WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS Angioedema, increased risk in patients with a prior history ( 5.1 ) Hypotension and hyperkalemia ( 5.5 , 5.8 ) Renal impairment: monitor renal function during therapy ( 5.3 ) Avoid concomitant use of an ACE inhibitor and angiotensin blocker ( 5.7 ) Rare cholestatic jaundice and hepatic failure ( 5.2 ) Rare neutropenia and agranulocytosis ( 5.4 ) 5.1 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.

Patients taking concomitant mammalian target of rapamycin (mTOR) inhibitor (e.g.

temsirolimus) therapy or a neprilysin inhibitor may be at increased risk for angioedema [see Drug Interactions (7.7) ] .

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.

5.2 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.

5.3 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.

5.4 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.

5.5 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.

5.6 Fetal Toxicity 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 [see Use in Specific Populations (8.1) ] .

5.7 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 m 2 ) .

5.8 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 [see Drug Interactions (7.2) ] .

5.9 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.