WARNINGS

Anaphylactoid and Possibly Related Reactions: Presumably because angiotensin-converting enzyme inhibitors affect the metabolism of eicosanoids and polypeptides, including endogenous bradykinin, patients receiving ACE inhibitors (including ACEON® Tablets) may be subject to a variety of adverse reactions, some of them serious.

Angioedema: Angioedema involving the face, extremities, lips, tongue, glottis and/or larynx has been reported in patients treated with ACE inhibitors, including ACEON® (perindopril erbumine) Tablets (0.1% of patients treated with ACEON® Tablets in U.S. clinical trials). In such cases, ACEON® Tablets should be promptly discontinued and the patient carefully observed until the swelling disappears. In instances where swelling has been confined to the face and lips, the condition has generally resolved without treatment, although antihistamines have been useful in relieving symptoms. Angioedema associated with involvement of the tongue, glottis or larynx may be fatal due to airway obstruction. Appropriate therapy, such as subcutaneous epinephrine solution 1:1000 (0.3 to 0.5 mL), should be promptly administered. Patients with a history of angioedema unrelated to ACE inhibitor therapy may be at increased risk of angioedema while receiving an ACE inhibitor.

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.

Hypotension: Like other ACE inhibitors, ACEON® Tablets can cause symptomatic hypotension. ACEON® Tablets has been associated with hypotension in 0.3% of uncomplicated hypertensive patients in U.S. placebo-controlled trials. Symptoms related to orthostatic hypotension were reported in another 0.8% of patients.

Symptomatic hypotension associated with the use of ACE inhibitors is more 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. Volume and/or salt depletion should be corrected before initiating therapy with ACEON® Tablets. (See DOSAGE AND ADMINISTRATION.)

In patients with congestive heart failure, with or without associated renal insufficiency, ACE inhibitors may cause excessive hypotension, and may be associated with oliguria or azotemia, and rarely with acute renal failure and death. In patients with ischemic heart disease or cerebrovascular disease such an excessive fall in blood pressure could result in a myocardial infarction or a cerebrovascular accident.

In patients at risk of excessive hypotension, ACEON® Tablets therapy should be started under very close medical supervision. Patients should be followed closely for the first two weeks of treatment and whenever the dose of ACEON® Tablets and/or diuretic is increased.

If excessive hypotension occurs, the patient should be placed immediately in a supine position and, if necessary, treated with an intravenous infusion of physiological saline. ACEON® Tablets treatment can usually be continued following restoration of volume and blood pressure.

Neutropenia/Agranulocytosis: Another ACE inhibitor, captopril, has been shown to cause agranulocytosis and bone marrow depression, rarely in uncomplicated patients but more frequently in patients with renal impairment, especially patients with a collagen vascular disease such as systemic lupus erythematosus or scleroderma. Available data from clinical trials of ACEON® Tablets are insufficient to show whether ACEON® Tablets causes agranulocytosis at similar rates.

Fetal/Neonatal Morbidity and Mortality: ACE 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, ACE inhibitors should be discontinued 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 due to the ACE-inhibitor exposure.

These adverse effects do not appear to have resulted from intrauterine ACE-inhibitor exposure that has been limited to the first trimester. Mothers whose embryos and fetuses are exposed to ACE inhibitors only during the first trimester should be so informed. Nonetheless, when patients become pregnant, physicians should make every effort to discontinue the use of ACEON® Tablets as soon as possible.

Rarely (probably less often than once in every thousand pregnancies), no alternative to ACE inhibitors will be found. In these rare cases, the mothers should be apprised of the potential hazards to their fetuses, and serial ultrasound examinations should be performed to assess the intra-amniotic environment.

If oligohydramnios is observed, ACEON® Tablets should be discontinued unless it is considered life-saving for the mother. Contraction stress testing (CST), a non-stress test (NST) or biophysical profiling (BPP) 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.

Infants with histories of in utero exposure to ACE inhibitors should be closely observed for hypotension, oliguria and hyperkalemia. If oliguria occurs, attention should be directed toward support of blood pressure and renal perfusion. Exchange transfusion or dialysis may be required as means of reversing hypotension and/or substituting for disordered renal function. Perindopril, which crosses the placenta, can theoretically 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.

No teratogenic effects of perindopril were seen in studies of pregnant rats, mice, rabbits and cynomologous monkeys. On a mg/m2 basis, the doses used in these studies were 6 times (in mice), 670 times (in rats), 50 times (in rabbits) and 17 times (in monkeys) the maximum recommended human dose (assuming a 50 kg adult). On a mg/kg basis, these multiples are 60 times (in mice), 3,750 times (in rats), 150 times (in rabbits) and 50 times (in monkeys) the maximum recommended human dose.

Hepatic Failure: Rarely, ACE inhibitors 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. Patients receiving ACE inhibitors who develop jaundice or marked elevations of hepatic enzymes should discontinue the ACE inhibitor and receive appropriate medical follow-up.

PRECAUTIONS

General: Impaired Renal Function: As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in susceptible individuals.

Hypertensive Patients with Congestive Heart Failure: In patients with severe congestive heart failure, where renal function may depend on the activity of the renin-angiotensin-aldosterone system, treatment with ACE inhibitors, including ACEON® Tablets, may be associated with oliguria and/or progressive azotemia, and rarely with acute renal failure and/or death.

Hypertensive Patients with Renal Artery Stenosis: In hypertensive patients with unilateral or bilateral renal artery stenosis, increases in blood urea nitrogen and serum creatinine may occur. Experience with ACE inhibitors suggests that these increases are usually reversible upon discontinuation of the drug. In such patients, renal function should be monitored during the first few weeks of therapy.

Some hypertensive patients without apparent pre-existing renal vascular disease have developed increases in blood urea nitrogen and serum creatinine, usually minor and transient. These increases are more likely to occur in patients treated concomitantly with a diuretic and in patients with pre-existing renal impairment. Reduction of dosages of ACEON® Tablets, the diuretic or both may be required. In some cases, discontinuation of either or both drugs may be necessary.

Evaluation of hypertensive patients should always include an assessment of renal function. (See DOSAGE AND ADMINISTRATION.)

Hyperkalemia: Elevations of serum potassium have been observed in some patients treated with ACE inhibitors, including ACEON® Tablets. In U.S. controlled clinical trials, 1.4% of the patients receiving ACEON® Tablets and 2.3% of patients receiving placebo showed increased serum potassium levels to greater than 5.7 mEq/L. Most cases were isolated single values that did not appear clinically relevant and were rarely a cause for withdrawal. Risk factors for the development of hyperkalemia include renal insufficiency, diabetes mellitus and the concomitant use of agents such as potassium-sparing diuretics, potassium supplements and/or potassium-containing salt substitutes. Drugs associated with increases in serum potassium should be used cautiously, if at all, with ACEON® Tablets. (See Drug Interactions.)

Cough: Presumably due to the inhibition of the degradation of endogenous bradykinin, persistent nonproductive cough has been reported with all ACE inhibitors, always resolving after discontinuation of therapy. ACE inhibitor-induced cough should be considered in the differential diagnosis of cough. In controlled trials with perindopril, cough was present in 12% of perindopril patients and 4.5% of patients given placebo.

Surgery/Anesthesia: In patients undergoing surgery or during anesthesia with agents that produce hypotension, ACEON® Tablets may block angiotensin II formation that would otherwise occur secondary to compensatory renin release. Hypotension attributable to this mechanism can be corrected by volume expansion.

Information for Patients: Angioedema: Angioedema, including laryngeal edema, can occur with ACE inhibitor therapy, especially following the first dose. Patients should be told to report immediately signs or symptoms suggesting angioedema (swelling of face, extremities, eyes, lips, tongue, hoarseness or difficulty in swallowing or breathing) and to take no more drug before consulting a physician.

Symptomatic Hypotension: As with any antihypertensive therapy, patients should be cautioned that lightheadedness can occur, especially during the first few days of therapy and that it should be reported promptly. Patients should be told that if fainting occurs, ACEON® Tablets should be discontinued and a physician consulted.

All patients should be cautioned that inadequate fluid intake or excessive perspiration, diarrhea or vomiting can lead to an excessive fall in blood pressure in association with ACE inhibitor therapy.

Hyperkalemia: Patients should be advised not to use potassium supplements or salt substitutes containing potassium without a physician’s advice.

Neutropenia: Patients should be told to report promptly any indication of infection (e.g., sore throat, fever) which could be a sign of neutropenia.

Pregnancy: Female patients of childbearing age should be told about the consequences of second and third trimester exposure to ACE inhibitors, and they should also be told that these consequences do not appear to have resulted from intrauterine ACE-inhibitor exposure that has been limited to the first trimester. These patients should be asked to report pregnancies to their physicians as soon as possible.