaO7 P Molecular weight: 585.65
Fosinopril Sodium is available for oral administration as 10 mg, 20 mg, and 40 mg tablets. Inactive ingredients include: lactose, microcrystalline cellulose, carnauba wax, crospovidone, and zinc stearate.
Mechanism of Action
In animals and humans, fosinopril sodium is hydrolyzed by esterases to the pharmacologically active form, fosinoprilat, a specific competitive inhibitor of angiotensin-converting enzyme (ACE).
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.
In 647 hypertensive patients treated with fosinopril alone for an average of 29 weeks, mean increases in serum potassium of 0.1 mEq/L were observed. Similar increases were observed among all patients treated with fosinopril, including those receiving concomitant diuretic therapy. Removal of angiotensin II negative feedback on renin secretion leads to increased plasma renin activity.
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 fosinopril sodium remains to be elucidated.
While the mechanism through which fosinopril sodium lowers blood pressure is believed to be primarily suppression of the renin-angiotensin-aldosterone system, fosinopril sodium has an antihypertensive effect even in patients with low-renin hypertension. Although fosinopril sodium was antihypertensive in all races studied, black hypertensive patients (usually a low-renin hypertensive population) had a smaller average response to ACE inhibitor monotherapy than non-black patients.
In patients with heart failure, the beneficial effects of fosinopril sodium are thought to result primarily from suppression of the renin-angiotensin-aldosterone system; inhibition of the angiotensin-converting enzyme produces decreases in both preload and afterload.
Pharmacokinetics and Metabolism
Following oral administration, fosinopril (the prodrug) is absorbed slowly. The absolute absorption of fosinopril averaged 36% of an oral dose. The primary site of absorption is the proximal small intestine (duodenum/jejunum). While the rate of absorption may be slowed by the presence of food in the gastrointestinal tract, the extent of absorption of fosinopril is essentially unaffected.
Fosinoprilat is highly protein-bound (approximately 99.4%), has a relatively small volume of distribution, and has negligible binding to cellular components in blood. After single and multiple oral doses, plasma levels, areas under plasma concentration-time curves (AUCs), and peak concentrations (Cmaxs ) are directly proportional to the dose of fosinopril. Times to peak concentrations are independent of dose and are achieved in approximately 3 hours.
After an oral dose of radiolabeled fosinopril, 75% of radioactivity in plasma was present as active fosinoprilat, 20% to 30% as a glucuronide conjugate of fosinoprilat, and 1% to 5% as a p -hydroxy metabolite of fosinoprilat. Since fosinoprilat is not biotransformed after intravenous administration, fosinopril, not fosinoprilat, appears to be the precursor for the glucuronide and p -hydroxy metabolites. In rats, the p -hydroxy metabolite of fosinoprilat is as potent an inhibitor of ACE as fosinoprilat; the glucuronide conjugate is devoid of ACE inhibitory activity.
After intravenous administration, fosinoprilat was eliminated approximately equally by the liver and kidney. After oral administration of radiolabeled fosinopril, approximately half of the absorbed dose is excreted in the urine and the remainder is excreted in the feces. In two studies involving healthy subjects, the mean body clearance of intravenous fosinoprilat was between 26 mL/min and 39 mL/min.
In healthy subjects, the terminal elimination half-life (t1⁄2 ) of an intravenous dose of radiolabeled fosinoprilat is approximately 12 hours. In hypertensive patients with normal renal and hepatic function, who received repeated doses of fosinopril, the effective t1⁄2 for accumulation of fosinoprilat averaged 11.5 hours. In patients with heart failure, the effective t1⁄2 was 14 hours.
In patients with mild to severe renal insufficiency (creatinine clearance 10-80 mL/min/1.73m2), the clearance of fosinoprilat does not differ appreciably from normal, because of the large contribution of hepatobiliary elimination. In patients with end-stage renal disease (creatinine clearance <10 mL/min/1.73m2), the total body clearance of fosinoprilat is approximately one-half of that in patients with normal renal function (see DOSAGE AND ADMINISTRATION).
Fosinopril is not well dialyzed. Clearance of fosinoprilat by hemodialysis and peritoneal dialysis averages 2% and 7%, respectively, of urea clearances.
In patients with hepatic insufficiency (alcoholic or biliary cirrhosis), the extent of hydrolysis of fosinopril is not appreciably reduced, although the rate of hydrolysis may be slowed; the apparent total body clearance of fosinoprilat is approximately one-half of that in patients with normal hepatic function.
In elderly (male) subjects (65 to 74 years old) with clinically normal renal and hepatic function, there appear to be no significant differences in pharmacokinetic parameters for fosinoprilat compared to those of younger subjects (20 to 35 years old).
In pediatric patients , (N=20) age 6 to 16 years, with glomerular filtration rate ≥25 mL/min, given a single dose of fosinopril (0.3 mg/kg given as solution), the mean AUC and Cmax values of fosinoprilat (the active form of fosinopril) were similar to those seen in healthy adults receiving 20 mg (about 0.3 mg/kg for a 70 kg adult) of fosinopril as a solution. The terminal elimination half-life of fosinoprilat in pediatric patients was 11 to 13 hours, also similar to that observed in adults.
Fosinoprilat was found to cross the placenta of pregnant animals. Studies in animals indicate that fosinopril and fosinoprilat do not cross the blood-brain barrier.
Pharmacodynamics and Clinical Effects
Serum ACE activity was inhibited by ≥ 90% at 2 to 12 hours after single doses of 10 mg to 40 mg of fosinopril. At 24 hours, serum ACE activity remained suppressed by 85%, 93%, and 93% in the 10 mg, 20 mg, and 40 mg dose groups, respectively.
Administration of fosinopril sodium tablets 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). Use of fosinopril sodium in combination with thiazide diuretics gives a blood pressure-lowering effect greater than that seen with either agent alone.
Following oral administration of single doses of 10 mg to 40 mg, fosinopril sodium lowered blood pressure within one hour, with peak reductions achieved 2 to 6 hours after dosing. The antihypertensive effect of a single dose persisted for 24 hours. Following four weeks of monotherapy in placebo-controlled trials in patients with mild to moderate hypertension, once daily doses of 20 mg to 80 mg lowered supine or seated systolic and diastolic blood pressures 24 hours after dosing by an average of 8-9/6-7 mmHg more than placebo. The trough effect was about 50% to 60% of the peak diastolic response and about 80% of the peak systolic response.
In most trials, the antihypertensive effect of fosinopril sodium increased during the first several weeks of repeated measurements. The antihypertensive effect of fosinopril sodium has been shown to continue during long-term therapy for at least 2 years. Abrupt withdrawal of fosinopril sodium has not resulted in a rapid increase in blood pressure.
Limited experience in controlled and uncontrolled trials combining fosinopril sodium with a calcium channel blocker or a loop diuretic has indicated no unusual drug-drug interactions. Other ACE inhibitors have had less than additive effects with beta-adrenergic blockers, presumably because both drugs lower blood pressure by inhibiting parts of the renin-angiotensin system.
ACE inhibitors are generally less effective in blacks than in non-blacks. The effectiveness of fosinopril sodium was not influenced by age, sex, or weight.
In hemodynamic studies in hypertensive patients, after three months of therapy, responses (changes in BP, heart rate, cardiac index, and PVR) to various stimuli (e.g., isometric exercise, 45° head-up tilt, and mental challenge) were unchanged compared to baseline, suggesting that fosinopril sodium does not affect the activity of the sympathetic nervous system. Reduction in systemic blood pressure appears to have been mediated by a decrease in peripheral vascular resistance without reflex cardiac effects. Similarly, renal, splanchnic, cerebral, and skeletal muscle blood flow were unchanged compared to baseline, as was glomerular filtration rate.
All MedLibrary.org resources are included in as near-original form as possible, meaning that the information from the original provider has been rendered here with only typographical or stylistic modifications and not with any substantive alterations of content, meaning or intent.