Hypertension
Altace® is indicated for the treatment of hypertension. It may be used alone or in combination with thiazide diuretics.
Reduction in the Risk of Myocardial Infarction, Stroke, and Death from Cardiovascular Causes
Altace is indicated in patients 55 years or older at high risk of developing a major cardiovascular event because of a history of coronary artery disease, stroke, peripheral vascular disease, or diabetes that is accompanied by at least one other cardiovascular risk factor (hypertension, elevated total cholesterol levels, low HDL levels, cigarette smoking, or documented microalbuminuria), to reduce the risk of myocardial infarction, stroke, or death from cardiovascular causes. Altace can be used in addition to other needed treatment (such as antihypertensive, antiplatelet, or lipid-lowering therapy) [see CLINICAL STUDIES (14.2)].
Heart Failure Post-Myocardial Infarction
Altace is indicated in stable patients who have demonstrated clinical signs of congestive heart failure within the first few days after sustaining acute myocardial infarction. Administration of Altace to such patients has been shown to decrease the risk of death (principally cardiovascular death) and to decrease the risks of failure-related hospitalization and progression to severe/resistant heart failure [see CLINICAL STUDIES (14.3)].
Altace Dosage and Administration
Hypertension
The recommended initial dose for patients not receiving a diuretic is 2.5 mg once a day. Adjust dose according to blood pressure response. The usual maintenance dosage range is 2.5 mg to 20 mg per day administered as a single dose or in two equally divided doses. In some patients treated once daily, the antihypertensive effect may diminish toward the end of the dosing interval. In such patients, consider an increase in dosage or twice daily administration. If blood pressure is not controlled with Altace alone, a diuretic can be added.
Reduction in Risk of Myocardial Infarction, Stroke, and Death from Cardiovascular Causes
Initiate dosing at 2.5 mg once daily for 1 week, 5 mg once daily for the next 3 weeks, and then increase as tolerated, to a maintenance dose of 10 mg once daily. If the patient is hypertensive or recently post-myocardial infarction, Altace can also be given as a divided dose.
Heart Failure Post-Myocardial Infarction
For the treatment of post-myocardial infarction patients who have shown signs of congestive heart failure, the recommended starting dose of Altace is 2.5 mg twice daily (5 mg per day). A patient who becomes hypotensive at this dose may be switched to 1.25 mg twice daily. After one week at the starting dose, increase dose (if tolerated) toward a target dose of 5 mg twice daily, with dosage increases being about 3 weeks apart.
After the initial dose of Altace, observe the patient under medical supervision for at least two hours and until blood pressure has stabilized for at least an additional hour. If possible, reduce the dose of any concomitant diuretic as this may diminish the likelihood of hypotension. The appearance of hypotension after the initial dose of Altace does not preclude subsequent careful dose titration with the drug, following effective management of the hypotension [see WARNINGS AND PRECAUTIONS (5.5), DRUG INTERACTIONS (7.1)].
General Dosing Information
Generally, swallow Altace capsules whole. The Altace capsule can also be opened and the contents sprinkled on a small amount (about 4 oz.) of applesauce or mixed in 4 oz. (120 mL) of water or apple juice. To be sure that ramipril is not lost when such a mixture is used, consume the mixture in its entirety. The described mixtures can be pre-prepared and stored for up to 24 hours at room temperature or up to 48 hours under refrigeration.
Concomitant administration of Altace with potassium supplements, potassium salt substitutes, or potassium-sparing diuretics can lead to increases of serum potassium [see WARNINGS AND PRECAUTIONS (5.8)].
Dosage Adjustment
Renal Impairment
Establish baseline renal function in patients initiating Altace. Usual regimens of therapy with Altace may be followed in patients with estimated creatinine clearance >40 mL/min. However, in patients with worse impairment, 25% of the usual dose of ramipril is expected to produce full therapeutic levels of ramiprilat [see USE IN SPECIFIC POPULATIONS (8.6)].
Hypertension
For patients with hypertension and renal impairment, the recommended initial dose is 1.25 mg Altace once daily. Dosage may be titrated upward until blood pressure is controlled or to a maximum total daily dose of 5 mg.
Heart Failure Post-Myocardial Infarction
For patients with heart failure and renal impairment, the recommended initial dose is 1.25 mg Altace once daily. The dose may be increased to 1.25 mg twice daily, and up to a maximum dose of 2.5 mg twice daily depending on clinical response and tolerability.
Volume Depletion or Renal Artery Stenosis
Blood pressure decreases associated with any dose of Altace depend, in part, on the presence or absence of volume depletion (e.g., past and current diuretic use) or the presence or absence of renal artery stenosis. If such circumstances are suspected to be present, initiate dosing at 1.25 mg once daily. Adjust dosage according to blood pressure response.
Dosage Forms and Strengths
Altace (ramipril) is supplied as hard gelatin capsules containing 1.25 mg, 2.5 mg, 5 mg, and 10 mg of ramipril.
Contraindications
Altace is contraindicated in patients who are hypersensitive to this product or any other ACE inhibitor (e.g., a patient who has experienced angioedema during therapy with any other ACE inhibitor).
Warnings and Precautions
Anaphylactoid and Possibly Related Reactions
Presumably because drugs that act directly on the renin-angiotensin-aldosterone system (e.g., ACE inhibitors) affect the metabolism of eicosanoids and polypeptides, including endogenous bradykinin, patients receiving these drugs (including Altace) may be subject to a variety of adverse reactions, some of them serious.
Angioedema
Head and Neck Angioedema
Patients with a history of angioedema unrelated to ACE inhibitor therapy may be at increased risk of angioedema while receiving an ACE inhibitor.
Angioedema of the face, extremities, lips, tongue, glottis, and larynx has been reported in patients treated with ACE inhibitors. Angioedema associated with laryngeal edema can be fatal. If laryngeal stridor or angioedema of the face, tongue, or glottis occurs, discontinue treatment with Altace and institute appropriate therapy immediately. Where there is involvement of the tongue, glottis, or larynx likely to cause airway obstruction, administer appropriate therapy (e.g., subcutaneous epinephrine solution 1:1000 [0.3 mL to 0.5 mL]) promptly [see ADVERSE REACTIONS (6)].
In considering the use of Altace, note that in controlled clinical trials ACE inhibitors cause a higher rate of angioedema in Black patients than in non-Black patients.
In a large U.S. post-marketing study, angioedema (defined as reports of angio, face, larynx, tongue, or throat edema) was reported in 3/1523 (0.20%) Black patients and in 8/8680 (0.09%) non-Black patients. These rates were not different statistically.
Intestinal Angioedema
Intestinal angioedema has been reported in patients treated with ACE inhibitors. These patients presented with abdominal pain (with or without nausea or vomiting); in some cases there was no prior history of facial angioedema and C-1 esterase levels were normal. The angioedema was diagnosed by procedures including abdominal CT scan or ultrasound, or at surgery, and symptoms resolved after stopping the ACE inhibitor. Include intestinal angioedema in the differential diagnosis of patients on ACE inhibitors presenting with abdominal pain.
Anaphylactoid Reactions During Desensitization
Two patients undergoing desensitizing treatment with hymenoptera venom while receiving ACE inhibitors sustained life-threatening anaphylactoid reactions. In the same patients, these reactions were avoided when ACE inhibitors were temporarily withheld, but they reappeared upon inadvertent rechallenge.
Anaphylactoid Reactions During Membrane Exposure
Anaphylactoid reactions have been reported in patients dialyzed with high-flux membranes and treated concomitantly with an ACE inhibitor. Anaphylactoid reactions have also been reported in patients undergoing low-density lipoprotein apheresis with dextran sulfate absorption.
Hepatic Failure and Impaired Liver Function
Rarely, ACE inhibitors, including Altace, have been associated with a syndrome that starts with cholestatic jaundice and progresses to fulminant hepatic necrosis and sometimes death. The mechanism of this syndrome is not understood. Discontinue Altace if patient develops jaundice or marked elevations of hepatic enzymes.
As ramipril is primarily metabolized by hepatic esterases to its active moiety, ramiprilat, patients with impaired liver function could develop markedly elevated plasma levels of ramipril. No formal pharmacokinetic studies have been carried out in hypertensive patients with impaired liver function.
Renal Impairment
As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in susceptible individuals. In patients with severe congestive heart failure whose renal function may depend on the activity of the renin-angiotensin-aldosterone system, treatment with ACE inhibitors, including Altace, may be associated with oliguria or progressive azotemia and rarely with acute renal failure or death.
In hypertensive patients with unilateral or bilateral renal artery stenosis, increases in blood urea nitrogen and serum creatinine may occur. Experience with another ACE inhibitor suggests that these increases would be reversible upon discontinuation of Altace and/or diuretic therapy. In such patients, monitor renal function during the first few weeks of therapy. Some hypertensive patients with no apparent pre-existing renal vascular disease have developed increases in blood urea nitrogen and serum creatinine, usually minor and transient, especially when Altace has been given concomitantly with a diuretic. This is more likely to occur in patients with pre-existing renal impairment. Dosage reduction of Altace and/or discontinuation of the diuretic may be required.
Neutropenia and Agranulocytosis
In rare instances, treatment with ACE inhibitors may be associated with mild reductions in red blood cell count and hemoglobin content, blood cell or platelet counts. In isolated cases, agranulocytosis, pancytopenia, and bone marrow depression may occur. Hematological reactions to ACE inhibitors are more likely to occur in patients with collagen-vascular disease (e.g., systemic lupus erythematosus, scleroderma) and renal impairment. Consider monitoring white blood cell counts in patients with collagen-vascular disease, especially if the disease is associated with impaired renal function.
Hypotension
General Considerations
Altace can cause symptomatic hypotension, after either the initial dose or a later dose when the dosage has been increased. Like other ACE inhibitors, Altace, has been only rarely associated with hypotension in uncomplicated hypertensive patients. Symptomatic hypotension is most likely to occur in patients who have been volume- and/or salt-depleted as a result of prolonged diuretic therapy, dietary salt restriction, dialysis, diarrhea, or vomiting. Correct volume- and salt-depletion before initiating therapy with Altace.
If excessive hypotension occurs, place the patient in a supine position and, if necessary, treat with intravenous infusion of physiological saline. Altace treatment usually can be continued following restoration of blood pressure and volume.
Heart Failure Post-Myocardial Infarction
In patients with heart failure post-myocardial infarction who are currently being treated with a diuretic, symptomatic hypotension occasionally can occur following the initial dose of Altace. If the initial dose of 2.5 mg Altace cannot be tolerated, use an initial dose of 1.25 mg Altace to avoid excessive hypotension. Consider reducing the dose of concomitant diuretic to decrease the incidence of hypotension.
Congestive Heart Failure
In patients with congestive heart failure, with or without associated renal insufficiency, ACE inhibitor therapy may cause excessive hypotension, which may be associated with oliguria or azotemia and rarely, with acute renal failure and death. In such patients, initiate Altace therapy under close medical supervision and follow patients closely for the first 2 weeks of treatment and whenever the dose of Altace or diuretic is increased.
Surgery and Anesthesia
In patients undergoing surgery or during anesthesia with agents that produce hypotension, ramipril may block angiotensin II formation that would otherwise occur secondary to compensatory renin release. Hypotension that occurs as a result of this mechanism can be corrected by volume expansion.
Fetal/Neonatal Morbidity and Mortality
Angiotensin converting enzyme inhibitors can cause fetal and neonatal morbidity and death when administered to pregnant women. Several dozen cases have been reported in the world literature. When pregnancy is detected, discontinue ACE inhibitors as soon as possible.
The use of ACE inhibitors during the second and third trimesters of pregnancy has been associated with fetal and neonatal injury, including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death. Oligohydramnios has also been reported, presumably resulting from decreased fetal renal function; oligohydramnios in this setting has been associated with fetal limb contractures, craniofacial deformation, and hypoplastic lung development. Prematurity, intrauterine growth retardation, and patent ductus arteriosus have also been reported, although it is not clear whether these occurrences were caused by the ACE inhibitor exposure.
In a published retrospective epidemiological study, infants whose mothers had taken an ACE inhibitor during their first trimester of pregnancy appeared to have an increased risk of major congenital malformations compared with infants whose mothers had not undergone first trimester exposure to ACE inhibitor drugs. The number of cases of birth defects is small and the findings of this study have not yet been confirmed.
Rarely (probably less than once in every thousand pregnancies), no alternative to a drug acting on the renin-angiotensin-aldosterone system will be found. In these rare cases, inform mothers about the potential hazards to their fetuses, and perform serial ultrasound examinations to assess the intraamniotic environment.
If oligohydramnios is observed, discontinue Altace unless it is considered life-saving for the mother. Contraction stress testing, a nonstress test, or biophysical profiling may be appropriate, depending upon the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury.
Closely observe infants with histories of in utero exposure to ACE inhibitors for hypotension, oliguria, and hyperkalemia. If oliguria occurs, direct attention towards support of blood pressure and renal perfusion. Exchange transfusion or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function. Ramipril, which crosses the placenta, can be removed from the neonatal circulation by these means, but limited experience has not shown that such removal is central to the treatment of these infants.
Dual Blockade of the Renin-Angiotensin-Aldosterone System
Telmisartan
The ONTARGET trial enrolled 25,620 patients >55 years old with atherosclerotic disease or diabetes with end-organ damage, randomized them to telmisartan only, ramipril only, or the combination, and followed them for a median of 56 months. Patients receiving the combination of telmisartan and ramipril did not obtain any benefit in the composite endpoint of cardiovascular death, MI, stroke and heart failure hospitalization compared to monotherapy, but experienced an increased incidence of clinically important renal dysfunction (death, doubling of serum creatinine, or dialysis) compared with groups receiving telmisartan alone or ramipril alone. Concomitant use of telmisartan and ramipril is not recommended.
Hyperkalemia
In clinical trials with Altace, hyperkalemia (serum potassium >5.7 mEq/L) occurred in approximately 1% of hypertensive patients receiving Altace. In most cases, these were isolated values, which resolved despite continued therapy. None of these patients were discontinued from the trials because of hyperkalemia. Risk factors for the development of hyperkalemia include renal insufficiency, diabetes mellitus, and the concomitant use of potassium-sparing diuretics, potassium supplements, and/or potassium-containing salt substitutes, which should be used cautiously, if at all, with Altace [ see DRUG INTERACTIONS (7.1)].
Cough
Presumably caused by inhibition of the degradation of endogenous bradykinin, persistent nonproductive cough has been reported with all ACE inhibitors, always resolving after discontinuation of therapy. Consider the possibility of angiotensin converting enzyme inhibitor induced-cough in the differential diagnosis of cough.
Adverse Reactions
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Hypertension
Altace has been evaluated for safety in over 4000 patients with hypertension; of these, 1230 patients were studied in U.S. controlled trials, and 1107 were studied in foreign controlled trials. Almost 700 of these patients were treated for at least one year. The overall incidence of reported adverse events was similar in Altace and placebo patients. The most frequent clinical side effects (possibly or probably related to study drug) reported by patients receiving Altace in placebo-controlled trials were: headache (5.4%), dizziness (2.2%), and fatigue or asthenia (2.0%), but only the last one was more common in Altace patients than in patients given placebo. Generally the side effects were mild and transient, and there was no relation to total dosage within the range of 1.25 mg–20 mg. Discontinuation of therapy because of a side effect was required in approximately 3% of U.S. patients treated with Altace. The most common reasons for discontinuation were: cough (1.0%), dizziness (0.5%), and impotence (0.4%).
Of observed side effects considered possibly or probably related to study drug that occurred in U.S. placebo-controlled trials in more than 1% of patients treated with Altace, only asthenia (fatigue) was more common on Altace than placebo (2% [n=13/651] vs. 1% [n=2/286], respectively).
In placebo-controlled trials, there was also an excess of upper respiratory infection and flu syndrome in the Altace group, not attributed at that time to ramipril. As these studies were carried out before the relationship of cough to ACE inhibitors was recognized, some of these events may represent ramipril-induced cough. In a later 1-year study, increased cough was seen in almost 12% of Altace patients, with about 4% of patients requiring discontinuation of treatment.
Reduction in the Risk of Myocardial Infarction, Stroke, and Death from Cardiovascular Causes
HOPE Study
Safety data in the Heart Outcomes Prevention Evaluation (HOPE) study were collected as reasons for discontinuation or temporary interruption of treatment. The incidence of cough was similar to that seen in the Acute Infarction Ramipril Efficacy (AIRE) trial. The rate of angioedema was the same as in previous clinical trials [see WARNINGS AND PRECAUTIONS (5.1)].
Table 1. Reasons for Discontinuation or Temporary Interruption of Treatment—HOPE Study
|
Placebo
(N=4652) |
Altace
(N=4645) |
| Discontinuation at any time |
32% |
34% |
| Permanent discontinuation |
28% |
29% |
| Reasons for stopping |
|
| Cough |
2% |
7% |
| Hypotension or dizziness |
1.5% |
1.9% |
| Angioedema |
0.1% |
0.3% |
Heart Failure Post-Myocardial Infarction
AIRE Study
Adverse reactions (except laboratory abnormalities) considered possibly/probably related to study drug that occurred in more than 1% of patients and more frequently on Altace are shown below. The incidences are from the AIRE study. The follow-up time was between 6 and 46 months for this study.
Table 2. Percentage of Patients with Adverse Events Possibly/ Probably Related to Study Drug—Placebo-Controlled (AIRE) Mortality Study
| Adverse Event |
Placebo
(N=982) |
Altace
(N=1004) |
| Hypotension |
5% |
11% |
| Cough increased |
4% |
8% |
| Dizziness |
3% |
4% |
| Angina pectoris |
2% |
3% |
| Nausea |
1% |
2% |
| Postural hypotension |
1% |
2% |
| Syncope |
1% |
2% |
| Vomiting |
0.5% |
2% |
| Vertigo |
0.7% |
2% |
| Abnormal kidney function |
0.5% |
1% |
| Diarrhea |
0.4% |
1% |
Other Adverse Reactions
Other adverse reactions reported in controlled clinical trials (in less than 1% of Altace patients), or rarer events seen in post-marketing experience, include the following (in some, a causal relationship to drug is uncertain):
Body as a whole: Anaphylactoid reactions [see WARNINGS AND PRECAUTIONS (5.1)].
Cardiovascular: Symptomatic hypotension (reported in 0.5% of patients in U.S. trials) [see WARNINGS AND PRECAUTIONS (5.5)], syncope, and palpitations.
Hematologic: Pancytopenia, hemolytic anemia, and thrombocytopenia.
Decreases in hemoglobin or hematocrit (a low value and a decrease of 5 g/dL or 5%, respectively) were rare, occurring in 0.4% of patients receiving Altace alone and in 1.5% of patients receiving Altace plus a diuretic.
Renal: Acute renal failure. Some hypertensive patients with no apparent pre-existing renal disease have developed minor, usually transient, increases in blood urea nitrogen and serum creatinine when taking Altace, particularly when Altace was given concomitantly with a diuretic [see WARNINGS AND PRECAUTIONS (5.3)].
Angioneurotic edema: Angioneurotic edema has been reported in 0.3% of patients in U.S. clinical trials of Altace [see WARNINGS AND PRECAUTIONS (5.1)].
Gastrointestinal: Hepatic failure, hepatitis, jaundice, pancreatitis, abdominal pain (sometimes with enzyme changes suggesting pancreatitis), anorexia, constipation, diarrhea, dry mouth, dyspepsia, dysphagia, gastroenteritis, increased salivation, and taste disturbance.
Dermatologic: Apparent hypersensitivity reactions (manifested by urticaria, pruritus, or rash, with or without fever), photosensitivity, purpura, onycholysis, pemphigus, pemphigoid, erythema multiforme, toxic epidermal necrolysis, and Stevens-Johnson syndrome.
Neurologic and Psychiatric: Anxiety, amnesia, convulsions, depression, hearing loss, insomnia, nervousness, neuralgia, neuropathy, paresthesia, somnolence, tinnitus, tremor, vertigo, and vision disturbances.
Miscellaneous: As with other ACE inhibitors, a symptom complex has been reported which may include a positive ANA, an elevated erythrocyte sedimentation rate, arthralgia/arthritis, myalgia, fever, vasculitis, eosinophilia, photosensitivity, rash and other dermatologic manifestations. Additionally, as with other ACE inhibitors, eosinophilic pneumonitis has been reported.
Other: Arthralgia, arthritis, dyspnea, edema, epistaxis, impotence, increased sweating, malaise, myalgia, and weight gain.
Post-Marketing Experience
In addition to adverse reactions reported from clinical trials, there have been rare reports of hypoglycemia reported during Altace therapy when given to patients concomitantly taking oral hypoglycemic agents or insulin. The causal relationship is unknown.
Clinical Laboratory Test Findings
Creatinine and Blood Urea Nitrogen: Increases in creatinine levels occurred in 1.2% of patients receiving Altace alone, and in 1.5% of patients receiving Altace and a diuretic. Increases in blood urea nitrogen levels occurred in 0.5% of patients receiving Altace alone and in 3% of patients receiving Altace with a diuretic. None of these increases required discontinuation of treatment. Increases in these laboratory values are more likely to occur in patients with renal insufficiency or those pretreated with a diuretic and, based on experience with other ACE inhibitors, would be expected to be especially likely in patients with renal artery stenosis [see WARNINGS AND PRECAUTIONS (5.3)]. As ramipril decreases aldosterone secretion, elevation of serum potassium can occur. Use potassium supplements and potassium sparing diuretics with caution, and monitor the patient’s serum potassium frequently [see WARNINGS AND PRECAUTIONS (5.8)].
Hemoglobin and Hematocrit: Decreases in hemoglobin or hematocrit (a low value and a decrease of 5 g/dL or 5%, respectively) were rare, occurring in 0.4% of patients receiving Altace alone and in 1.5% of patients receiving Altace plus a diuretic. No US patients discontinued treatment because of decreases in hemoglobin or hematocrit.
Other (causal relationships unknown): Clinically important changes in standard laboratory tests were rarely associated with Altace administration. Elevations of liver enzymes, serum bilirubin, uric acid, and blood glucose have been reported, as have cases of hyponatremia and scattered incidents of leucopenia, eosinophilia, and proteinuria. In US trials, less than 0.2% of patients discontinued treatment for laboratory abnormalities; all of these were cases of proteinuria or abnormal liver-function tests.
Drug Interactions
Diuretics
Patients on diuretics, especially those in whom diuretic therapy was recently instituted, may occasionally experience an excessive reduction of blood pressure after initiation of therapy with Altace. The possibility of hypotensive effects with Altace can be minimized by either decreasing or discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with Altace. If this is not possible, reduce the starting dose [see DOSAGE AND ADMINISTRATION (2)].
Altace can attenuate potassium loss caused by thiazide diuretics. Potassium-sparing diuretics (spironolactone, amiloride, triamterene, and others) or potassium supplements can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, monitor the patient's serum potassium frequently.
Other Antihypertensive Agents
Limited experience in controlled and uncontrolled trials combining Altace with a calcium channel blocker, a loop diuretic, or triple therapy (beta-blocker, vasodilator, and a diuretic) indicate no unusual drug-drug interactions. Other ACE inhibitors have had less than additive effects with beta adrenergic blockers, presumably because both drug classes lower blood pressure by inhibiting parts of the renin-angiotensin-aldosterone system.
The combination of ramipril and propranolol showed no adverse effects on dynamic parameters (blood pressure and heart rate).
In a large-scale, long-term clinical efficacy study, the combination of telmisartan and ramipril resulted in an increased incidence of clinically important renal dysfunction (death, doubling of serum creatinine, dialysis) compared with groups receiving either drug alone. Therefore, concomitant use of telmisartan and ramipril is not recommended [see Dual Blockade of the Renin-Angiotensin-Aldosterone System (5.7)].
Lithium
Increased serum lithium levels and symptoms of lithium toxicity have been reported in patients receiving ACE inhibitors during therapy with lithium; therefore, frequent monitoring of serum lithium levels is recommended. If a diuretic is also used, the risk of lithium toxicity may be increased.
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 Altace.
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 ramipril, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving ramipril and NSAID therapy.
The antihypertensive effect of ACE inhibitors, including ramipril, may be attenuated by NSAIDs.
Other
Neither ramipril nor its metabolites have been found to interact with food, digoxin, antacid, furosemide, cimetidine, indomethacin, and simvastatin. The co-administration of ramipril and warfarin did not adversely affect the anticoagulation effects of the latter drug. Additionally, co-administration of ramipril with phenprocoumon did not affect minimum phenprocoumon levels or interfere with the patients’ state of anticoagulation.
USE IN SPECIFIC POPULATIONS
Pregnancy
Pregnancy Categories C (first trimester) and D (second and third trimesters) [see WARNINGS AND PRECAUTIONS (5.6)].
Nursing Mothers
Ingestion of a single 10 mg oral dose of Altace resulted in undetectable amounts of ramipril and its metabolites in breast milk. However, because multiple doses may produce low milk concentrations that are not predictable from a single dose, do not use Altace in nursing mothers.
Pediatric Use
Safety and effectiveness in pediatric patients have not been established. Irreversible kidney damage has been observed in very young rats given a single dose of Altace.
Geriatric Use
Of the total number of patients who received Altace in U.S. clinical studies of Altace, 11.0% were ≥65 years of age while 0.2% were ≥75 years of age. No overall differences in effectiveness or safety were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but a greater sensitivity of some older individuals cannot be ruled out.
One pharmacokinetic study conducted in hospitalized elderly patients indicated that peak ramiprilat levels and area under the plasma concentration-time curve (AUC) for ramiprilat are higher in older patients.
Renal Impairment
A single-dose pharmacokinetic study was conducted in hypertensive patients with varying degrees of renal impairment who received a single 10 mg dose of ramipril. Patients were stratified into four groups based on initial estimates of creatinine clearance: normal (>80 mL/min), mild impairment (40-80 mL/min), moderate impairment (15-40 mL/min), and severe impairment (<15 mL/min). On average, the AUC0-24h for ramiprilat was approximately 1.7-fold higher, 3.0-fold higher, and 3.2-fold higher in the groups with mild, moderate, and severe renal impairment, respectively, compared to the group with normal renal function. Overall, the results suggest that the starting dose of ramipril should be adjusted downward in patients with moderate-to-severe renal impairment.
Overdosage
Single oral doses of ramipril in rats and mice of 10 g/kg–11 g/kg resulted in significant lethality. In dogs, oral doses as high as 1 g/kg induced only mild gastrointestinal distress. Limited data on human overdosage are available. The most likely clinical manifestations would be symptoms attributable to hypotension.
Laboratory determinations of serum levels of ramipril and its metabolites are not widely available, and such determinations have, in any event, no established role in the management of ramipril overdose.
No data are available to suggest physiological maneuvers (e.g., maneuvers to change the pH of the urine) that might accelerate elimination of ramipril and its metabolites. Similarly, it is not known which, if any, of these substances can be effectively removed from the body by hemodialysis.
Angiotensin II could presumably serve as a specific antagonist-antidote in the setting of ramipril overdose, but angiotensin II is essentially unavailable outside of scattered research facilities. Because the hypotensive effect of ramipril is achieved through vasodilation and effective hypovolemia, it is reasonable to treat ramipril overdose by infusion of normal saline solution.
Altace Description
Ramipril is a 2-aza-bicyclo [3.3.0]-octane-3-carboxylic acid derivative. It is a white, crystalline substance soluble in polar organic solvents and buffered aqueous solutions. Ramipril melts between 105°–112°C.
The CAS Registry Number is 87333-19-5. Ramipril’s chemical name is (2S,3aS,6aS)-1[(S)-N-[(S)-1-Carboxy-3-phenylpropyl] alanyl] octahydrocyclopenta [b]pyrrole-2-carboxylic acid, 1-ethyl ester.
The inactive ingredients present are pregelatinized starch NF, gelatin, and titanium dioxide. The 1.25 mg capsule shell contains yellow iron oxide, the 2.5 mg capsule shell contains D&C yellow #10 and FD&C red #40, the 5 mg capsule shell contains FD&C blue #1 and FD&C red #40, and the 10 mg capsule shell contains FD&C blue #1.
The structural formula for ramipril is:
Its empirical formula is C23H32N2O5 and its molecular weight is 416.5.
Ramiprilat, the diacid metabolite of ramipril, is a non-sulfhydryl ACE inhibitor. Ramipril is converted to ramiprilat by hepatic cleavage of the ester group.
Altace - Clinical Pharmacology
Mechanism of Action
Ramipril and ramiprilat inhibit ACE in human subjects and animals. Angiotensin converting enzyme 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 hypertensive patients with normal renal function treated with Altace alone for up to 56 weeks, approximately 4% of patients during the trial had an abnormally high serum potassium and an increase from baseline greater than 0.75 mEq/L, and none of the patients had an abnormally low potassium and a decrease from baseline greater than 0.75 mEq/L. In the same study, approximately 2% of patients treated with Altace and hydrochlorothiazide for up to 56 weeks had abnormally high potassium values and an increase from baseline of 0.75 mEq/L or greater; and approximately 2% had abnormally low values and decreases from baseline of 0.75 mEq/L or greater [see WARNINGS AND PRECAUTIONS (5.8)]. Removal of angiotensin II negative feedback on renin secretion leads to increased plasma renin activity.
The effect of ramipril on hypertension appears to result at least in part from inhibition of both tissue and circulating ACE activity, thereby reducing angiotensin II formation in tissue and plasma.
Angiotensin converting enzyme is identical to kininase, an enzyme that degrades bradykinin. Whether increased levels of bradykinin, a potent vasopressor peptide, play a role in the therapeutic effects of Altace remains to be elucidated.
While the mechanism through which Altace lowers blood pressure is believed to be primarily suppression of the renin-angiotensin-aldosterone system, Altace has an antihypertensive effect even in patients with low-renin hypertension. Although Altace was antihypertensive in all races studied, Black hypertensive patients (usually a low-renin hypertensive population) had a blood pressure lowering response to monotherapy, albeit a smaller average response, than non-Black patients.
Pharmacodynamics
Single doses of ramipril of 2.5 mg–20 mg produce approximately 60%–80% inhibition of ACE activity 4 hours after dosing with approximately 40%–60% inhibition after 24 hours. Multiple oral doses of ramipril of 2.0 mg or more cause plasma ACE activity to fall by more than 90% 4 hours after dosing, with over 80% inhibition of ACE activity remaining 24 hours after dosing. The more prolonged effect of even small multiple doses presumably reflects saturation of ACE binding sites by ramiprilat and relatively slow release from those sites.
Pharmacokinetics
Absorption
Following oral administration of Altace, peak plasma concentrations (Cmax) of ramipril are reached within 1 hour. The extent of absorption is at least 50%–60%, and is not significantly influenced by the presence of food in the gastrointestinal tract, although the rate of absorption is reduced.
In a trial in which subjects received Altace capsules or the contents of identical capsules dissolved in water, dissolved in apple juice, or suspended in applesauce, serum ramiprilat levels were essentially unrelated to the use or non-use of the concomitant liquid or food.
Distribution
Cleavage of the ester group (primarily in the liver) converts ramipril to its active diacid metabolite, ramiprilat. Peak plasma concentrations of ramiprilat are reached 2–4 hours after drug intake. The serum protein binding of ramipril is about 73% and that of ramiprilat about 56%; in vitro, these percentages are independent of concentration over the range of 0.01 µg/mL–10 µg/mL.
Metabolism
Ramipril is almost completely metabolized to ramiprilat, which has about 6 times the ACE inhibitory activity of ramipril, and to the diketopiperazine ester, the diketopiperazine acid, and the glucuronides of ramipril and ramiprilat, all of which are inactive.
Plasma concentrations of ramipril and ramiprilat increase with increased dose, but are not strictly dose-proportional. The 24-hour AUC for ramiprilat, however, is dose-proportional over the 2.5 mg-20 mg dose range. The absolute bioavailabilities of ramipril and ramiprilat were 28% and 44%, respectively, when 5 mg of oral ramipril was compared with the same dose of ramipril given intravenously.
After once-daily dosing, steady-state plasma concentrations of ramiprilat are reached by the fourth dose. Steady-state concentrations of ramiprilat are somewhat higher than those seen after the first dose of Altace, especially at low doses (2.5 mg), but the difference is clinically insignificant.
Plasma concentrations of ramiprilat decline in a triphasic manner (initial rapid decline, apparent elimination phase, terminal elimination phase). The initial rapid decline, which represents distribution of the drug into a large peripheral compartment and subsequent binding to both plasma and tissue ACE, has a half-life of 2–4 hours. Because of its potent binding to ACE and slow dissociation from the enzyme, ramiprilat shows two elimination phases. The apparent elimination phase corresponds to the clearance of free ramiprilat and has a half-life of 9–18 hours. The terminal elimination phase has a prolonged half-life (>50 hours) and probably represents the binding/dissociation kinetics of the ramiprilat/ACE complex. It does not contribute to the accumulation of the drug. After multiple daily doses of Altace 5 mg-10 mg, the half-life of ramiprilat concentrations within the therapeutic range was 13–17 hours.
In patients with creatinine clearance <40 mL/min/1.73 m2, peak levels of ramiprilat are approximately doubled, and trough levels may be as much as quintupled. In multiple-dose regimens, the total exposure to ramiprilat (AUC) in these patients is 3–4 times as large as it is in patients with normal renal function who receive similar doses.
In patients with impaired liver function, the metabolism of ramipril to ramiprilat appears to be slowed, possibly because of diminished activity of hepatic esterases, and plasma ramipril levels in
