Drug Monograph
Ramipril (Altace)
ramipril
Pharmacokinetic Profile
Half-Life
13–17 h (effective, ramiprilat)
Metabolism
Hepatic CES1 (prodrug → ramiprilat)
Protein Binding
Ramipril 73%; Ramiprilat 56%
Bioavailability
50–60% (oral)
Tmax
~1 h (ramipril); 1.5–4 h (ramiprilat)
Clinical Information
Drug Class
ACE Inhibitor
Available Doses
1.25, 2.5, 5, 10 mg capsules/tablets; 1 mg/mL oral solution
Route
Oral only
Renal Adjustment
Yes — CrCl <40 mL/min
Hepatic Adjustment
Caution — ramipril levels ↑3-fold
Pregnancy
Contraindicated (Boxed Warning)
Lactation
Not recommended
Schedule
Prescription only (not scheduled)
Generic Available
Yes
Indications
| Indication | Approved Population | Therapy Type | Status |
|---|---|---|---|
| Hypertension | Adults | Monotherapy or combination with thiazides | FDA Approved |
| Cardiovascular risk reduction (MI, stroke, CV death) | Adults ≥55 years at high risk of atherosclerotic events | Added to standard care | FDA Approved |
| Heart failure post-MI | Adults with clinical signs of HF 2–9 days after acute MI | Adjunctive to standard post-MI therapy | FDA Approved |
Ramipril has one of the broadest evidence bases among ACE inhibitors. The HOPE trial (2000) established its role in cardiovascular protection for high-risk patients irrespective of baseline blood pressure, while the AIRE trial (1993) demonstrated mortality reduction in post-MI heart failure. The AHA/ACC/HFSA 2022 guideline includes ACE inhibitors as guideline-directed therapy for HFrEF.
Off-Label Uses
Heart failure with reduced ejection fraction (HFrEF) — chronic — Recommended in AHA/ACC 2022 guidelines as part of GDMT for LVEF <40%. Evidence: High
Diabetic nephropathy / proteinuric CKD — ACE inhibitors reduce proteinuria and slow CKD progression, especially with albuminuria. Evidence: High
Stable coronary artery disease — Vascular-protective effects independent of blood pressure reduction per HOPE data. Evidence: High
Prevention of new-onset diabetes — HOPE and DREAM data suggest reduced incidence of diabetes with ramipril. Evidence: Moderate
Dosing
Adult Dosing by Clinical Scenario
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| Hypertension — not on a diuretic | 2.5 mg PO once daily | 2.5–20 mg/day | 20 mg/day | Give once daily or divide BID if trough effect wanes Onset: 1–2 h; peak BP reduction: 3–6 h (FDA PI) |
| Hypertension — already on a diuretic | 1.25 mg PO once daily | 2.5–20 mg/day | 20 mg/day | Discontinue diuretic 2–3 days before starting if possible; supervise first dose closely |
| CV risk reduction (HOPE protocol) | 2.5 mg PO once daily × 1 week | 5 mg × 3 weeks → 10 mg once daily | 10 mg/day | Target 10 mg/day; achieved in 83% of HOPE patients at 1 year Benefit extends beyond BP reduction |
| Heart failure post-MI (AIRE protocol) | 2.5 mg PO BID | 5 mg PO BID (target) | 5 mg BID (10 mg/day) | Start 2–9 days post-MI if haemodynamically stable; reduce to 1.25 mg BID if initial dose not tolerated |
| HFrEF — chronic (GDMT) | 1.25–2.5 mg PO once daily | Titrate to 10 mg once daily | 10 mg/day | Titrate over weeks; combine with beta-blocker, MRA, and SGLT2i per 2022 guidelines |
Renal Impairment Adjustments
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| CrCl ≥40 mL/min | No adjustment | Standard | 20 mg/day (HTN) | Monitor renal function periodically |
| CrCl <40 mL/min | 1.25 mg PO once daily | Titrate to response | 5 mg/day | Ramiprilat AUC 3–4× higher than in normal renal function (FDA PI) |
| Hepatic impairment | Reduced starting dose | Titrate cautiously | Per clinical response | Ramipril levels increase ~3-fold; ramiprilat levels unchanged. Use with caution. |
Clinical Pearl: Capsule Administration Options
Ramipril capsules can be opened and the contents sprinkled on applesauce (~120 mL) or mixed in water or apple juice for patients who cannot swallow capsules whole. The mixture can be stored for up to 24 hours at room temperature or 48 hours refrigerated. Tablets should be swallowed whole. An oral solution (1 mg/mL) is also available for precise low-dose titration.
Pharmacology
Mechanism of Action
Ramipril is an oral prodrug that is rapidly de-esterified in the liver by carboxylesterase 1 (CES1) to form ramiprilat, a potent non-sulfhydryl ACE inhibitor. Ramiprilat competitively inhibits angiotensin-converting enzyme, preventing conversion of angiotensin I to angiotensin II. This reduces systemic vascular resistance, aldosterone secretion, and sodium/water retention while increasing levels of the vasodilator bradykinin. Ramiprilat has high tissue affinity, with preferential distribution to the liver, kidneys, and lungs, which may contribute to its sustained organ-protective effects observed in the HOPE trial. Unlike captopril, ramipril lacks a sulfhydryl group, resulting in a lower incidence of dysgeusia and rash. Multiple doses of 2 mg or more produce over 90% inhibition of plasma ACE activity at 4 hours, with over 80% inhibition persisting at 24 hours.
ADME Profile
| Parameter | Value | Clinical Implication |
|---|---|---|
| Absorption | Bioavailability 50–60%; Tmax ramipril ~1 h, ramiprilat 1.5–4 h | Food slows rate but not extent of absorption; can be taken with or without food |
| Distribution | Protein binding: ramipril 73%, ramiprilat 56%; high tissue penetration (liver, kidneys, lungs) | High tissue ACE affinity may underlie vascular-protective effects beyond BP reduction |
| Metabolism | Hepatic de-esterification (CES1) to ramiprilat (active); further to glucuronide conjugate and diketopiperazine (inactive); no CYP involvement | Hepatic impairment increases ramipril (not ramiprilat) levels ~3-fold; minimal CYP interaction risk |
| Elimination | 60% urine, 40% faeces; <2% unchanged ramipril; triphasic: distribution t½ 2–4 h, apparent elimination t½ 9–18 h, terminal t½ >50 h; effective t½ 13–17 h | Steady state by 4th dose; dose reduction when CrCl <40 mL/min (AUC 3–4× higher) |
Side Effects
≥10%Very Common
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Cough (long-term use) | ~12% | In a 1-year study, almost 12% developed cough, with ~4% requiring discontinuation (FDA PI). In the AIRE post-MI population, 8% vs 4% placebo. In HOPE, 7.3% discontinued due to cough vs 1.8% placebo. Class effect due to bradykinin accumulation; switch to ARB if intolerable. |
1–10%Common
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Headache | 5.4% | Similar to placebo rate in hypertension trials; rarely treatment-limiting |
| Hypotension (post-MI population) | 5% | From AIRE trial; risk highest during initial treatment; monitor closely for first 2 weeks and after dose increases (FDA PI) |
| Dizziness | 2.2–4% | 2.2% in hypertension trials (FDA PI); 4% in AIRE (vs 3% placebo); usually transient |
| Fatigue / asthenia | 2.0% | Only adverse effect more frequent than placebo in hypertension trials (FDA PI) |
| Nausea | 2% vs 1% placebo | From AIRE trial; generally mild |
| Postural hypotension | 2% vs 1% placebo | From AIRE trial; risk increased with concurrent diuretics or volume depletion |
| Syncope | 2% vs 1% placebo | From AIRE trial; slow titration and volume repletion reduce risk |
| Elevated serum creatinine | 1.2% | 1.2% alone, 1.5% with diuretic (FDA PI); generally reversible and haemodynamic in nature |
| Hyperkalemia (K >5.7 mEq/L) | ~1% | In hypertensive patients (FDA PI); risk increases with renal impairment, diabetes, or K-sparing agents |
SeriousSerious (Regardless of Frequency)
| Adverse Effect | Estimated Frequency | Typical Onset | Required Action |
|---|---|---|---|
| Angioedema | 0.3% (US trials); 0.4% (HOPE) | Any time during therapy; higher rate in Black patients | Discontinue immediately; secure airway; epinephrine if laryngeal involvement; never rechallenge with any ACE inhibitor |
| Acute renal failure | Rare | Days to weeks; bilateral renal artery stenosis is highest risk | Discontinue ramipril; IV fluids; evaluate for renovascular disease |
| Neutropenia / agranulocytosis / pancytopenia | Rare | Weeks to months; higher risk with collagen vascular disease + renal impairment | Monitor WBC in high-risk patients; discontinue and refer if confirmed |
| Hepatic failure / cholestatic jaundice | Very rare | Variable | Discontinue ACE inhibitor; urgent hepatology referral; can be fatal |
| Stevens-Johnson syndrome / toxic epidermal necrolysis | Very rare (post-marketing) | Variable | Immediate discontinuation; dermatology/burns referral |
| Fetal toxicity | Expected with 2nd/3rd trimester exposure | Second and third trimesters | Discontinue immediately when pregnancy detected; fetal monitoring |
DiscontinuationDiscontinuation Rates
Hypertension Trials (US)
~3% (FDA PI)
Top reasons: Cough (1.0%), dizziness (0.5%), impotence (0.4%)
HOPE Trial (CV Risk Reduction, ~4.5 years)
28.9% vs 27.3% placebo
Key DC reasons (ramipril vs placebo): Cough 7.3% vs 1.8%; hypotension/dizziness 1.9% vs 1.5%
| Reason for Discontinuation | Rate (Ramipril vs Placebo) | Context |
|---|---|---|
| Cough | 7.3% vs 1.8% (HOPE) | Most common reason for DC across all trials; resolves within 1–4 weeks of stopping |
| Hypotension / dizziness | 1.9% vs 1.5% (HOPE) | Higher in first weeks; mitigate with slow titration and volume repletion |
| Angioedema | 0.4% vs 0.2% (HOPE) | Mandates permanent discontinuation of all ACE inhibitors |
| Impotence | 0.4% (HTN trials) | Not clearly dose-related; may improve after discontinuation |
Managing ACE Inhibitor Cough
Ramipril-associated cough is the leading cause of treatment discontinuation. In a large pharmacoepidemiological study (n = 10,380), ramipril-related cough occurred in 7.1% of patients, with female sex, smoking, COPD, and asthma as independent risk factors. The cough is dry, non-productive, and typically appears within 1–2 weeks of starting therapy. Switching to an ARB is the recommended approach for patients with intolerable cough, as ARBs do not inhibit bradykinin degradation. In ONTARGET, cough was significantly less frequent with telmisartan than with ramipril (1.1% vs 4.2%).
Drug Interactions
Ramipril is a prodrug activated by hepatic carboxylesterase, not CYP enzymes, so cytochrome P450-mediated interactions are not a significant concern. The key interaction risks involve additive effects on the renin-angiotensin-aldosterone system, potassium homeostasis, and renal haemodynamics.
MajorAliskiren
MechanismDual RAS blockade
EffectIncreased risk of hypotension, hyperkalaemia, and acute renal failure
ManagementContraindicated in patients with diabetes; avoid if GFR <60 mL/min
FDA PIMajorSacubitril/Valsartan (Entresto)
MechanismDual neprilysin and ACE inhibition increases bradykinin
EffectElevated risk of angioedema
ManagementDo not co-administer; allow at least 36-hour washout when switching
FDA PIMajorPotassium-Sparing Diuretics / K Supplements
MechanismAdditive potassium retention via reduced aldosterone
EffectPotentially life-threatening hyperkalaemia
ManagementMonitor K⁺ frequently; use with caution, especially in renal impairment
FDA PIModerateNSAIDs (ibuprofen, naproxen, celecoxib)
MechanismReduced prostaglandin-mediated renal vasodilation
EffectBlunted antihypertensive effect; increased risk of renal impairment and hyperkalaemia
ManagementUse lowest effective NSAID dose for shortest duration; monitor renal function and BP
FDA PIModerateLithium
MechanismReduced renal lithium clearance
EffectElevated serum lithium with risk of toxicity
ManagementMonitor lithium levels frequently when initiating, adjusting, or stopping ramipril
FDA PIModerateInjectable Gold (sodium aurothiomalate)
MechanismUnclear; possibly bradykinin-mediated
EffectNitritoid reactions (flushing, nausea, hypotension)
ManagementUse with caution; monitor after gold injections
FDA PIModeratemTOR Inhibitors (sirolimus, everolimus, temsirolimus)
MechanismPossible additive effect on bradykinin levels
EffectIncreased risk of angioedema
ManagementMonitor closely for angioedema, especially during initial co-administration
FDA PIMinorAntidiabetic Agents (insulin, sulfonylureas)
MechanismACE inhibitors may reduce insulin resistance
EffectPossible enhanced hypoglycaemic effect
ManagementMonitor blood glucose more closely during initiation
FDA PIMonitoring
- Blood PressureEach visit; closely after first dose
RoutineSeated and standing BP at initiation and each dose increase. In post-MI or HF patients, monitor for symptomatic hypotension especially in the first 2 weeks. - Renal FunctionBaseline, 1–2 weeks, then periodically
RoutineSerum creatinine and BUN. A rise up to 30% may be acceptable (haemodynamic); >30% or progressive increase warrants dose reduction. Check more frequently with concurrent NSAIDs or renal impairment. - Serum PotassiumBaseline, 1–2 weeks, after dose changes
RoutineTarget K⁺ <5.5 mEq/L. Risk of hyperkalaemia with renal impairment, diabetes, K-sparing agents, or potassium supplements. - WBC / DifferentialBaseline, then periodically if high-risk
Trigger-basedMonitor in patients with collagen vascular disease and/or renal impairment who are at elevated risk for neutropenia. Advise patients to report signs of infection (sore throat, fever). - Hepatic EnzymesIf symptoms develop
Trigger-basedCheck ALT, AST, and bilirubin if patient develops jaundice or unexplained hepatic symptoms. ACE inhibitors have rarely been linked to cholestatic hepatitis progressing to hepatic necrosis. - Pregnancy StatusBefore starting and ongoing
RoutineConfirm negative pregnancy test before initiation in women of childbearing potential. Counsel on reliable contraception and immediate reporting of pregnancy.
Contraindications & Cautions
Absolute Contraindications
- History of angioedema associated with any ACE inhibitor, or hereditary/idiopathic angioedema
- Hypersensitivity to ramipril or any ACE inhibitor
- Pregnancy (discontinue immediately when detected)
- Concurrent aliskiren in patients with diabetes mellitus
- Concurrent neprilysin inhibitor (e.g., sacubitril/valsartan); must allow 36-hour washout
Relative Contraindications (Specialist Input Recommended)
- Bilateral renal artery stenosis or stenosis of a solitary kidney — high risk of acute renal failure
- Haemodynamically significant aortic stenosis — afterload reduction may cause critical hypotension
- Collagen vascular disease with renal impairment — elevated risk of agranulocytosis
Use with Caution
- Volume depletion or hyponatraemia — correct before starting; consider lower initial dose
- Elderly patients — higher peak ramiprilat levels and AUC; start low and titrate carefully
- Pre-existing renal impairment — dose reduction required when CrCl <40 mL/min
- Hepatic impairment — ramipril levels increase ~3-fold; ramiprilat levels are not significantly affected
- Desensitisation therapy (e.g., hymenoptera venom) — increased anaphylactoid risk
FDA Boxed Warning
Fetal Toxicity
Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus. When pregnancy is detected, ramipril should be discontinued as soon as possible. Second and third trimester exposure has been associated with fetal renal dysfunction, oligohydramnios, skull hypoplasia, limb contractures, lung hypoplasia, and neonatal death.
Patient Counselling
Purpose of Therapy
Ramipril works by blocking a hormone system that raises blood pressure and stresses the heart and blood vessels. Depending on the reason for prescribing, it may lower blood pressure, protect the heart after a heart attack, or reduce the long-term risk of stroke and heart attack. It does not cure these conditions but provides ongoing protection when taken consistently. Patients should not stop taking ramipril without discussing with their prescriber.
How to Take
Take ramipril at the same time each day, with or without food. Capsules can be swallowed whole or opened and mixed with applesauce, water, or apple juice. If a dose is missed, take it as soon as remembered unless the next dose is due soon. Never double up.
Dizziness & Lightheadedness
Tell patientMost likely in the first few days, particularly when standing up. Rise slowly, stay well hydrated, and avoid alcohol. The body usually adjusts within 1–2 weeks.
Call prescriberIf dizziness is severe, persistent beyond the first week, or if fainting occurs.
Persistent Dry Cough
Tell patientA dry, tickly cough is a recognised side effect. It is not dangerous but can be bothersome. It usually resolves within 1–4 weeks of stopping. Do not take cough suppressants without medical advice.
Call prescriberIf the cough is persistent and affecting sleep or daily life; an alternative medication (ARB) may be considered.
Swelling (Angioedema Warning)
Tell patientRarely, ramipril can cause swelling of the face, lips, tongue, or throat. This can happen at any time during treatment.
Call prescriberSeek emergency medical attention immediately if swelling of face, lips, tongue, or throat occurs, or if there is difficulty breathing. Do not take another dose.
Pregnancy Prevention
Tell patientRamipril can cause serious harm to an unborn baby, particularly in the second and third trimesters. Women of childbearing age must use reliable contraception.
Call prescriberReport a positive pregnancy test or planned pregnancy immediately so ramipril can be safely replaced.
Signs of Infection
Tell patientVery rarely, ramipril may affect white blood cell production. Any unexplained sore throat, fever, or mouth sores should be reported.
Call prescriberIf symptoms of infection develop, especially sore throat with fever, for prompt blood count evaluation.
Potassium & Salt Substitutes
Tell patientRamipril can raise potassium levels. Avoid potassium-containing salt substitutes and do not take potassium supplements unless instructed by a clinician.
Call prescriberIf experiencing muscle weakness, irregular heartbeat, or tingling, which may indicate elevated potassium.
Sources
Regulatory (PI / SmPC)
- Altace (ramipril) capsules prescribing information. Pfizer. Revised 2013. FDA LabelPrimary regulatory source for approved indications, dosing, adverse reactions, and pharmacokinetics.
- Altace (ramipril) tablets prescribing information. Revised 2012. FDA LabelTablet formulation label with detailed PK data including triphasic elimination and renal impairment effects.
Key Clinical Trials
- Yusuf S, Sleight P, Pogue J, et al. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients (HOPE). N Engl J Med. 2000;342(3):145–153. doi:10.1056/NEJM200001203420301Landmark trial demonstrating 22% relative risk reduction in MI, stroke, and CV death with ramipril 10 mg/day in high-risk patients without HF.
- The Acute Infarction Ramipril Efficacy (AIRE) Study Investigators. Effect of ramipril on mortality and morbidity of survivors of acute myocardial infarction with clinical evidence of heart failure. Lancet. 1993;342(8875):821–828. doi:10.1016/0140-6736(93)92693-NEstablished 27% mortality reduction with ramipril in post-MI patients with heart failure; primary source for AIRE-specific adverse event data.
- ONTARGET Investigators, Yusuf S, Teo KK, et al. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med. 2008;358(15):1547–1559. doi:10.1056/NEJMoa0801317Established telmisartan as noninferior to ramipril; key comparative tolerability data (cough 1.1% vs 4.2%, angioedema 0.1% vs 0.3%).
- Arnold JMO, Yusuf S, Young J, et al. Prevention of heart failure in patients in the HOPE study. Circulation. 2003;107(9):1284–1290. doi:10.1161/01.CIR.0000054165.93055.42HOPE substudy confirming ramipril reduces development of new heart failure in high-risk patients; discontinuation data source.
Guidelines
- 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.0000000000001063Current guideline positioning ACE inhibitors as GDMT for HFrEF (Stage C, LVEF ≤40%).
- 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.
Mechanistic / Basic Science
- Chauhan P, Alexander ST, Ganesan N, et al. Ramipril. In: StatPearls. Treasure Island (FL): StatPearls Publishing; updated October 6, 2024. NCBI BookshelfComprehensive review covering ramipril pharmacology, dosing, adverse effects, and monitoring considerations.
Pharmacokinetics / Special Populations
- Shionoiri H. Clinical pharmacokinetics of ramipril. Clin Pharmacokinet. 1994;26(1):7–15. doi:10.2165/00003088-199426010-00002Definitive PK review: protein binding (ramipril 73%, ramiprilat 56%), metabolism, and renal impairment effects.
- Frampton JE, Peters DH. Ramipril: an updated review of its therapeutic use in essential hypertension and heart failure. Drugs. 1995;49(3):440–466. doi:10.2165/00003495-199549030-00008Comprehensive review of ramipril clinical pharmacology and therapeutic use across hypertension and heart failure.
- Wyskida K, Jura-Szoltys E, Smertka M, Owczarek A, Chudek J. Factors that favor the occurrence of cough in patients treated with ramipril. Int J Environ Res Public Health. 2012;9(10):3579–3594. doi:10.3390/ijerph9103579Pharmacoepidemiological study (n = 10,380) establishing cough incidence of 7.1% and identifying risk factors including female sex, smoking, and COPD.