Fosinopril Sodium and Hydrochlorothiazide

INDICATIONS AND USAGE Fosinopril sodium and hydrochlorothiazide tablets are indicated for the treatment of hypertension. These fixed dose combinations are not indicated for initial therapy. (See DOSAGE AND ADMINISTRATION ) In using fosinopril sodium and hydrochlorothiazide tablets, consideration should be given to the fact that another angiotensin-converting enzyme inhibitor, captopril, has caused agranulocytosis, particularly in patients with renal impairment or collagen-vascular disease. Available data are insufficient to show that fosinopril does not have a similar risk (see WARNINGS: Neutropenia/Agranulocytosis ). ACE inhibitors (for which adequate data are available) cause a higher rate of angioedema in black than in non-black patients (see WARNINGS : Head and Neck Angioedema and Intestinal Angioedema ).

DOSAGE AND ADMINISTRATION Fosinopril is an effective treatment of hypertension in once-daily doses of 10 to 80 mg, while hydrochlorothiazide is effective in doses of 12.5 to 50 mg per day. In clinical trials of fosinopril/hydrochlorothiazide combination therapy using fosinopril doses of 2.5 to 40 mg and hydrochlorothiazide doses at 5 to 37.5 mg, the antihypertensive effects increased with increasing dose of either component. The hazards (see WARNINGS ) of fosinopril are generally rare and apparently independent of dose; those of hydrochlorothiazide are a mixture of dose-dependent phenomena (primarily hypokalemia) and dose-independent phenomena (e.g., pancreatitis), the former much more common than the latter. Therapy with any combination of fosinopril and hydrochlorothiazide will be associated with both sets of dose-independent hazards. To minimize dose-independent hazards, it is usually appropriate to begin combination therapy only after a patient has failed to achieve the desired effect with monotherapy. Dose Titration by Clinical Effect A patient whose blood pressure is not adequately controlled with fosinopril or hydrochlorothiazide monotherapy may be switched to combination therapy with fosinopril sodium and hydrochlorothiazide tablets. Dosage must be guided by clinical response; controlled clinical trials showed that the addition of 12.5 mg of hydrochlorothiazide to 10 to 20 mg of fosinopril will typically be associated with additional reduction in seated diastolic blood pressure at 24 hours after dosing. On average, the effect of the combination of 10 mg of fosinopril with 12.5 mg of hydrochlorothiazide was similar to the effect seen with monotherapy using either 40 mg of fosinopril or 37.5 mg of hydrochlorothiazide. Use in Renal Impairment In patients with severe renal impairment (creatinine clearance is <30 mL/min/1.73 m 2 , serum creatine roughly ≥3 mg/dL or 265 μmol/L), loop diuretics are preferred to thiazides, so fosinopril sodium and hydrochlorothiazide tablets are not recommended. In patients with lesser degrees of renal impairment, fosinopril sodium and hydrochlorothiazide tablets may be used with no change in dosage.

CONTRAINDICATIONS Fosinopril sodium and hydrochlorothiazide tablets are contraindicated in patients who are anuric. Fosinopril sodium and hydrochlorothiazide tablets are also contraindicated in patients who are hypersensitive to fosinopril, to any other ACE inhibitor, to hydrochlorothiazide, or other sulfonamide-derived drugs, or any other ingredient or component in the formulation. Hypersensitivity reactions are more likely to occur in patients with a history of allergy or bronchial asthma.

ADVERSE REACTIONS Fosinopril sodium and hydrochlorothiazide tablets have been evaluated for safety in over 660 patients with hypertension; approximately 137 of these patients were treated for more than one year. The observed adverse events were generally mild, transient, and similar to those seen with fosinopril and hydrochlorothiazide taken separately. There was no relationship between the incidence of side effects and age. In placebo-controlled clinical trials of fosinopril sodium and hydrochlorothiazide, the usual duration of therapy was two months. Adverse clinical or laboratory events led to discontinuation of therapy by 4.3% of 368 placebo-treated patients and by 3.5% of 660 fosinopril sodium and hydrochlorothiazide-treated patients. The most common reasons for discontinuation of therapy with fosinopril sodium and hydrochlorothiazide in U.S. studies were headache (0.3%), cough (0.3%; see PRECAUTIONS ), and fatigue (0.2%). The side effects considered probably or possibly related to study drug that occurred in placebo-controlled trials in more than 2% of patients treated with fosinopril sodium and hydrochlorothiazide are shown in the table below. Reactions Possibly or Probably Drug-Related (Incidence in Placebo-Controlled Studies) Fosinopril Sodium and Hydrochlorothiazide (N=660) Placebo (N=368) % % Headache 7 12.8 Cough 5.6 1.1 Fatigue 3.9 2.4 Dizziness 3.2 2.2 Upper Respiratory Infection 2.3 2.7 Musculoskeletal Pain 2 1.9 Other side effects considered possibly or probably related to study drug that occurred in controlled trials in 0.5% to <2% of patients treated with fosinopril sodium and hydrochlorothiazide, and rarer but clinically significant events regardless of causal relationship were: General: Chest pain, weakness, fever, viral infection. Cardiovascular: Orthostatic hypotension (seen in 1.8% of fosinopril sodium and hydrochlorothiazide patients and 0.3% of placebo patients; no patients discontinued therapy due to orthostatic hypotension), edema, flushing, rhythm disturbance, syncope. Dermatologic: Pruritus, rash. Endocrine/Metabolic: Sexual dysfunction, change in libido, breast mass. Gastrointestinal: Nausea/vomiting, diarrhea, dyspepsia/heartburn, abdominal pain, gastritis/esophagitis. Immunologic: Angioedema (see WARNINGS: Head and Neck Angioedema and Intestinal Angioedema ). Musculoskeletal: Myalgia/muscle cramps. Neurologic/Psychiatric: Somnolence, depression, numbness/paresthesia. Respiratory: Sinus congestion, pharyngitis, rhinitis. Special Senses: Tinnitus. Urogenital: Urinary tract infection, urinary frequency, dysuria. Laboratory Test Abnormalities: Serum electrolytes, uric acid, glucose, magnesium, cholesterol, triglycerides, and calcium (see PRECAUTIONS ). Neutropenia. Antihypertensive monotherapy with fosinopril has been evaluated for safety in more than 1500 patients, of whom approximately 450 patients were treated for a year or more. The observed adverse events included events similar to those seen with fosinopril sodium and hydrochlorothiazide; in addition, the following others have also been reported with fosinopril: Cardiovascular: Angina, myocardial infarction, cerebrovascular accident, hypertensive crisis, hypotension, claudication. Dermatologic: Urticaria, photosensitivity. Endocrine/Metabolic: Gout. Gastrointestinal: Pancreatitis, hepatitis, dysphagia, abdominal distention, flatulence, appetite/weight change, dry mouth. Hematologic: Lymphadenopathy. Musculoskeletal: Arthralgia. Neurologic/Psychiatric: Memory disturbance, tremor, confusion, mood change, sleep disturbance. Respiratory: Bronchospasm, laryngitis/hoarseness, epistaxis, and (in two patients) a symptom-complex of cough, bronchospasm, and eosinophilia. Special Senses: Vision disturbance, taste disturbance, eye irritation. Urogenital: Renal insufficiency. Laboratory Test Abnormalities: Elevations (usually transient and minor) of BUN and creatinine have been observed, but these have not been more frequent than in parallel patients treat …

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 f …

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.

DESCRIPTION Fosinopril sodium, USP is a white to almost white powder, soluble (>100 mg/mL) in water, in ethanol, and in methanol, and slightly soluble in hexane. Fosinopril sodium is designated chemically as L-proline, 4-cyclohexyl-1-[[[2-methyl-1-(1-oxopropoxy)propoxy](4-phenylbutyl)phosphinyl]acetyl]-, sodium salt, trans- ; its structural formula is: Its molecular formula is C 30 H 45 NNaO 7 P, and its molecular weight is 585.65. Fosinoprilat, the active metabolite of fosinopril, is a non-sulfhydryl angiotensin-converting enzyme inhibitor. Fosinopril is converted to fosinoprilat by hepatic cleavage of the ester group. Hydrochlorothiazide, USP is a white or practically white, practically odorless, crystalline powder. It is slightly soluble in water; freely soluble in sodium hydroxide solution, in n-butylamine, and in dimethylformamide; sparingly soluble in methanol; and insoluble in ether, in chloroform, and in dilute mineral acids. Hydrochlorothiazide is designated chemically as 6-chloro-3,4-dihydro-2 H -1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide; its structural formula is: Its molecular formula is C 7 H 8 ClN 3 O 4 S 2 , and its molecular weight is 297.73. Hydrochlorothiazide is a thiazide diuretic. Fosinopril sodium and hydrochlorothiazide tablets, USP are a combination of fosinopril sodium, USP and hydrochlorothiazide, USP. They are available for oral use in two tablet strengths: fosinopril sodium and hydrochlorothiazide tablets, USP 10 mg/12.5 mg, containing 10 mg of fosinopril sodium, USP and 12.5 mg of hydrochlorothiazide, USP; and fosinopril sodium and hydrochlorothiazide tablets, USP 20 mg/12.5 mg, containing 20 mg of fosinopril sodium, USP and 12.5 mg of hydrochlorothiazide, USP. The inactive ingredients of the tablets include lactose anhydrous, ferric oxide red, ferric oxide yellow, croscarmellose sodium, povidone, isopropyl alcohol, glyceryl distearate, and sodium lauryl sulfate. Fosinopril Sodium Chemical Structure Hydrochlorothiazide Chemical Structure

OVERDOSAGE To obtain up-to-date information about the treatment of overdose, a good resource is a certified Regional Poison Control Center. Telephone numbers of certified poison control centers are listed in the Physicians' Desk Reference(PDR). In managing overdose, consider the possibilities of multiple-drug overdoses, drug-drug interactions, and unusual drug kinetics in your patient. No specific information is available on the treatment of overdosage with fosinopril sodium and hydrochlorothiazide tablets; treatment should be symptomatic and supportive. Therapy with fosinopril sodium and hydrochlorothiazide tablets should be discontinued, and the patient should be observed. Dehydration, electrolyte imbalance, and hypotension should be treated by established procedures. In rats, single oral doses of 2600 mg/kg of fosinopril were associated with significant lethality. In single-dose studies of hydrochlorothiazide, most rats survived doses of up to 2750 mg/kg. Both doses are more than 6000 times (on a mg/kg basis) the maximum recommended daily dose of either fosinopril or hydrochlorothiazide in fosinopril sodium and hydrochlorothiazide tablets. Data from human overdoses of fosinopril are scanty, but the most common manifestation of human fosinopril overdosage is likely to be hypotension. In human hydrochlorothiazide overdose, the most common signs and symptoms observed have been those of dehydration and electrolyte depletion (hypokalemia, hypochloremia, hyponatremia). If digitalis has also been administered, hypokalemia may accentuate cardiac arrhythmias. Laboratory determinations of serum levels of fosinopril and its metabolites are not widely available, and such determinations have, in any event, no established role in the management of fosinopril overdose. No data are available to suggest physiological maneuvers (e.g., maneuvers to change the pH of the urine) that might accelerate elimination of fosinopril and its metabolites. Fosinoprilat is poorly removed from the body by hemodialysis or peritoneal dialysis. Angiotensin II could presumably serve as a specific antagonist-antidote in the setting of fosinopril overdose, but angiotensin II is essentially unavailable outside of scattered research facilities. Because the hypotensive effect of fosinopril is achieved through vasodilation and effective hypovolemia, it is reasonable to treat fosinopril overdose by infusion of normal saline solution.

HOW SUPPLIED Fosinopril Sodium and Hydrochlorothiazide Tablets USP, 10 mg/12.5 mg are peach colored, round biconvex, uncoated tablets debossed with ‘C 84’ on one side and plain on the other side. Bottle of 30 NDC 65862-308-30 Bottle of 100 NDC 65862-308-01 Bottle of 1,000 NDC 65862-308-99 Fosinopril Sodium and Hydrochlorothiazide Tablets USP, 20 mg/12.5 mg are peach colored, round biconvex, uncoated tablets debossed with ‘C 85’ on one side and “deep score line” on the other side. Bottle of 30 NDC 65862-309-30 Bottle of 100 NDC 65862-309-01 Bottle of 1,000 NDC 65862-309-99 Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Protect from moisture by keeping bottle tightly closed. Distributed by: Aurobindo Pharma USA, Inc. 279 Princeton-Hightstown Road East Windsor, NJ 08520 Manufactured by: Aurobindo Pharma Limited Hyderabad-500 032, India Revised: 01/2022