Mechanism of Action

Fosinopril and fosinoprilat 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 fosinopril alone for an average of 8 weeks had elevations of serum potassium of approximately 0.1 mEq/L. Similar patients treated with hydrochlorothiazide alone had a mean reduction in serum potassium of 0.15 mEq/L, while patients who received combined treatment with 10/12.5 mg or 20/12.5 mg of fosinopril and hydrochlorothiazide had reductions of 0.07 and 0.03 mEq/L, respectively. (See PRECAUTIONS)

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 and hydrochlorothiazide tablets remains to be elucidated.

While the mechanism through which fosinopril lowers blood pressure is believed to be primarily suppression of the renin-angiotensin-aldosterone system, fosinopril has an antihypertensive effect even in patients with low-renin hypertension.

Hydrochlorothiazide is a thiazide diuretic. Thiazides affect the renal tubular mechanisms of electrolyte reabsorption, directly increasing excretion of sodium and chloride in approximately equivalent amounts. Indirectly, the diuretic action of hydrochlorothiazide reduces plasma volume, with consequent increases in plasma renin activity, increases in aldosterone secretion, increases in urinary potassium loss, and decreases in serum potassium. The renin-aldosterone link is mediated by angiotensin, so coadministration of an ACE inhibitor tends to reverse the potassium loss associated with these diuretics.

The mechanism of the antihypertensive effect of thiazides is unknown.

Pharmacokinetics and Metabolism

The absolute absorption of fosinopril averages 36% of an oral dose. The primary site of absorption is the proximal small intestine. 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.

Following oral administration of hydrochlorothiazide, peak plasma concentrations are achieved in 1 to 2.5 hours, and the extent of absorption is 50 to 80%. The reported studies of food effects on hydrochlorothiazide absorption have been inconclusive. The absorption of hydrochlorothiazide is increased by agents that reduce gastrointestinal motility. It is reported to be decreased by 50% in patients with congestive heart failure.

Cleavage of the ester group (primarily in the liver) converts fosinopril to its active metabolite, fosinoprilat. The time to peak plasma concentrations of fosinoprilat is about 3 hours, independent of the administered dose of fosinopril. In patients with hepatic dysfunction due to cirrhosis, conversion of fosinopril to fosinoprilat may be slowed, but the extent of this conversion is unchanged.

Fosinoprilat is highly protein bound (95%), but has negligible binding to cellular components of blood. The peak serum concentration and the area under the concentration-time curve of fosinoprilat is directly proportional to the administered dose of fosinopril.

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.

Studies in animals indicate that fosinopril and fosinoprilat do not cross the blood-brain barrier, but fosinoprilat does cross the placenta of pregnant animals. In humans, hydrochlorothiazide crosses the placenta freely, and levels in umbilical-cord blood are similar to those in the maternal circulation.

Hydrochlorothiazide is not metabolized. Its apparent volume of distribution is 3.6 to 7.8 L/kg, and its measured plasma protein binding is 67.9%. The drug also accumulates in red blood cells, so that whole blood levels are 1.6 to 1.8 times those measured in plasma.

After intravenous administration, fosinoprilat is 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 and 39 mL/min.

In hypertensive patients with normal renal and hepatic function, the effective half-life of accumulation of fosinoprilat following multiple dosing of fosinopril sodium is 11.5 hours. Thus, steady-state concentrations of fosinoprilat should bereached after 2 or 3 doses of fosinopril sodium and hydrochlorothiazide tablets given once daily.

In patients with renal insufficiency (creatinine clearance < 80 mL/min/1.73 m2), the total body clearance of fosinoprilat is approximately one half of that in patients with normal renal function, while absorption, bioavailability, and protein binding are not appreciably altered. The clearance of fosinoprilat does not differ appreciably with the degree of renal insufficiency, because the diminished renal elimination is offset by increased hepatobiliary elimination. A modest increase in plasma AUC levels (less than two times that in normals) was observed in patients with various degrees of renal insufficiency, including end-stage renal failure (creatinine clearance < 10 mL/min/1.73 m2). (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 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).

Thiazide diuretics are eliminated by the kidney, with a terminal half-life of 5 to 15 hours. In a study of patients with impaired renal function (mean creatine clearance of 19 mL/min), the half-life of hydrochlorothiazide elimination was lengthened to 21 hours.

When fosinopril and hydrochlorothiazide are administered concomitantly, the pharmacokinetics of hydrochlorothiazide are essentially unaffected. Serum levels of fosinoprilat are increased after several weeks of coadministration of hydrochlorothiazide and fosinopril, but the increase is not sufficient to warrant any change in dosing.

Pharmacodynamics

After single doses of 10 to 40 mg of fosinopril, serum ACE activity was inhibited by at least 90% from 2 to 12 hours after dosing. At 24 hours, serum ACE activity remains suppressed by 85 to 93%.

Administration of fosinopril 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. In studies in hypertensive patients after three months of fosinopril monotherapy, hemodynamic responses to various stimuli (isometric exercise, 45° head-up tilt, mental challenges) were unchanged compared to baseline, suggesting that fosinopril did not affect the activity of the sympathetic nervous system. Instead, fosinopril-induced reduction in blood pressure appears to be mediated by a reduction in peripheral vascular resistance without reflex cardiac effects. In similar studies, renal, splanchnic, cerebral, and skeletal muscle blood flows were all unchanged compared to baseline, as was glomerular filtration rate. Symptomatic postural hypotension is infrequent, although it can occur in patients who are salt- and/or volume-depleted (see WARNINGS).

Following oral administration of single doses of 10 to 40 mg, fosinopril lowered blood pressure within one hour, with peak reductions achieved 2to 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 to 80 mg lowered supine or seated blood pressures (systolic/diastolic) 24 hours after dosing by an average of 8 to 9/6 to 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 clinical studies of various combinations that included 0 to 40 mg of fosinopril and 0 to 37.5 mg of hydrochlorothiazide, the antihypertensive effects were increased with increasing dose of either component. Peak blood pressure reductions were achieved 2 to 6 hours after dosing. The mean reductions in seated blood pressure (systolic/diastolic) associated with fosinopril sodium and hydrochlorothiazide tablets, 10 mg/12.5 mg after 24 hours were 9 to 18/5 to 7 mmHg greater than those associated with placebo; those associated with fosinopril sodium and hydrochlorothiazide tablets, 20 mg/12.5 mg after 24 hours were 12 to 17/8 to 10 mmHg greater than those associated with placebo. These trough effects were 60 to 90% of the corresponding peak effects.

Although hydrochlorothiazide tends to be more effective in low-renin hypertensive patients (mainly blacks), and fosinopril-like other ACE inhibitors-tends to be more effective in high-renin patients (mainly non-blacks), the effectiveness of fosinopril sodium and hydrochlorothiazide tablets is independent of race, age, and gender.

General

Derangements of Serum Electrolytes:

In clinical trials of fosinopril monotherapy, hyperkalemia (serum potassium at least 10% greater than the upper limit of normal) occurred in approximately 2.6% of hypertensive patients receiving fosinopril. In most cases, these were isolated values which resolved despite continued therapy. Risk factors for the development of hyperkalemia included renal insufficiency, diabetes mellitus, and the concomitant use of potassium-sparing diuretics, potassium supplements, and/or potassium-containing salt substitutes.

Conversely, treatment with thiazide diuretics has been associated with hypokalemia, hyponatremia, and hypochloremic alkalosis. These disturbances have sometimes been manifest as one or more of dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, nausea, and vomiting. Hypokalemia can also sensitize or exaggerate the response of the heart to the toxic effects of digitalis. The risk of hypokalemia is greatest in patients with cirrhosis of the liver, in patients experiencing a brisk diuresis, in patients who are receiving inadequate oral intake of electrolytes, and in patients receiving concomitant therapy with corticosteroids or ACTH.

The opposite effects of fosinopril and hydrochlorothiazide on serum potassium will approximately balance each other in many patients, so that no net effect upon serum potassium will be seen. In other patients, one or the other effect may be dominant. Initial and periodic determinations of serum electrolytes to detect possible electrolyte imbalance should be performed at appropriate intervals.

Chloride deficits are generally mild and require specific treatment only under extraordinary circumstances (e.g., in liver disease or renal disease). Dilutional hyponatremia may occur in edematous patients; appropriate therapy is water restriction rather than administration of salt, except in rare instances when the hyponatremia is life-threatening. In actual salt depletion, appropriate replacement is the therapy of choice.

Calcium excretion is decreased by thiazides. In a few patients on prolonged thiazide therapy, pathological changes in the parathyroid gland have been observed, with hypercalcemia and hypophosphatemia. More serious complications of hyperparathyroidism (renal lithiasis, bone resorption, and peptic ulceration) have not been seen.

Thiazides increase the urinary excretion of magnesium, and hypomagnesemia may result.

Other Metabolic Disturbances:

Thiazide diuretics tend to reduce glucose tolerance and to raise serum levels of cholesterol, triglycerides and uric acid. These effects are usually minor, but frank gout may be precipitated or overt diabetes in susceptible patients.

Cough:

Presumably due to the inhibition of the degradation of endogenous bradykinin, persistent nonreproductive cough has been reported with all ACE inhibitors, always resolving after discontinuation of therapy. ACE inhibitor-induced cough should be considered in the differential diagnosis of cough.

Surgery/Anesthesia:

In patients undergoing surgery or during anesthesia with agents that produce hypotension, fosinopril 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.

Information for patients

Angioedema: Angioedema, including laryngeal edema, can occur with treatment with ACE inhibitors, especially following the first dose. A patient receiving fosinopril sodium and hydrochlorothiazide tablets should be told to report immediately any signs or symptoms suggesting angioedema (swelling of face, eyes, lips, or tongue, or difficulty in breathing) and to take no more drug until after consulting with the prescribing physician.

Pregnancy: Female patients of childbearing age should be told about the consequences of exposure to fosinopril and hydrochlorothiazide during pregnancy. Discuss treatment options with women planning to become pregnant. Patients should be asked to report pregnancies to their physicians as soon as possible.

Symptomatic Hypotension: A patient receiving fosinopril sodium and hydrochlorothiazide tablets should be cautioned that lightheadedness can occur, especially during the first days of therapy, and that it should be reported to the prescribing physician. The patients should be told that if syncope occurs, fosinopril sodium and hydrochlorothiazide tablets should be discontinued until the physician has been consulted.

All patients should be cautioned that inadequate fluid intake, excessive perspiration, diarrhea, or vomiting can lead to an excessive fall in blood pressure, with the same consequences of lightheadedness and possible syncope.

Hyperkalemia: A patient receiving fosinopril sodium and hydrochlorothiazide tablets should be told not to use potassium supplements or salt substitutes containing potassium without consulting the prescribing physician.

Neutropenia: Patients should be told to promptly report any indication of infection (e.g., sore throat, fever), which could be a sign of neutropenia.

Non-melanoma Skin Cancer: Instruct patients taking hydrochlorothiazide to protect skin from the sun and undergo regular skin cancer screening.

Laboratory tests

Therapy with fosinopril sodium and hydrochlorothiazide tablets should be interrupted for a few days before carrying out tests of parathyroid function.

Fosinopril may cause false low measurement of serum digoxin levels when the DIGI-TAB® (Nuclear Medical) RIA Kit is used. The accuracy of the COAT-A-COUNT® (Diagnostic Products Corporation) kit is not affected.

Drug interactions

Potassium supplements and potassium-sparing Diuretics: As noted above ("Derangements of Serum Electrolytes"), the net effect of fosinopril sodium and hydrochlorothiazide tablets may be to elevate a patient's serum potassium, to reduce it, or to leave it unchanged. 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, they should be given with caution, and 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. Because renal clearance of lithium is reduced by thiazides, the risk of lithium toxicity is presumably raised further when, as in therapy with fosinopril sodium and hydrochlorothiazide tablets, a thiazide diuretic is coadministered with the ACE inhibitor. Fosinopril sodium and hydrochlorothiazide tablets and lithium should be coadministered with caution, and frequent monitoring of serum lithium levels is recommended.

Antacids: In a clinical pharmacology study, serum levels and urinary excretion of fosinoprilat were reduced when fosinopril was coadministered with an antacid (aluminum hydroxide, magnesium hydroxide, and simethicone) suggesting that antacids may impair absorption of fosinopril. If concomitant administration of these agents is indicated, dosing should be separated by 2 hours.

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 including fosinopril sodium and hydrochlorothiazide tablets.

Other: The bioavailability of unbound fosinoprilat is not altered by coadministration of fosinopril with aspirin, chlorthalidone, cimetidine, digoxin, metoclopramide, nifedipine, propranolol, propantheline, or warfarin. Other ACE inhibitors have had less than additive effects with betaadrenergic blockers, presumably because drugs of both classes lower blood pressure by inhibiting parts of the renin-angiotensin system.

Interaction studies with warfarin have failed to identify any clinically important effects of fosinopril on the serum concentration or clinical effects of the anticoagulant.

Insulin requirements in diabetic patients may be increased, decreased, or unchanged.

Thiazides may decrease arterial responsiveness to norepinephrine, but not enough to preclude effectiveness of the pressor agent for therapeutic use.

Thiazides may increase the responsiveness to tubocurarine.

The diuretic, natriuretic, and antihypertensive effects of thiazide diuretics may be reduced by concurrent administration of nonsteroidal anti-inflammatory agents; the effects (if any) of these agents on the antihypertensive effect of fosinopril sodium and hydrochlorothiazide tablets have not been studied.

By alkalinizing the urine, hydrochlorothiazide may decrease the effectiveness of methenamine.

Cholestyramine and Colestipol Resins: Absorption of hydrochlorothiazide is impaired in the presence of anionic exchange resins. Single doses of either cholestyramine or colestipol resins bind the hydrochlorothiazide and reduce its absorption from the gastrointestinal tract by up to 85% and 43%, respectively.

Dual Blockade of Renin-Angiotensin System (RAS)

Dual blockade of the RAS with angiotensin receptor blockers, ACE inhibitors, or aliskiren is associated with increased risks of hypotension, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy. Closely monitor blood pressure, renal function and electrolytes in patients on fosinopril and hydrochlorothiazide and other agents that affect the RAS.

Do not co-administer aliskiren with fosinopril and hydrochlorothiazide in patients with diabetes. Avoid use of aliskiren with fosinopril and hydrochlorothiazide in patients with renal impairment (GFR <60 mL/min).

Carcinogenesis, Mutagenesis, Impairment of Fertility

Fosinopril-Hydrochlorothiazide:

Reproductive studies and long-term carcinogenicity studies with fosinopril sodium and hydrochlorothiazide tablets have not been conducted. The combination of fosinopril and hydrochlorothiazide was not mutagenic in the Ames microbial mutagen test, the mouse lymphoma forward mutation assay, or the Chinese hamster ovary cell cytogenetic assay. The combination was also not genotoxic in a mouse micronucleus test in vivo.

Fosinopril Sodium:

No evidence of a carcinogenicity was found when fosinopril was given in the diet to rats and mice for up to 24 months at doses up to 400 mg/kg/day. On a body weight basis, the highest dose was about 250 times the maximum human dose of 80 mg, given to a 50 kg subject. On a body surface area basis, this dose is 20 (mice) to 40 (rats) times the maximum human dose.

Neither fosinopril nor the fosinoprilat moiety was mutagenic in the Ames microbial mutagen test, the mouse lymphoma forward mutation assay, or a mitotic gene conversion assay. Fosinopril was also not genotoxic in a mouse micronucleus test in vivo and a mouse bone marrow cytogenetic assay in vivo.

In Chinese hamster ovary cell cytogenetic assay, fosinopril increased the frequency of chromosomal aberrations when tested without metabolic activation at a concentration that was toxic to the cells. However, there was no increase in chromosomal aberrations at lower drug concentrations without metabolic activation or at any concentration with metabolic activation.

There were no adverse reproductive effects in male and female rats treated with up to 60 mg/kg daily. At doses 4 times higher, slight increases in pairing time were seen. This higher dose is about 125 (body surface area basis) or 600 (body weight basis) times greater than the dose received by a 50 kg human receiving 20 mg a day.

Hydrochlorothiazide:

Under the auspices of the National Toxicology Program, rats and mice received hydrochlorothiazide for two years at doses up to 100 (rats) and 600 (mice) mg/kg/day. On a body weight basis, these highest doses were about 2400 times (mice) or 400 times (rats) the fosinopril sodium and hydrochlorothiazide tablet dose of 12.5 mg, given to a 50 kg subject. On a body surface area basis, these doses are 226 times (mice) and 82 times (rats) the fosinopril sodium and hydrochlorothiazide tablet dose. These studies uncovered no evidence of carcinogenicity in rats or female mice, but there was equivocal evidence of hepatocarcinogenicity in male mice.

Hydrochlorothiazide was not genotoxic in in vitro assays using strains TA 98, TA 100, TA 1535, TA 1537, and TA 1538 of Salmonella typhimurium (Ames assay); in the Chinese Hamster Ovary (CHO) test for chromosomal aberrations; or in in vivo assays using mouse germinal cell chromosomes; Chinese Hamster bone-marrow chromosomes, and the Drosophila sex-linked recessive lethal trait gene. Using concentrations of hydrochlorothiazide of 43 to 1300 mg/mL, positive test results were obtained in the in vitro CHO Sister Chromatid Exchange (clastogenicity) test and in the Mouse Lymphoma Cell (mutagenicity) assays. Using an unspecified concentration of hydrochlorothiazide, positive test results were also obtained in the Aspergillus nidulans nondisjunction assay.

No adverse effects upon fertility were seen when rats and mice received dietary hydrochlorothiazide prior to mating and throughout gestation at doses up to 4 (rats) and 100 (mice) mg/kg/day. These doses are from 3.2 (body surface area basis in rats) to 400 (weight basis in mice) times greater than the dose received by a 50 kg human receiving 12.5 mg a day.

Nursing mothers

Both fosinopril and hydrochlorothiazide are excreted in human milk. Because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue fosinopril sodium and hydrochlorothiazide tablets, taking into account the importance of the drug to the mother.

Geriatric use

Clinical studies of fosinopril sodium-hydrochlorothiazide did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Pediatric use

Neonates with a history of in utero exposure to fosinopril and hydrochlorothiazide:

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. Removal of fosinopril and hydrochlorothiazide, which crosses the placenta, from the neonatal circulation is not significantly accelerated by these means.

Safety and effectiveness in pediatric patients have not been established.

Other Adverse Events Reported with ACE Inhibitors

Other adverse effects reported with ACE inhibitors include cardiac arrest; pancytopenia, hemolytic anemia; aplastic anemia; thrombocytopenia; bullous pemphigus, exfoliative dermatitis; and a syndrome that may include one or more of arthralgia/arthritis, vasculitis, serositis, myalgia, fever, rash or other dermopathy, positive ANA titer, leukocytosis, eosinophilia, and elevated ESR.

Hydrochlorothiazide has now been extensively prescribed for many years, but there has not been enough systematic collection of data to support an estimate of the frequency of the observed adverse reactions. Within organ-system groups, the reported reactions are listed here in decreasing order of severity, without regard to frequency.

Cardiovascular: Orthostatic hypotension (may be potentiated by alcohol, barbiturates, or narcotics).

Gastrointestinal: Pancreatitis, jaundice (intrahepatic cholestatic), sialadenitis, vomiting, diarrhea, cramping, nausea, gastric irritation, constipation, and anorexia.

Hematologic: Aplastic anemia, agranulocytosis, leukopenia, thrombocytopenia, and hemolytic anemia.

Immunologic: Necrotizing angiitis, Stevens-Johnson syndrome, respiratory distress (including pneumonitis and pulmonary edema), anaphylactic reactions, purpura, urticaria, rash, and photosensitivity.

Metabolic: Hyperglycemia, glycosuria, and hyperuricemia.

Musculoskeletal: Muscle spasm.

Neurologic: Vertigo, lightheadedness, transient blurred vision, headache, paresthesia, xanthopsia, weakness, and restlessness.

Non-melanoma Skin Cancer

Hydrochlorothiazide is associated with an increased risk of non-melanoma skin cancer. In a study conducted in the Sentinel System, increased risk was predominantly for squamous cell carcinoma (SCC) and in white patients taking large cumulative doses. The increased risk for SCC in the overall population was approximately 1 additional case per 16,000 patients per year, and for white patients taking a cumulative dose of ≥50,000 mg the risk increase was approximately 1 additional SCC case for every 6,700 patients per year.