Ramipril

Pronunciation

(ra MI pril)

U.S. Brand Names

Altace®

Generic Available

Canadian Brand Names

Altace®

Use

Treatment of hypertension, alone or in combination with thiazide diuretics; treatment of congestive heart failure; treatment of left ventricular dysfunction after myocardial infarction; to reduce risk of heart attack, stroke, and death in patients at increased risk for these problems

Pregnancy Risk Factor

C/D (2nd and 3rd trimesters)

Pregnancy Implications

Cranial defects, hypocalvaria/acalvaria, oligohydramnios, persistent anuria following delivery, hypotension, renal defects, renal dysgenesis/dysplasia, renal failure, pulmonary hypoplasia, limb contractures secondary to oligohydramnios, and stillbirth reported. ACE inhibitors should be avoided during pregnancy, particularly in the 2nd and 3rd trimesters.

Lactation

Enters breast milk/not recommended

Contraindications

Hypersensitivity to ramipril or any component of the formulation; prior hypersensitivity (including angioedema) to ACE inhibitors; bilateral renal artery stenosis; pregnancy (2nd and 3rd trimesters)

Warnings/Precautions

Anaphylactic or anaphylactoid reactions can occur. Angioedema can occur at any time during treatment (especially following first dose). Angioedema may involve head and neck (potentially affecting the airway) or the intestine (presenting with abdominal pain). Careful blood pressure monitoring with first dose (hypotension can occur especially in volume depleted patients). Dosage adjustment needed in renal impairment. Use with caution in hypovolemia; collagen vascular diseases; valvular stenosis (particularly aortic stenosis); hyperkalemia; or before, during, or immediately after anesthesia. Avoid rapid dosage escalation, which may lead to renal insufficiency. Rare toxicities associated with ACE inhibitors include cholestatic jaundice (which may progress to hepatic necrosis) and neutropenia/agranulocytosis with myeloid hyperplasia. If patient has renal impairment then a baseline WBC with differential and serum creatinine should be evaluated and monitored closely during the first 3 months of therapy. Hypersensitivity reactions may be seen during hemodialysis with high-flux dialysis membranes (eg, AN69). Use with caution in unilateral renal artery stenosis and pre-existing renal insufficiency.

Adverse Reactions

Note: Frequency ranges include data from hypertension and heart failure trials. Higher rates of adverse reactions have generally been noted in patients with CHF. However, the frequency of adverse effects associated with placebo is also increased in this population.

>10%: Respiratory: Cough (increased) (7% to 12%)

1% to 10%:

Cardiovascular: Hypotension (11%), angina (3%), postural hypotension (2%), syncope (2%)

Central nervous system: Headache (1% to 5%), dizziness (2% to 4%), fatigue (2%), vertigo (2%)

Endocrine & metabolic: Hyperkalemia (1% to 10%)

Gastrointestinal: Nausea/vomiting (1% to 2%)

Neuromuscular & skeletal: Chest pain (noncardiac) (1%)

Renal: Renal dysfunction (1%), elevation in serum creatinine (1% to 2%), increased BUN (<1% to 3%); transient elevations of creatinine and/or BUN may occur more frequently

Respiratory: Cough (estimated 1% to 10%)

<1%: Agranulocytosis, abdominal pain, amnesia, anaphylactoid reaction, angina, angioedema, anorexia, anxiety, arrhythmia, arthralgia, arthritis, bone marrow depression, cerebrovascular events, constipation, convulsions, decreased hematocrit, decreased hemoglobin, depression, diarrhea, dyspepsia, dysphagia, dyspnea, edema, eosinophilia, epistaxis, erythema multiforme, gastroenteritis, hearing loss, hemolytic anemia, hepatitis, hypersensitivity reactions (fever, rash, urticaria), hyponatremia, impotence, increased diaphoresis, increased salivation, insomnia, malaise, myalgia, MI, nervousness, neuralgia, neuropathy, onycholysis, palpitation, pancreatitis, pancytopenia, paresthesia, pemphigoid, pemphigus, photosensitivity, proteinuria, purpura, somnolence, Stevens-Johnson syndrome, symptomatic hypotension, syncope, taste disturbance, thrombocytopenia, tinnitus, toxic epidermal necrolysis, transaminases increased, tremor, vertigo, vision disturbances, weight gain, xerostomia

Postmarketing and/or case reports: Agitation

Worsening of renal function may occur in patients with bilateral renal artery stenosis or in hypovolemia. In addition, a syndrome which may include fever, myalgia, arthralgia, interstitial nephritis, vasculitis, rash, eosinophilia and positive ANA, and elevated ESR has been reported with ACE inhibitors. Risk of pancreatitis and agranulocytosis may be increased in patients with collagen vascular disease or renal impairment.

Overdosage/Toxicology

Mild hypotension has been the primary toxic effect seen with acute overdose. Bradycardia may also occur. Hyperkalemia occurs even with therapeutic doses, especially in patients with renal insufficiency and those taking NSAIDs. Treatment is symptom-directed and supportive.

Drug Interactions

Alpha1 blockers: Hypotensive effect increased.

Aspirin: The effects of ACE inhibitors may be blunted by aspirin administration, particularly at higher dosages (see Cardiovascular Considerations) and/or increase adverse renal effects.

Diuretics: Hypovolemia due to diuretics may precipitate acute hypotensive events or acute renal failure.

Insulin: Risk of hypoglycemia may be increased.

Lithium: Risk of lithium toxicity may be increased; monitor lithium levels, especially the first 4 weeks of therapy.

Mercaptopurine: Risk of neutropenia may be increased.

NSAIDs: May attenuate hypertensive efficacy; effect has been seen with captopril and may occur with other ACE inhibitors; monitor blood pressure. May increase risk of adverse renal effects or hyperkalemia.

Potassium-sparing diuretics (amiloride, spironolactone, triamterene): Increased risk of hyperkalemia.

Potassium supplements may increase the risk of hyperkalemia.

Trimethoprim (high dose) may increase the risk of hyperkalemia.

Ethanol/Nutrition/Herb Interactions

Herb/Nutraceutical: Avoid dong quai if using for hypertension (has estrogenic activity). Avoid ephedra, yohimbe, ginseng (may worsen hypertension). Avoid garlic (may have increased antihypertensive effect).

Stability

Store at controlled room temperature.

Mechanism of Action

Ramipril is an ACE inhibitor which prevents the formation of angiotensin II from angiotensin I and exhibits pharmacologic effects that are similar to captopril. Ramipril must undergo enzymatic saponification by esterases in the liver to its biologically active metabolite, ramiprilat. The pharmacodynamic effects of ramipril result from the high-affinity, competitive, reversible binding of ramiprilat to angiotensin-converting enzyme thus preventing the formation of the potent vasoconstrictor angiotensin II. This isomerized enzyme-inhibitor complex has a slow rate of dissociation, which results in high potency and a long duration of action; a CNS mechanism may also be involved in the hypotensive effect as angiotensin II increases adrenergic outflow from CNS; vasoactive kallikreins may be decreased in conversion to active hormones by ACE inhibitors, thus reducing blood pressure

Pharmacodynamics/Kinetics

Onset of action: 1-2 hours

Duration: 24 hours

Absorption: Well absorbed (50% to 60%)

Distribution: Plasma levels decline in a triphasic fashion; rapid decline is a distribution phase to peripheral compartment, plasma protein and tissue ACE (half-life 2-4 hours); 2nd phase is an apparent elimination phase representing the clearance of free ramiprilat (half-life: 9-18 hours); and final phase is the terminal elimination phase representing the equilibrium phase between tissue binding and dissociation

Metabolism: Hepatic to the active form, ramiprilat

Half-life elimination: Ramiprilat: Effective: 13-17 hours; Terminal: >50 hours

Time to peak, serum: ~1 hour

Excretion: Urine (60%) and feces (40%) as parent drug and metabolites

Dosage

Adults: Oral:

Hypertension: 2.5-5 mg once daily, maximum: 20 mg/day

Reduction in risk of MI, stroke, and death from cardiovascular causes: Initial: 2.5 mg once daily for 1 week, then 5 mg once daily for the next 3 weeks, then increase as tolerated to 10 mg once daily (may be given as divided dose)

Heart failure postmyocardial infarction: Initial: 2.5 mg twice daily titrated upward, if possible, to 5 mg twice daily.

Note: The dose of any concomitant diuretic should be reduced. If the diuretic cannot be discontinued, initiate therapy with 1.25 mg. After the initial dose, the patient should be monitored carefully until blood pressure has stabilized.

Dosing adjustment in renal impairment:

Clcr<40 mL/minute: Administer 25% of normal dose.

Renal failure and hypertension: Administer 1.25 mg once daily, titrated upward as possible.

Renal failure and heart failure: Administer 1.25 mg once daily, increasing to 1.25 mg twice daily up to 2.5 mg twice daily as tolerated.

Administration

Capsule is usually swallowed whole, but may be may be mixed in water, apple juice, or applesauce.

Test Interactions

Increases BUN, creatinine, potassium, positive Coombs' [direct]; decreases cholesterol (S); may cause false-positive results in urine acetone determinations using sodium nitroprusside reagent

Patient Education

Inform prescriber of all prescriptions, OTC medications, or herbal products you are taking, and any allergies you have. Do not take any new medication during therapy without consulting prescriber. Take as directed; do not alter dose or discontinue without consulting prescriber. Take first dose at bedtime or when sitting down (hypotension may occur). This drug does not eliminate need for diet or exercise regimen as recommended by prescriber. May cause increased cough (if persistent or bothersome, contact prescriber); headache (consult prescriber for approved analgesic); postural hypotension (use caution when rising from lying or sitting position or climbing stairs); dizziness (use caution when driving or engaging in tasks that require alertness until response to drug is known); or nausea or vomiting (small, frequent meals, frequent mouth care, sucking lozenges, or chewing gum may help). Immediately report swelling of face, mouth, lips, tongue or throat; chest pain or irregular heartbeat. Report respiratory difficulty or persistent cough; persistent pain in muscles, joints, or back; or other persistent adverse reactions. Pregnancy/breast-feeding precautions: Inform prescriber if you are or intend to become pregnant. This drug should not be used in the 2nd or 3rd trimester of pregnancy. Consult prescriber for appropriate contraceptive measures if necessary. Breast-feeding is not recommended.

Anesthesia and Critical Care Concerns/Other Considerations

ACE inhibitors decrease morbidity and mortality in patients with asymptomatic and symptomatic left ventricular dysfunction. ACE inhibitors are also indicated in patients postmyocardial infarction in whom left ventricular ejection fraction is <40%.

Cardiovascular Considerations

A recently completed trial (HOPE), examining the use of ramipril (at a dose of between 2.5-10 mg daily) in patients at high risk for cardiovascular events but who did not have heart failure, documented a significant improvement in cardiovascular outcome in the treated group. Thus, the benefits of ACE inhibitor therapy may also include a cardioprotective effect when used in patients at risk for cardiovascular events. The FDA has recently approved ramipril to reduce the risk of stroke, myocardial infarction, and death from cardiovascular causes in patients

55 years of age with a history of coronary artery disease, stroke, or peripheral vascular disease or with diabetes and one other cardiovascular risk factor (eg, elevated cholesterol levels, cigarette smoking).

ACE inhibitors decrease morbidity and mortality in patients with asymptomatic and symptomatic left ventricular dysfunction. In this situation, they decrease hospitalizations for, and retard progression to, congestive heart failure. According to 2004 ACC/AHA STEMI guidelines, an ACE inhibitor should be administered orally within the first 24 hours of STEMI to patients with anterior infarction, pulmonary congestion or LVEF <0.4, in the absence of hypotension or known contraindications to that class of medicines. In the emergency management of complicated STEMI, a short-acting ACEI (eg, captopril 1-6.25 mg) may be added once the patient's systolic blood pressure is >100 mm Hg and not <30 mm Hg below baseline. When used in patients with heart failure, the target dose of 5 mg twice daily should be achieved, if possible. Lower daily doses of ACE inhibitors have not demonstrated the same cardioprotective effects. ACE inhibitors have renal protective effects in patients with proteinuria and possibly cardioprotective effects in high-risk patients.

ACE inhibitor therapy may elicit rapid increases in potassium and creatinine, especially when used in patients with bilateral renal artery stenosis. When ACE inhibition is introduced in patients with pre-existing diuretic therapy who are hypovolemic, the ACE inhibitor may induce acute hypotension. In those patients experiencing cough on an ACE inhibitor, the ACE inhibitor may be discontinued and, if necessary, angiotensin receptor blocker therapy instituted. Concomitant NSAID therapy may attenuate blood pressure control; use of NSAIDs should be avoided or limited, with monitoring of blood pressure control. In the setting of heart failure, NSAID use may be associated with an increased risk for fluid accumulation and edema. Because of the potent teratogenic effects of ACE inhibitors, these drugs should be avoided, if possible, when treating women of childbearing potential not on effective birth control measures.

In the treatment of unstable angina/non-ST-segment elevation MI, ACE inhibitors are recommended when hypertension persists despite treatment with nitroglycerin and a beta-blocker in patients with LV systolic dysfunction or CHF and in ischemic patients with diabetes (Class I). ACE inhibitors are also recommended for all post-ACS individuals (Class IIa).

Dental Health: Effects on Dental Treatment

No significant effects or complications reported

Dental Health: Vasoconstrictor/Local Anesthetic Precautions

No information available to require special precautions

Mental Health: Effects on Mental Status

May cause dizziness or drowsiness; may rarely cause nervousness, amnesia, insomnia, or depression

Mental Health: Effects on Psychiatric Treatment

May cause neutropenia; use caution with clozapine and carbamazepine; may decrease lithium clearance resulting in an increase in serum lithium levels and potential lithium toxicity; monitor serum lithium levels

Dosage Forms

Capsule: 1.25 mg, 2.5 mg, 5 mg, 10 mg

References

Antman EM, Anbe SC, Alpert JS, et al, "ACC/AHA Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction - Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 1999 Guidelines for the Management of Patients With Acute Myocardial Infarction)," Circulation, 2004, 110:588-636. Available at: http://www.circulationaha.org/cgi/content/full/110/5/588. Last accessed October 26, 2004.

Braunwald E, Antman EM, Beasley JW, et al, "ACC/AHA 2002 Guideline Update for the Management of Patients With Unstable Angina and Non-ST-Segment Elevation Myocardial Infarction - Summary Article: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients With Unstable Angina)," J Am Coll Cardiol , 2002, 40(7):1366-74. Available at: http://www.acc.org/clinical/guidelines/unstable/incorporated/index.htm. Accessed May 20, 2003.

Chase MP, Fiarman GS, Scholz FJ, et al, "Angioedema of the Small Bowel Due to an Angiotensin-Converting Enzyme Inhibitor," J Clin Gastroenterol , 2000, 31(3):254-7.

Chobanian AV, Bakris GL, Black HR, et al, "The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: The JNC 7 Report," JAMA , 2003, 289(19):2560-71.

Conlin P, Moore T, Swartz S, et al, "Effect of Indomethacin on Blood Pressure Lowering by Captopril and Losartan in Hypertensive Patients," Hypertension , 2000, 36(3):461-5.

"Consensus Recommendations for the Management of Chronic Heart Failure. On Behalf of the Membership of the Advisory Council to Improve Outcomes Nationwide in Heart Failure," Am J Cardiol , 1999, 83(2A):1A-38A.

"Effects of an Angiotensin-Converting-Enzyme Inhibitor, Ramipril, on Death From Cardiovascular Causes, Myocardial Infarction, and Stroke in High-Risk Patients. The Heart Outcomes Prevention Evaluation (HOPE) Study Investigators," N Engl J Med , 2000, 342(3):145-53.

"Effects of Ramipril on Cardiovascular and Microvascular Outcomes in People with Diabetes Mellitus: Results of the HOPE Study and MICRO-HOPE Substudy. Heart Outcomes Prevention Evaluation (HOPE) Study Investigators," Lancet , 2000 355(9200):253-9.

"Guidelines for the Evaluation and Management of Heart Failure. Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Evaluation and Management of Heart Failure)," Circulation , 1995, 92(9):2764-84.

Hunt SA, Baker DW, Chin MH, et al, "ACC/AHA Guidelines for the Evaluation and Management of Chronic Heart Failure in the Adult: Executive Summary. A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1995 Guidelines for the Evaluation and Management of Heart Failure)," J Am Coll Cardiol , 2001, 38(7):2101-13.

"K/DOQI Clinical Practice Guidelines for Chronic Kidney Disease: Evaluation, Classification, and Stratification. Kidney Disease Outcome Quality Initiative," Am J Kidney Dis , 2002, 39(2 Suppl 2):1-246. Available at: http://www.kidney.org/professionals/doqi/kdoqi/toc.htm. Accessed August 1, 2003.

Packer M, Poole-Wilson PA, Armstrong PW, et al, "Comparative Effects of Low and High Doses of the Angiotensin-Converting Enzyme Inhibitor, Lisinopril, on Morbidity and Mortality in Chronic Heart Failure," Circulation , 1999, 100(23):2312-8.

Pfeffer MA, Greaves SC, Arnold JM, et al, "Early Versus Delayed Angiotensin-Converting Enzyme Inhibition Therapy in Acute Myocardial Infarction. The Healing and Early Afterload Reducing Therapy Trial," Circulation , 1997, 95(12):2643-51.

Smoger SH and Sayed MA, "Simultaneous Mucosal and Small Bowel Angioedema Due to Captopril," South Med J , 1998, 91(11):1060-3.

International Brand Names

Acovil® (ES); Altace® (CA); Carasel® (ES); Cardace® (BD, FI, IN); Corpril® (RU, TH); Delix® (DE, TR); Hypren® (AT); Lostapres® (AR); Pramace® (SE); Quark® (IT); Ramace® (AU, BE, DK, FI, LU, MX, ZA); Ramicard® (DE); Ramicar® (DO); Ramicor® (PL); Ramigamma® (DE); RamiLich® (DE); Ramipres® (DO); Ramipril 1A Pharma® (DE); Ramipril AbZ® (DE); Ramipril AL® (DE); Ramipril Basics® (DE); Ramipril beta® (DE); Ramipril Copyfarm® (DK); Ramipril dura® (DE); Ramipril GEA® (DK); Ramipril Heumann® (DE); Ramipril Hexal® (DE); Ramipril-Isis® (DE); Ramipril Nycomed® (DK); Ramipril-ratiopharm® (DE, DK); Ramipril Sandoz® (DE); Ramipril-STADA® (DE); Ramipril UNP® (DK); Ramipril von ct® (DE); Rami TAD® (DE); Triatec® (BR, CH, CL, DK, FR, ID, IT, NO, PT, SE); Tritace® (AR, AT, AU, BE, CO, CR, CZ); Tritace® (DO, EC, GB, GT, HN, HR, HU, IE, IL, LU, MX, NL, PA, PL, RO, RU, SG, SV, TH, YU, ZA); Tritace "Orifarm"® (DK); Unipril® (IT); Vagulan® (DE); Vesdil® (CH, DE); Zabien® (DE)

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