Fosinopril Sodium

INDICATIONS AND USAGE Fosinopril sodium tablets are indicated for the treatment of hypertension. They may be used alone or in combination with thiazide diuretics. Fosinopril sodium tablets are indicated in the management of heart failure as adjunctive therapy when added to conventional therapy including diuretics with or without digitalis (see DOSAGE AND ADMINISTRATION ) . In using fosinopril sodium 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 sodium tablets do not have a similar risk (see WARNINGS ). In considering use of fosinopril sodium tablets, it should be noted that in controlled trials ACE inhibitors have an effect on blood pressure that is less in black patients than in non-blacks. In addition, ACE inhibitors (for which adequate data are available) cause a higher rate of angioedema in black than in non-black patients (see WARNINGS, Anaphylactoid and Possible Related Reactions, Head and Neck Angioedema and Intestinal Angioedema) .

DOSAGE AND ADMINISTRATION Hypertension Adults The recommended initial dose of fosinopril sodium tablets USP is 10 mg once a day, both as monotherapy and when the drug is added to a diuretic. Dosage should then be adjusted according to blood pressure response at peak (2 to 6 hours) and trough (about 24 hours after dosing) blood levels. The usual dosage range needed to maintain a response at trough is 20 to 40 mg but some patients appear to have a further response to 80 mg. In some patients treated with once daily dosing, the antihypertensive effect may diminish toward the end of the dosing interval. If trough response is inadequate, dividing the daily dose should be considered. If blood pressure is not adequately controlled with fosinopril sodium tablets USP alone, a diuretic may be added. Concomitant administration of fosinopril sodium tablets USP with potassium supplements, potassium salt substitutes, or potassium-sparing diuretics can lead to increases of serum potassium (see PRECAUTIONS ). In patients who are currently being treated with a diuretic, symptomatic hypotension occasionally can occur following the initial dose of fosinopril sodium tablets USP. To reduce the likelihood of hypotension, the diuretic should, if possible, be discontinued 2 to 3 days prior to beginning therapy with fosinopril sodium tablets USP (see WARNINGS ). Then, if blood pressure is not controlled with fosinopril sodium tablets USP alone, diuretic therapy should be resumed. If diuretic therapy cannot be discontinued, an initial dose of 10 mg of fosinopril sodium tablets USP should be used with careful medical supervision for several hours and until blood pressure has stabilized (see WARNINGS and PRECAUTIONS , Information for Patients and Drug Interactions ). Since concomitant administration of fosinopril sodium tablets USP with potassium supplements, or potassium-containing salt substitutes or potassium-sparing diuretics may lead to increases in serum potassium, they should be used with caution (see PRECAUTIONS ). Pediatrics In children, doses of fosinopril sodium tablets between 0.1 and 0.6 mg/kg have been studied and shown to reduce blood pressure to a similar extent (see CLINICAL PHARMACOLOGY , Pharmacodynamics and Clinical Effects ). Based on this, the recommended dose of fosinopril sodium tablets USP in children weighing more than 50 kg is 5 to 10 mg once per day as monotherapy. An appropriate dosage strength is not available for children weighing less than 50 kg. Heart Failure Digitalis is not required for fosinopril sodium tablets USP to manifest improvements in exercise tolerance and symptoms. Most placebo-controlled clinical trial experience has been with both digitalis and diuretics present as background therapy. The usual starting dose of fosinopril sodium tablets USP should be 10 mg once daily. Following the initial dose of fosinopril sodium tablets USP, the patient should be observed under medical supervision for at least 2 hours for the presence of hypotension or orthostasis, and if present, until blood pressure stabilizes. An initial dose of 5 mg is preferred in heart failure patients with moderate to severe renal failure or those who have been vigorously diuresed. Dosage should be increased, over a several week period, to a dose that is maximal and tolerated but not exceeding 40 mg once daily. The usual effective dosage range is 20 to 40 mg once daily. The appearance of hypotension, orthostasis, or azotemia early in dose titration should not preclude further careful dose titration. Consideration should be given to reducing the dose of concomitant diuretic. For Hypertensive or Heart Failure Patients With Renal Impairment In patients with impaired renal function, the total body clearance of fosinoprilat is approximately 50% slower than in patients with normal renal function. Since hepatobiliary elimination partially compensates for diminished renal elimination, the total body clearance of fosinoprilat does not differ appreciably wit …

CONTRAINDICATIONS Fosinopril sodium tablets are contraindicated in patients who are hypersensitive to this product or to any other angiotensin converting enzyme inhibitor (e.g., a patient who has experienced angioedema with any other ACE inhibitor therapy). Do not co-administer fosinopril sodium tablets with aliskiren in patients with diabetes.

ADVERSE REACTIONS Fosinopril sodium has been evaluated for safety in more than 2,100 individuals in hypertension and heart failure trials, including approximately 530 patients treated for a year or more. Generally, adverse events were mild and transient, and their frequency was not prominently related to dose within the recommended daily dosage range. Hypertension In placebo-controlled clinical trials (688 fosinopril sodium-treated patients), the usual duration of therapy was two to three months. Discontinuations due to any clinical or laboratory adverse event were 4.1% and 1.1% in fosinopril sodium-treated and placebo-treated patients, respectively. The most frequent reasons (0.4% to 0.9%) were headache, elevated transaminases, fatigue, cough (see PRECAUTIONS, General, Cough ), diarrhea, and nausea and vomiting. During clinical trials with any fosinopril sodium regimen, the incidence of adverse events in the elderly (≥65 years old) was similar to that seen in younger patients. Clinical adverse events probably or possibly related or of uncertain relationship to therapy, occurring in at least 1% of patients treated with fosinopril sodium alone and at least as frequent on fosinopril sodium as on placebo in placebo-controlled clinical trials are shown in the table below. Clinical Adverse events In Placebo-Controlled Trials (Hypertension) Fosinopril Sodium (N=688) Incidence (Discontinuation) Placebo (N=184) Incidence (Discontinuation) Cough 2.2 (0.4) 0.0 (0.0) Dizziness 1.6 (0.0) 0.0 (0.0) Nausea/Vomiting 1.2 (0.4) 0.5 (0.0) The following events were also seen at >1% on fosinopril sodium tablets but occurred in the placebo group at a greater rate: headache, diarrhea, fatigue, and sexual dysfunction. Other clinical events probably or possibly related, or of uncertain relationship to therapy occurring in 0.2% to 1.0% of patients (except as noted) treated with fosinopril sodium in controlled or uncontrolled clinical trials (N; 1 ,479) and less frequent, clinically significant events include (listed by body system): General : Chest pain, edema, weakness, excessive sweating. Cardiovascular : Angina/myocardial infarction, cerebrovascular accident, hypertensive crisis, rhythm disturbances, palpitations, hypotension, syncope, flushing, claudication. Orthostatic : hypotension occurred in 1.4% of patients treated with fosinopril monotherapy. Hypotension or orthostatic hypotension was a cause for discontinuation of therapy in 0.1% of patients. Dermatologic : Urticaria, rash, photosensitivity, pruritus. Endocrine/Metabolic: Gout, decreased libido. Gastrointestinal: Pancreatitis, hepatitis, dysphagia, abdominal distention, abdominal pain, flatulence, constipation, heartburn, appetite/weight change, dry mouth. Hematologic: Lymphadenopathy. Immunologic: Angioedema. (See WARNINGS, Anaphylactoid and Possible Related Reactions, Head and Neck Angioedema and Intestinal Angioedema) . Musculoskeletal : Arthralgia, musculoskeletal pain, myalgia/muscle cramp. Nervous/Psychiatric: Memory disturbance, tremor, confusion, mood change, paresthesia, sleep disturbance, drowsiness, vertigo. Respiratory: Bronchospasm, pharyngitis, sinusitis/rhinitis, laryngitis/hoarseness, epistaxis. A symptom-complex of cough, bronchospasm, and eosinophilia has been observed in two patients treated with fosinopril. Special Senses: Tinnitus, vision disturbance, taste disturbance, eye irritation. Urogenita l: Renal insufficiency, urinary frequency. Heart Failure In placebo-controlled clinical trials (361 fosinopril sodium-treated patients), the usual duration of therapy was 3 to 6 months. Discontinuations due to any clinical or laboratory adverse event, except for heart failure, were 8.0% and 7.5% in fosinopril sodium-treated and placebo-treated patients, respectively. The most frequent reason for discontinuation of fosinopril sodium was angina pectoris (1.1 %). Significant hypotension after the first dose of fosinopril sodium occurred in 14/590 (2.4%) of patients; 5/590 (0.8%) pa …

Drug Interactions Diuretics Patients on diuretics, especially those with intravascular volume depletion, may occasionally experience an excessive reduction of blood pressure after initiation of therapy with fosinopril sodium tablets. The possibility of hypotensive effects with fosinopril sodium can be minimized by either discontinuing the diuretic or increasing salt intake prior to initiation of treatment with fosinopril sodium. If this is not possible, the starting dose should be reduced and the patient should be observed closely for several hours following an initial dose and until blood pressure has stabilized (see DOSAGE AND ADMINISTRATION ). Agents increasing serum potassium Coadministration of fosinopril with potassium sparing diuretics, potassium supplements, potassium-containing salt substitutes or other drugs that raise serum potassium levels may result in hyperkalemia. Monitor serum potassium in such patients. Lithium Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving ACE inhibitors during therapy with lithium. These drugs should be coadministered with caution, and frequent monitoring of serum lithium levels is recommended. If a diuretic is also used, the risk of lithium toxicity may be increased. Antacids In a clinical pharmacology study, coadministration of an antacid (aluminum hydroxide, magnesium hydroxide, and simethicone) with fosinopril reduced serum levels and urinary excretion of fosinoprilat as compared with fosinopril administrated alone, suggesting that antacids may impair absorption of fosinopril. Therefore, 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. 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 fosinopril, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving quinapril and NSAID therapy. The antihypertensive effect of ACE inhibitors, including fosinopril may be attenuated by NSAIDs. Agents that inhibit mTOR Patients taking concomitant mTOR inhibitor (e.g. temsirolimus) therapy may be at increased risk for angioedema. Dual Blockade of the 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. Most patients receiving the combination of two RAS inhibitors do not obtain any additional benefit compared to monotherapy. In general, avoid combined use of RAS inhibitors. Closely monitor blood pressure, renal function and electrolytes in patients on fosinopril and other agents that affect the RAS. Do not co-administer aliskiren with fosinopril in patients with diabetes. Avoid concomitant use of aliskiren with fosinopril in patients with renal impairment (GFR<60 mL/min/1.73 m 2 ). Other Neither fosinopril sodium nor its metabolites have been found to interact with food. In separate single or multiple dose pharmacokinetic interaction studies with chlorthalidone, nifedipine, propranolol, hydrochlorothiazide, cimetidine, metoclopramide, propantheline, digoxin, and warfarin, the bioavailability of fosinoprilat was not altered by coadministration of fosinopril with any one of these drugs. In a study with concomitant administration of aspirin and f …

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.

DESCRIPTION Fosinopril sodium is 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 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: C 30 H 45 NNaO 7 P M.W. 585.65 Fosinopril sodium, USP, is available for oral administration as 10 mg, 20 mg, and 40 mg tablets. Inactive ingredients include: crospovidone, lactose monohydrate, microcrystalline cellulose, povidone, and sodium stearyl fumarate. D:\FOSINOPRIL SODIUM\FOSINOPRILSODIUM-TEVA,2009\SPL-FOSINOPRILSODIUM07232012-TEVA,2009\6213b69f-39e1-4f48-a110-a83bd5459c4a-01.jpg

OVERDOSAGE Oral doses of fosinopril at 2600 mg/kg in rats were associated with significant lethality. Human overdoses of fosinopril have not been reported, but the most common manifestation of human fosinopril overdosage is likely to be hypotension. Laboratory determinations of serum levels of fosinoprilat 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 both hemodialysis and 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. No adverse clinical events were reported in 23 pediatric patients, age 6 months to 6 years, given a single 0.3 mg/kg oral dose of fosinopril sodium. There is a published report of a 20-month-old female, weighing 12 kg, who ingested approximately 200 mg fosinopril sodium. After receiving gastric lavage and activated charcoal within one hour of the ingestion, she made an uneventful recovery.

HOW SUPPLIED Fosinopril Sodium Tablets USP, 10 mg are white to off-white, flat, capsule shaped, uncoated tablets with notched sides at double bisect and debossed with ‘X’ and ‘77’ on either side of the score line on one side and plain on the other side. Bottles of 30 NDC 65862-471-30 Bottles of 90 NDC 65862-471-90 Bottles of 1,000 NDC 65862-471-99 Fosinopril Sodium Tablets USP, 20 mg are white to off-white, round, biconvex, uncoated tablets debossed with ‘X’ on one side and ‘84’ on the other side. Bottles of 30 NDC 65862-472-30 Bottles of 90 NDC 65862-472-90 Bottles of 1,000 NDC 65862-472-99 Fosinopril Sodium Tablets USP, 40 mg are white to off-white, round, biconvex, uncoated tablets debossed with ‘X’ on one side and ‘69’ on the other side. Bottles of 30 NDC 65862-473-30 Bottles of 90 NDC 65862-473-90 Bottles of 1,000 NDC 65862-473-99 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-500 038, India Revised: 07/2019