Fosinopril
fosinopril sodium — formerly marketed as Monopril
Indications
| Indication | Approved Population | Therapy Type | Status |
|---|---|---|---|
| Hypertension | Adults; children ≥6 years (>50 kg) | Monotherapy or combination (especially with thiazides) | FDA Approved |
| Heart failure | Adults | Adjunctive with diuretics ± digitalis | FDA Approved |
Fosinopril is the only phosphinate-containing ACE inhibitor, distinguished by its balanced dual renal-hepatobiliary elimination pathway. This pharmacokinetic property means no dose adjustment is needed for any degree of renal impairment, making fosinopril uniquely suited among ACE inhibitors for patients with CKD or fluctuating renal function. The FEST trial (1995) demonstrated that fosinopril improved exercise tolerance and reduced hospitalizations for worsening heart failure.
Acute myocardial infarction — Early fosinopril post-MI may prevent LV remodelling (FAMIS trial). Evidence: Moderate
Diabetic nephropathy — ACE inhibitors reduce proteinuria and slow CKD progression; fosinopril’s renal-sparing PK is advantageous. Evidence: High (class level)
Dosing
Adult Dosing by Clinical Scenario
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| Hypertension — monotherapy or added to diuretic | 10 mg PO once daily | 20–40 mg/day | 80 mg/day | Onset ~1 h; peak BP reduction 2–6 h; effect persists 24 h If trough effect wanes, divide dose or add diuretic (FDA PI) |
| Hypertension — currently on a diuretic | 10 mg PO once daily | 20–40 mg/day | 80 mg/day | Discontinue diuretic 2–3 days before if possible; if not, use 10 mg with careful medical supervision (FDA PI) |
| Heart failure — standard initiation | 10 mg PO once daily | 20–40 mg once daily | 40 mg/day | Observe ≥2 h after first dose for hypotension Titrate over several weeks; concomitant diuretics ± digitalis (FDA PI) |
| Heart failure — moderate-to-severe renal failure or vigorously diuresed | 5 mg PO once daily | 20–40 mg once daily | 40 mg/day | Higher sensitivity to hemodynamic effects of ACE inhibition in this population |
Pediatric Dosing (Age ≥6 Years, >50 kg)
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| Hypertension — pediatric | 5–10 mg PO once daily | Titrate as needed | 40 mg/day | Dose range studied: 0.1–0.6 mg/kg Appropriate dosage form not available for <50 kg (FDA PI) |
Renal & Hepatic Impairment
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| Any degree of renal impairment (including ESRD) | No adjustment required | Standard | Standard | Hepatobiliary elimination compensates for reduced renal clearance; unique among ACE inhibitors (FDA PI) |
| Hepatic impairment (cirrhosis) | Standard; use with caution | Standard | Standard | Rate of hydrolysis may be slowed; clearance ~50% lower; no specific PI dose adjustment but monitor closely |
| Haemodialysis | Standard | Standard | Standard | Poorly dialysed: HD clears 2%, PD clears 7% of urea clearances; avoid high-flux membranes (anaphylactoid risk) |
Fosinopril is the only ACE inhibitor that requires no dose adjustment for renal impairment. Approximately 50% of fosinoprilat is eliminated renally and 50% hepatobiliary. When renal function declines, the liver compensates by increasing biliary excretion. In mild-to-severe renal insufficiency (CrCl 10–80 mL/min), total body clearance does not differ appreciably from normal. In ESRD (CrCl <10 mL/min), clearance is approximately halved, but the FDA PI still permits standard dosing because hepatobiliary compensation maintains clinically adequate drug elimination. This makes fosinopril a practical choice in patients with CKD, fluctuating renal function, or those at risk of acute kidney injury.
Pharmacology
Mechanism of Action
Fosinopril is a phosphinate-containing prodrug that is hydrolysed by hepatic and gut wall esterases to fosinoprilat, a potent competitive inhibitor of angiotensin-converting enzyme. Unlike most ACE inhibitors (which are carboxyl-containing), fosinopril’s phosphinate group confers distinct binding properties at the ACE active site. Inhibition of ACE prevents conversion of angiotensin I to angiotensin II, reducing vasopressor activity and aldosterone secretion while potentially increasing bradykinin. Serum ACE activity is inhibited by over 90% for 2–12 hours after single doses of 10–40 mg, with 85–93% suppression maintained at 24 hours. In heart failure, fosinopril reduces both preload and afterload, increasing cardiac index and stroke volume without tachyphylaxis. The antihypertensive effect is less pronounced in Black patients as monotherapy.
ADME Profile
| Parameter | Value | Clinical Implication |
|---|---|---|
| Absorption | Absolute bioavailability ~36%; Tmax ~3 h (fosinoprilat); dose-proportional PK; primary absorption in proximal small intestine | Food slows rate but not extent of absorption; can be taken with or without food; antacids reduce absorption (separate by 2 h) |
| Distribution | Protein binding ~99.4%; small Vd; negligible binding to cellular blood components; does not cross blood-brain barrier | Highly protein-bound; crosses placenta in animals |
| Metabolism | Esterase hydrolysis (liver/gut wall) to fosinoprilat (active, ~75% of plasma radioactivity); glucuronide conjugate (~20–30%); p-hydroxy metabolite (~1–5%) | No CYP involvement; hepatic impairment slows rate but not extent of hydrolysis; p-hydroxy metabolite retains ACE inhibitory activity |
| Elimination | ~50% renal, ~50% fecal (hepatobiliary); body clearance 26–39 mL/min; effective t½ 11.5 h (HTN), 14 h (HF) | Balanced dual elimination is unique among ACE inhibitors; hepatobiliary route compensates in renal failure, maintaining stable clearance; poorly dialysed (HD 2%, PD 7% of urea clearances) |
Side Effects
| Adverse Effect | Incidence (vs Placebo) | Clinical Note |
|---|---|---|
| Dizziness | 11.9% vs 5.4% | Most common adverse effect in HF trials; dose-related and more frequent during titration; DC rate 0.6% |
| Adverse Effect | Incidence — HTN (vs Placebo) | Incidence — HF (vs Placebo) | Clinical Note |
|---|---|---|---|
| Cough | 2.2% vs 0% | 9.7% vs 5.1% | Class effect; HTN DC rate 0.4%, HF DC rate 0.8%; resolves after stopping |
| Hypotension | — | 4.4% vs 0.8% | First-dose hypotension in 2.4% of HF patients (14/590); 0.8% DC; volume-depleted patients at highest risk |
| Nausea / vomiting | 1.2% vs 0.5% | 2.2% vs 1.6% | Generally mild and transient; HTN DC rate 0.4% |
| Dizziness (HTN) | 1.6% vs 0% | — | Lower incidence in hypertension vs HF trials |
| Musculoskeletal pain | — | 3.3% vs 2.7% | Reported in HF trials; minimal excess over placebo |
| Orthostatic hypotension | 1.4% | 1.9% vs 0.8% | DC rate 0.1% in HTN; advise rising slowly; risk increases with diuretics |
| Diarrhoea | — | 2.2% vs 1.3% | Reported in HF trials; mild and transient |
| Weakness | — | 1.4% vs 0.5% | HF trials only; DC rate 0.3%; may overlap with disease-related fatigue |
| Adverse Effect | Estimated Frequency | Typical Onset | Required Action |
|---|---|---|---|
| Angioedema | 0.2% (HF trials) | Any time; higher rate in Black patients | Discontinue immediately; secure airway; epinephrine if laryngeal involvement; never rechallenge |
| Hyperkalemia (>10% above ULN) | ~2.6% (HTN trials) | Days to weeks; risk with CKD, diabetes, K-sparing agents | Monitor K⁺ frequently; 0.1% DC rate; discontinue if persistent or severe |
| Hepatic failure / cholestatic jaundice | Rare | Variable | Discontinue ACE inhibitor; urgent hepatology referral; transaminase DC rate 0.7% |
| Acute renal failure | Rare | Days to weeks; bilateral RAS highest risk | Discontinue; IV volume resuscitation; evaluate for renovascular disease |
| Neutropenia / agranulocytosis | Rare (insufficient data) | Weeks to months; collagen vascular + renal impairment = highest risk | Monitor WBC in high-risk patients; discontinue if confirmed |
| Anaphylactoid reactions (dialysis) | Rare | During dialysis with high-flux membranes | Stop dialysis immediately; use different membrane type or different antihypertensive class |
| Fetal toxicity | Expected with 2nd/3rd trimester exposure | Second and third trimesters | Discontinue immediately when pregnancy detected; fetal monitoring |
Significant hypotension after the initial dose occurred in 2.4% of HF patients (14/590 in clinical trials), with 0.8% requiring discontinuation. Risk factors include vigorous diuresis, sodium or volume depletion, and renal impairment. All HF patients should be observed for at least 2 hours after the first dose and until blood pressure has stabilised. Consider reducing the concomitant diuretic dose in patients with normal or low blood pressure (FDA PI).
Drug Interactions
Fosinopril is activated by esterase hydrolysis, not CYP enzymes. The FDA PI confirms no PK interactions with chlorthalidone, nifedipine, propranolol, hydrochlorothiazide, cimetidine, metoclopramide, propantheline, digoxin, or warfarin. The unique antacid interaction is specific to fosinopril among ACE inhibitors.
Monitoring
- Blood PressureEach visit; closely after initiation
RoutineAssess peak (2–6 h) and trough (~24 h). Observe HF patients for ≥2 h after first dose. Monitor for first 2 weeks and after dose increases. - Renal FunctionBaseline, then periodically
RoutineBUN and creatinine. Despite no renal dose adjustment, monitor for RAAS-dependent renal impairment (bilateral RAS, severe HF, volume depletion). - Serum PotassiumPeriodically
RoutineHyperkalemia occurred in ~2.6% of HTN patients. Higher risk with renal impairment, diabetes, or K-sparing agents. - Hepatic FunctionIf symptoms develop
Trigger-based0.7% DC rate for transaminase elevations. Monitor for jaundice or hepatic enzyme rises. ACE inhibitors rarely cause fulminant hepatic necrosis. - WBC / DifferentialIf high-risk
Trigger-basedConsider in patients with collagen vascular disease and/or renal impairment. Insufficient data to exclude agranulocytosis risk. - Pregnancy StatusBefore starting and ongoing
RoutineConfirm negative pregnancy test in women of childbearing potential. Counsel on reliable contraception.
Contraindications & Cautions
Absolute Contraindications
- History of angioedema with or without previous ACE inhibitor treatment
- Hypersensitivity to fosinopril or any ACE inhibitor
- Pregnancy (discontinue immediately when detected)
- Concurrent aliskiren in patients with diabetes mellitus
- Concurrent neprilysin inhibitor (e.g., sacubitril/valsartan); 36-hour washout required
Relative Contraindications (Specialist Input Recommended)
- Bilateral renal artery stenosis or stenosis of a solitary kidney
- Collagen vascular disease with renal impairment — insufficient data to exclude agranulocytosis risk
- Haemodialysis with high-flux membranes — risk of anaphylactoid reactions; use different membrane type or antihypertensive class
Use with Caution
- Volume depletion or hyponatraemia — correct before starting; reduce diuretic dose if possible
- Hepatic impairment — clearance approximately halved; avoid in cirrhosis with ascites per AASLD
- Heart failure with SBP <100 mmHg — increased first-dose hypotension risk; start 5 mg with close monitoring
- Elderly patients — start at low end of dosing range; monitor renal function
- Nursing mothers — fosinoprilat detectable in breast milk; should not be administered (FDA PI)
When used during the second and third trimesters of pregnancy, ACE inhibitors can cause injury and death to the developing fetus. When pregnancy is detected, fosinopril should be discontinued as soon as possible. Exposure is associated with fetal hypotension, skull hypoplasia, anuria, renal failure, oligohydramnios, and neonatal death.
Patient Counselling
Purpose of Therapy
Fosinopril lowers blood pressure or helps the heart pump more efficiently by blocking a hormone system that tightens blood vessels. In hypertension, it reduces the risk of stroke and heart attack. In heart failure, it eases symptoms and reduces hospitalisations. Continue taking fosinopril even if you feel well; stopping suddenly may worsen your condition.
How to Take
Take fosinopril at the same time each day, with or without food. If you also take antacids (e.g., Maalox, Mylanta), separate the doses by at least 2 hours. If a dose is missed, take it as soon as remembered unless the next dose is due soon.
Sources
- Monopril (fosinopril sodium) tablets prescribing information. Bristol-Myers Squibb Company. Revised 2003. FDA LabelPrimary regulatory source for approved indications, dosing, adverse reactions, PK (dual elimination), and renal impairment guidance.
- Erhardt L, MacLean A, Ilgenfritz J, Gelperin K, Blumenthal M; for the FEST Study Group. Fosinopril attenuates clinical deterioration and improves exercise tolerance in patients with heart failure. Eur Heart J. 1995;16(12):1892–1899. doi:10.1093/oxfordjournals.eurheartj.a060844Pivotal 12-week placebo-controlled trial (n=308) showing fosinopril reduced HF hospitalisations and improved exercise tolerance.
- Brown EJ Jr, Chew PH, MacLean A, et al. Effects of fosinopril on exercise tolerance and clinical deterioration in patients with chronic congestive heart failure not taking digitalis. Am J Cardiol. 1995;75(8):596–600. doi:10.1016/s0002-9149(99)80624-924-week trial (n=241) demonstrating fosinopril benefits without digitalis co-therapy; improved exercise time, NYHA class, and symptoms.
- Borghi C, Marino P, Zardini P, Magnani B, Collatina S, Ambrosioni E. Short- and long-term effects of early fosinopril administration in patients with acute anterior myocardial infarction (FAMIS). Am Heart J. 1998;136(2):213–225. doi:10.1053/hj.1998.v136.89901FAMIS trial showing early fosinopril post-MI prevents LV remodelling; supports off-label acute MI use.
- Whelton PK, Carey RM, Aronow WS, et al. 2017 ACC/AHA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults. Hypertension. 2018;71(6):e13–e115. doi:10.1161/HYP.0000000000000065Major hypertension guideline supporting ACE inhibitors as first-line for compelling indications.
- Heidenreich PA, Bozkurt B, Aguilar D, et al. 2022 AHA/ACC/HFSA guideline for the management of heart failure. Circulation. 2022;145(18):e895–e1032. doi:10.1161/CIR.0000000000001063Positions ACE inhibitors as part of GDMT for HFrEF; supports fosinopril as an option in this class.
- Murdoch D, McTavish D. Fosinopril: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in essential hypertension. Drugs. 1992;43(1):123–140. doi:10.2165/00003495-199243010-00009Comprehensive early review detailing fosinopril’s unique phosphinate chemistry and dual elimination pharmacology.
- Davis R, Coukell A, McTavish D. Fosinopril: a review of its pharmacology and clinical efficacy in the management of heart failure. Drugs. 1997;54(1):103–116. doi:10.2165/00003495-199754010-00012Reviews fosinopril’s role in HF, including adverse event profile (dizziness 11.9%, cough 9.7%, hypotension 4.4%).
- Sica DA, Cutler RE, Parmer RJ, et al. Comparison of the steady-state pharmacokinetics of fosinopril, lisinopril and enalapril in patients with chronic renal insufficiency. Clin Pharmacokinet. 1991;20(5):420–427. doi:10.2165/00003088-199120050-00006Key PK comparison demonstrating fosinoprilat clearance is maintained in CKD unlike enalaprilat or lisinopril.
- Wagstaff AJ, Davis R, McTavish D. Fosinopril: a reappraisal of its pharmacology and therapeutic efficacy in essential hypertension. Drugs. 1996;51(5):777–791. doi:10.2165/00003495-199651050-00006Updated review covering fosinopril’s place in HTN therapy with emphasis on dual elimination advantage.
- Alessi K, Patel P, Parmar M. Fosinopril. In: StatPearls. Treasure Island (FL): StatPearls Publishing; updated January 31, 2024. NCBI BookshelfCurrent comprehensive review covering pharmacology, dosing, adverse effects, monitoring, and off-label uses.