Altace

Altace information, interactions and side effects, 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-3phenylpropyl] 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:

Altace

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.

INDICATIONS

Hypertension

ALTACE is indicated for the treatment of hypertension, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes including this drug.

Control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake. Many patients will require more than one drug to achieve blood pressure goals. For specific advice on goals and management, see published guidelines, such as those of the National High Blood Pressure Education Program’s Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC).

Numerous antihypertensive drugs, from a variety of pharmacologic classes and with different mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other pharmacologic property of the drugs, that is largely responsible for those benefits. The largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular mortality also have been seen regularly.

Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per mmHg is greater at higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit. Relative risk reduction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit is greater in patients who are at higher risk independent of their hypertension (for example, patients with diabetes or hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to a lower blood pressure goal.

Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and many antihypertensive drugs have additional approved indications and effects (e.g., on angina, heart failure, or diabetic kidney disease). These considerations may guide selection of therapy.

ALTACE 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).

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.

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.

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.

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.

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.

HOW SUPPLIED

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.

Storage And Handling

ALTACE is available in 1.25 mg, 2.5 mg, 5 mg, and 10 mg hard gelatin capsules. Descriptions of ALTACE capsules are summarized below.

 

Capsule Strength Capsule Color Package Configuration NDC#
1.25 mg yellow Bottle of 100 61570-110-01
2.5 mg orange Bottle of 100 61570-111-01
5 mg red Bottle of 100 61570-112-01
10 mg Process Blue Bottle of 100 61570-120-01

Dispense in well-closed container with safety closure.

Store at controlled room temperature (59°–86°F).

SIDE EFFECTS

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.

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.

Cardiovascular: Symptomatic hypotension (reported in 0.5% of patients in U.S. trials), 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.

Angioneurotic edema: Angioneurotic edema has been reported in 0.3% of patients in U.S. clinical trials of ALTACE.

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. 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.

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.

Agents Increasing Serum Potassium

Coadministration of ALTACE with other drugs that raise serum potassium levels may result in hyperkalemia. Monitor serum potassium in such patients.

Other Agents Affecting RAS

In general, avoid combined use of RAS inhibitors. Do not co-administer aliskiren with ALTACE in patients with diabetes.

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.

mTOR Inhibitors

Patients taking concomitant mTOR inhibitor (e.g. temsirolimus) therapy may be at increased risk for angioedema.

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.

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.

Patients taking concomitant mTOR inhibitor (e.g. temsirolimus) therapy may be at increased risk for angioedema.

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 Toxicity

Pregnancy Category D

Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue ALTACE as soon as possible.

Dual Blockade Of The Renin-Angiotensin System

Dual blockade of the RAS with angiotensin receptor blockers, ACE inhibitors, or aliskiren is associated with increased risks of hypotension, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy. Most patients receiving the combination of two RAS inhibitors do not obtain any additional benefit compared to monotherapy. In general, avoid combined use of RAS inhibitors. Closely monitor blood pressure, renal function and electrolytes in patients on ALTACE and other agents that affect the RAS.

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.

Aliskiren

Do not co-administer aliskiren with ALTACE in patients with diabetes. Avoid concomitant use of aliskiren with ALTACE in patients with renal impairment (GFR < 60 mL/min/1.73 man 2).

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 other drugs that raise serum potassium levels. Monitor serum potassium in such patients.

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.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

No evidence of a tumorigenic effect was found when ramipril was given by gavage to rats for up to 24 months at doses of up to 500 mg/kg/day or to mice for up to 18 months at doses of up to 1000 mg/kg/day. (For either species, these doses are about 200 times the maximum recommended human dose when compared on the basis of body surface area.) No mutagenic activity was detected in the Ames test in bacteria, the micronucleus test in mice, unscheduled DNA synthesis in a human cell line, or a forward gene-mutation assay in a Chinese hamster ovary cell line. Several metabolites and degradation products of ramipril were also negative in the Ames test. A study in rats with dosages as great as 500 mg/kg/day did not produce adverse effects on fertility.

No teratogenic effects of ramipril were seen in studies of pregnant rats, rabbits, and cynomolgus monkeys. On a body surface area basis, the doses used were up to approximately 400 times (in rats and monkeys) and 2 times (in rabbits) the recommended human dose.

Use In Specific Populations

Pregnancy

Pregnancy Category D

Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue ALTACE as soon as possible. These adverse outcomes are usually associated with use of these drugs in the second and third trimester of pregnancy. Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents. Appropriate management of maternal hypertension during pregnancy is important to optimize outcomes for both mother and fetus.

In the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus. Perform serial ultrasound examinations to assess the intra-amniotic environment. If oligohydramnios is observed, discontinue ALTACE unless it is considered life-saving for the mother. Fetal testing may be appropriate, based on 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 ALTACE for hypotension, oliguria, and hyperkalemia.

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

Neonates with a history of in utero exposure to ALTACE: If oliguria or hypotension occurs, direct attention toward support of blood pressure and renal perfusion. Exchange transfusions 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. 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.

OVERDOSE

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.

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). Do not co-administer ALTACE with aliskiren:

  • in patients with diabetes
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