Ramipril
(British Approved Name, US Adopted Name, rINN)
Drug Nomenclature
International Nonproprietary Names (INNs) in main languages (French, Latin, Russian, and Spanish):
Pharmacopoeias. In Europe and US.
European Pharmacopoeia, 6th ed., 2008 and Supplements 6.1 and 6.2 (Ramipril). A white or almost white, crystalline powder. Sparingly soluble in water; freely soluble in methyl alcohol. Protect from light.
The United States Pharmacopeia 31, 2008, and Supplements 1 and 2 (Ramipnl). A white to almost white, crystalline powder. Sparingly soluble in water; freely soluble in methyl alcohol. Store in airtight containers.
Adverse Effects, Treatment, and Precautions
As for ACE inhibitors.
Interactions
As for ACE inhibitors.
Pharmacokinetics
Ramipril acts as a prodrug of the diacid ramiprilat, its active metabolite. After oral doses at least 50 to 60% is absorbed. Ramipril is metabolised in the liver to ramiprilat; other metabolites are inactive. Peak plasma concentrations of ramiprilat are achieved 2 to 4 hours after an oral dose of ramipril. Ramiprilat is about 56% bound to plasma proteins. After oral doses ramipril is excreted primarily in the urine, as ramiprilat, other metabolites, and some unchanged drug. About 40% of an oral dose appears in the faeces; this may represent both biliary excretion and unabsorbed drug. The effective half-life for accumulation of ramiprilat is 13 to 17 hours after multiple doses of ramipril 5 to 10 mg, but is much longer for doses of 1.25 to 2.5 mg daily; the difference relates to the long terminal half-life associated with saturable binding to the angiotensin-converting enzyme. The clearance of ramiprilat is reduced in renal impairment.
Uses and Administration
Ramipril is an ACE inhibitor. It is used in the treatment of hypertension, heart failure, and after myocardial infarction to improve survival in patients with clinical evidence of heart failure. It is also used to reduce the risk of cardiovascular events in patients with certain risk factors (see Cardiovascular Risk Reduction).
Ramipril owes its activity to ramiprilat to which it is converted after oral doses. The haemodynamic effects are seen within 1 to 2 hours of a single oral dose and the maximum effect occurs after about 3 to 6 hours, although the full effect may not develop for several weeks during chronic dosing. The haemodynamic effect is maintained for at least 24 hours, allowing once-daily dosing.
In the treatment of hypertension an initial oral dose of 1.25 mg once daily is given. Since there may be a precipitous fall in blood pressure when starting therapy with an ACE inhibitor, the first dose should preferably be given at bedtime. Patients taking diuretics should, if possible, have the diuretic stopped 2 to 3 days before starting ramipril, and resumed later if necessary. The usual maintenance dose is 2.5 to 5 mg daily as a single dose, although up to 10 mg daily may be required. In the USA an initial dose of 2.5 mg once daily in hypertensive patients not taking a diuretic and a maintenance dose of 2.5 to 20 mg daily, as a single dose or in two divided doses, have been suggested.
In the management of heart failure, severe first-dose hypotension on introduction of an ACE inhibitor is common in patients on loop diuretics, but their temporary withdrawal may cause rebound pulmonary oedema. Thus treatment should begin with a low dose under close medical supervision; high doses of diuretics should be reduced before starting ramipril. Ramipril is given in an initial dose of 1.25 mg once daily. The usual maximum dose is 10 mg daily; doses of 2.5 mg or more daily may be taken in 1 or 2 divided doses.
After myocardial infarction, treatment with ramipril may be started in hospital 3 to 10 days after the infarction at a usual initial dose of 2.5 mg twice daily, increased after two days to 5 mg twice daily. The usual maintenance dose is 2.5 to 5 mg twice daily.
For the prophylaxis of cardiovascular events in patients considered to be at high risk, ramipril is given in an initial dose of 2.5 mg once daily. The dose should be increased, if tolerated, to 5 mg once daily after 1 week, then to the usual maintenance dose of 10 mg once daily after a further 3 weeks. In patients with hypertension or recent myocardial infarction it may also be given in divided doses.
A reduction in dosage of ramipril may be necessary in patients with impaired hepatic or renal function (see below).
Administration in hepatic or renal impairment. The UK licensed product information states that in patients with hepatic impairment, or renal impairment with a creatinine clearance of less than 30 mL/minute, the initial dose of ramipril should not exceed 1.25 mg daily. In hepatic impairment higher doses should be used with caution. In renal impairment the maintenance dose should not exceed 5 mg daily; for those with a creatinine clearance of less than 10 mL/minute, the maintenance dose should not exceed 2.5 mg daily.
Preparations
British Pharmacopoeia, 2008: Ramipril Capsules; Ramipril Tablets.
Proprietary Preparations
Single-ingredient Preparations
The symbol ¤ denotes a preparation which is discontinued or no longer actively marketed.
Argentina: Lostapres; Tritace; Australia: Ramace; Tritace; Austria: Hypren; Tritace; Belgium: Ramace; Tritace; Brazil: Naprix; Triatec; Canada: Altace; Chile: Ramipres; Triatec; Czech Republic: Tritace; Denmark: Ramace; Triatec; Finland: Cardace; Ramace; France: Triatec; Germany: Delix; Vesdil; Greece: Stibenyl; Triatec; Hong Kong: Tritace; Hungary: Tritace; India: Cardace; Hopecard; Preface; R-Pril; Ramcor; Ramipres; Ireland: Pramace¤; Tritace; Israel: Tritace; Italy: Quark; Triatec; Unipril; Malaysia: Tritace; Mexico: Ramace¤; Tritace; Netherlands: Remik; Tritace; Norway: Triatec; New Zealand: Tritace; Portugal: Triatec; South Africa: Ramace; Tritace; Singapore: Tritace; Spain: Acovil; Carasel; Sweden: Pramace; Triatec; Switzerland: Triatec; Vesdil; Thailand: Corpril; Tritace; United Kingdom: Tritace; United States: Altace; Venezuela: Altace
Multi-ingredient Preparations
Argentina: Tritace-HCT; Austria: Hypren plus; Lasitace; Trialix; Triapin; Tritazide; Unimax; Belgium: Tritazide; Brazil: Naprix A; Naprix D; Triatec D; Czech Republic: Triasyn; Tritazide; Unimax; Denmark: Triatec Comp; Finland: Cardace Comp; Unimax; Germany: Arelix ACE; Aretensin; Delix plus; Delmuno; Unimax; Vesdil plus; Greece: Triacor; Triatec Plus; Hungary: Triasyn; India: Ramcor H; Ramipres H; Ireland: Trialix; Israel: Tritace Comp; Italy: Idroquark; Prilace; Triatec HCT; Uniprildiur; Mexico: Triacor; Tritazide; Netherlands: Triapin; Tritazide; Unimax; Portugal: Triatec Composto; South Africa: Tri-Plen; Spain: Unimest¤; Sweden: Triatec Comp; Switzerland: Trialix; Triatec Comp; Unimax; United Kingdom: Triapin
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