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GENERIC NAME: trandolapril BRAND NAME: Mavik Trandolapril is generally well tolerated.

The most common side effects are headache, cough, dizziness, diarrhea, fatigue, nausea, vomiting, complaints of sexual dysfunction, and abnormal liver tests. Impairment of kidney function has been reported with ACE inhibitors, especially in patients with severe heart failure or pre-existing kidney disease. In rare instances, low white blood cell counts have been reported with the use of captopril, another ACE inhibitor. Low white blood cells increase the risk of infections. GENERIC NAME: perindopril - oral (per-IN-doh-prill) BRAND NAME(S): Aceon SIDE EFFECTS: Dizziness, lightheadedness, headache, tiredness, or dry cough may occur as your body adjusts to the medication. You may also experience decreased sexual ability. If any of these effects persist or worsen, notify your doctor or pharmacist promptly.Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.Tell your doctor immediately if any of these unlikely but serious side effects occur: muscle cramps, weakness, fast/slow/irregular heartbeat, fainting, signs of infection (e.g., fever, chills, persistent sore throat), numbness/tingling/swelling of the hands/feet, chest pain.This drug may rarely cause serious (possibly fatal) liver problems. Seek immediate medical attention if you notice any of the following rare but very serious side effects: yellowing eyes/skin, dark urine, severe stomach/abdominal pain, persistent tiredness, persistent nausea/vomiting.Seek immediate medical attention if this rare but very serious side effect occurs: unusual change in the amount of urine.A very serious allergic reaction to this drug is unlikely, but seek immediate medical attention if it occurs. Symptoms of a serious allergic reaction may include: rash, itching/swelling (especially of the face/tongue/throat), severe dizziness, trouble breathing.This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.In the US -Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.In Canada - Call your doctor for medical advice about side effects. You may report side effects to Health Canada at 1-866-234-2345. PRECAUTIONS: Before taking perindopril, tell your doctor or pharmacist if you are allergic to it; or to other ACE inhibitors (e.g., captopril, lisinopril); or if you have any other allergies (including an allergic reaction after exposure to certain membranes used for blood filtering). This product may contain inactive ingredients, which can cause allergic reactions or other problems. Talk to your pharmacist for more details.This medication should not be used if you have certain medical conditions. Before using this medicine, consult your doctor or pharmacist if you have: a history of an allergic reaction that included swelling of the face/lips/tongue/throat (angioedema).Before using this medication, tell your doctor or pharmacist your medical history, especially of: kidney problems, liver disease, untreated salt/mineral imbalance (e.g., high potassium or low sodium levels in the blood), loss of too much body water (dehydration), collagen vascular disease (e.g., lupus, scleroderma).This drug may make you dizzy. Do not drive,

Its structural formula is: Perindopril erbumine is a white. Consult your doctor for more details. especially dizziness.)It is not known if perindopril passes into breast milk.7∝S)-1-[(S)-N-[(S)-1-Carboxy-butyl]alanyl]hexahydro-2indolinecarboxylic acid.This medication is not recommended for use during pregnancy due to the risk for harm to an unborn baby.3∝S. ACE is a peptidyl dipeptidase that catalyzes conversion of the inactive decapeptide.Before having surgery. lactose. get up slowly when rising from a sitting or lying position. 1-ethyl ester. 4 mg and 8 mg strengths for oral administration. the elderly may be more sensitive to the effects of this drug. Therefore. This can cau se dizziness and lightheadedness due to low blood pressure. Perindopril erbumine is chemically described as (2S. DESCRIPTION ACEON® (perindopril erbumine) Tablets is the tert-butylamine salt of perindopril. to the . the ethyl ester of a non-sulfhydryl angiotensin-converting enzyme (ACE) inhibitor. The 4 and 8 mg tablets also contain iron oxide. It is freely soluble in water (60% w/w). compound with tert-butylamine (1:1). vomiting. Limit alcoholic beverages. and keep cool in hot weather. magnesium stearate and microcrystalline cellulose. CLINICAL PHARMACOLOGY Mechanism of Action: ACEON® (perindopril erbumine) Tablets is a pro-drug for perindoprilat. angiotensin I. Consult your doctor before breast-feeding. (See also Warning section.Kidney function declines as you grow older. Contact your doctor if you are unable to drink fluids or if you have persistent diarrhea or vomiting. In addition to perindopril erbumine. Avoid heavy exercise. This medication is removed by the kidneys. crystalline powder with a molecular weight of 368. The mechanism through which perindoprilat lowers blood pressure is believed to be primarily inhibition of ACE activity. tell your doctor or dentist that you are taking this medication.use machinery. or sweating. which inhibits ACE in human subjects and animals. alcohol and chloroform. is a pro-drug and metabolized in vivo by hydrolysis of the ester group to form perindoprilat.You can develop dehydration if you do not drink enough fluids or if you have too much diarrhea.To reduce the risk of dizziness and lightheadedness.47 (free acid) or 441. ACEON® Tablets is available in 2 mg. Perindopril is the free acid form of perindopril erbumine.61 (salt form). the biologically active metabolite. each tablet contains the following inactive ingredients: colloidal silica (hydrophobic). or do any activity that requires alertness until you are sure you can perform such activities safely. Its molecular formula is C19H32N2O5C4H11N.

While the principal mechanism of perindopril in blood pressure reduction is believed to be through the renin-angiotensin-aldosterone system. The pressor response to an angiotensin I infusion is reduced by perindopril. 8 and 16 mg doses of ACEON® Tablets. a potent vasodepressor peptide. Perindopril does not accumulate with a once-a-day multiple dosing regimen. ACE inhibitors have some effect even in apparent low-renin hypertension. . The degree of ACE inhibition achieved by a given dose appears to diminish over time (the ID50 increases). Twenty-four hour ACE inhibition is about 60% after these doses. The latter results in diuresis and natriuresis and may be associated with a small increase of serum potassium. Angiotensin II is a potent peripheral vasoconstrictor. and the average response of diastolic blood pressure to perindopril was about half the response seen in nonblacks. The absolute oral bioavailability of perindopril is about 75%. The presence of food in the gastrointestinal tract does not affect the rate or extent of absorption of perindopril but reduces bioavailability of perindoprilat by about 35%. which stimulates aldosterone secretion by the adrenal cortex. an enzyme that degrades bradykinin. a finding consistent with previous experience of other ACE inhibitors. which has a mean bioavailability of about 25%.vasoconstrictor. angiotensin II. there is a prolonged terminal elimination half-life. (See PRECAUTIONS: Food Interaction. Cmax and AUC of perindopril and perindoprilat increase in a linear and dose-proportional manner following both single oral dosing and at steady state during a once-a-day multiple dosing regimen. there is about 35% inhibition at 24 hours after a 12 mg dose. Mean total body clearance of perindopril is 219 to 362 mL/min and its mean renal clearance is 23. approximately 30 to 50% of systemically available perindopril is hydrolyzed to its active metabolite.6 mL/min. ACE is inhibited in a dose and blood concentration-related fashion. At very low plasma concentrations of perindopril (<3 ng/mL). Pharmacokinetics: Oral administration of ACEON® (perindopril erbumine) Tablets results in its rapid absorption with peak plasma concentrations occurring at approximately 1 hour.8 to 1 hours. Inhibition of ACE results in decreased plasma angiotensin II.3 to 28. with the maximal inhibition of 80 to 90% attained by 8 mg persisting for 10 to 12 hours. similar to that seen with other ACE inhibitors. Perindopril exhibits multiexponential pharmacokinetics following oral administration. and provides negative feedback on renin secretion. play a role in the therapeutic effects of ACEON® Tablets remains to be elucidated. Whether increased levels of bradykinin. The mean half-life of perindopril associated with most of its elimination is approximately 0. perindoprilat. usually a low-renin population.) With 4. Peak plasma concentrations of perindoprilat are attained 3 to 7 hours after perindopril administration. leading to decreased vasoconstriction. After administration of perindopril. Perindopril has been studied in relatively few black patients. that results from slow dissociation of perindopril from plasma/tissue ACE binding sites. increased plasma renin activity and decreased aldosterone secretion. Following absorption. but this effect is not as persistent as the effect on ACE. ACE is identical to kininase II.

Therefore. resulting in a 40% higher dose interval AUC.) Patients with Renal Insufficiency: With perindopril erbumine doses of 2 to 4 mg. reflecting both increased conversion of perindopril to perindoprilat and decreased renal excretion of perindoprilat. perindoprilat AUC increases with decreasing renal function.4 to 91 mL/min (mean 67.7 mL/min (mean 52 mL/min). with only 4 to 12% of the dose recovered unchanged in the urine. hepatic esterase appears to be responsible for the hydrolysis of perindopril. perindoprilat (hydrolyzed perindopril). At usual antihypertensive dosages. AUC is about double that of 100 mL/min.2 mL/min). In a limited number of patients studied. (See DOSAGE AND ADMINISTRATION) Patients with Hepatic Insufficiency: The bioavailability of perindoprilat is increased in patients with impaired hepatic function. The subsequent decline in plasma concentration shows an apparent mean half-life of 3 to 10 hours for the majority of the elimination. The clearance of perindoprilat and its metabolites is almost exclusively renal. Plasma concentrations of perindoprilat in patients with impaired . These include the active ACE inhibitor. (See PRECAUTIONS: Geriatric Use. Perindoprilat dialysis clearance ranged from 37. During repeated oral once-daily dosing with perindopril. AUC increases more markedly. When creatinine clearance drops below 30 mL/min. perindoprilat.7 to 76. At creatinine clearances of 30 to 80 mL/min. Formation of perindoprilat is gradual with peak plasma concentrations occurring between 3 and 7 hours. (See DOSAGE AND ADMINISTRATION. In humans. Elderly Patients: Plasma concentrations of both perindopril and perindoprilat in elderly patients (>70 yrs) are approximately twice those observed in younger patients. with a prolonged terminal elimination half-life of 30 to 120 hours resulting from slow dissociation of perindoprilat from plasma/tissue ACE binding sites. little radioactivity (<5% of the dose) was distributed to the brain after administration of 14C-perindopril to rats. perindoprilat accumulates about 1.) Heart Failure Patients: Perindoprilat clearance is reduced in congestive heart failure patients.Perindopril is extensively metabolized following oral administration. Approximately 60% of circulating perindopril is bound to plasma proteins. perindopril dialysis clearance ranged from 41. glucuronidation and cyclization via dehydration have been identified.5 to 2 fold and attains steady state plasma levels in 3 to 6 days. The active metabolite. Radioactivity was detectable in fetuses and in milk after administration of 14C-perindopril to pregnant and lactating rats. perindopril and perindoprilat glucuronides. and only 10 to 20% of perindoprilat is bound. Six metabolites resulting from hydrolysis. also exhibits multiexponential pharmacokinetics following the oral administration of ACEON® Tablets. drug interactions mediated through effects on protein binding are not anticipated. dehydrated perindopril and the diastereoisomers of dehydrated perindoprilat.

Intestinal angioedema should be included in the differential diagnosis of patients on ACE inhibitors presenting with abdominal pain. Appropriate therapy. although antihistamines have been useful in relieving symptoms. glottis and/or larynx has been reported in patients treated with ACE inhibitors. clinical trials).1% of patients treated with ACEON® Tablets in U. extremities. ACEON® Tablets should be promptly discontinued and the patient carefully observed until the swelling disappears. Head and Neck Angioedema: Angioedema involving the face. glottis or larynx may be fatal due to airway obstruction. Angioedema associated with involvement of the tongue. These patients presented with abdominal pain (with or without nausea or vomiting).liver function were about 50% higher than those observed in healthy subjects or hypertensive patients with normal liver function. lips. in some cases there was no prior history of facial angioedema and C-1 esterase levels were normal. Anaphylactoid Reactions During Desensitization: Two patients undergoing desensitizing treatment with hymenoptera venom while receiving ACE inhibitors sustained life-threatening anaphylactoid reactions. In instances where swelling has been confined to the face and lips. Patients with a history of angioedema unrelated to ACE inhibitor therapy may be at increased risk of angioedema while receiving an ACE inhibitor. WARNINGS Anaphylactoid and Possibly Related Reactions: Presumably because angiotensin-converting enzyme inhibitors affect the metabolism of eicosanoids and polypeptides. and symptoms resolved after stopping the ACE inhibitor. patients receiving ACE inhibitors (including ACEON® Tablets) may be subject to a variety of adverse reactions. tongue. In the same patients. but they reappeared upon inadvertent rechallenge. ACEON® Tablets is also contraindicated in patients with a history of angioedema related to previous treatment with an ACE inhibitor. some of them serious. the condition has generally resolved without treatment. or at surgery. In such cases. should be promptly administered. including endogenous bradykinin. these reactions were avoided when ACE inhibitors were temporarily withheld. including ACEON® (perindopril erbumine) Tablets (0.S. Anaphylactoid Reactions During Membrane Exposure: Anaphylactoid reactions have been reported in patients dialyzed with high-flux membranes and treated concomitantly with an ACE . such as subcutaneous epinephrine solution 1:1000 (0. The angioedema was diagnosed by procedures including abdominal CT scan or ultrasound. CONTRAINDICATIONS ACEON® (perindopril erbumine) Tablets is contraindicated in patients known to be hypersensitive to this product or to any other ACE inhibitor. Intestinal Angioedema: Intestinal angioedema has been reported in patients treated with ACE inhibitors.5 mL).3 to 0.

Patients should be followed closely for the first two weeks of treatment and whenever the dose of ACEON® Tablets and/or diuretic is increased. treated with an intravenous infusion of physiological saline. ACE inhibitors may cause excessive hypotension. (See DOSAGE AND ADMINISTRATION) In patients with congestive heart failure. Available data from clinical trials of ACEON® Tablets are insufficient to show whether ACEON® Tablets causes agranulocytosis at similar rates. Hypotension: Like other ACE inhibitors. Symptomatic hypotension associated with the use of ACE inhibitors is more likely to occur in patients who have been volume and/or salt-depleted.8% of patients. Symptoms related to orthostatic hypotension were reported in another 0. ACEON® Tablets can cause symptomatic hypotension. reversible or irreversible renal failure and death. Oligohydramnios has also been reported. ACEON® Tablets treatment can usually be continued following restoration of volume and blood pressure. especially patients with a collagen vascular disease such as systemic lupus erythematosus or scleroderma. and may be associated with oliguria or azotemia. dialysis. neonatal skull hypoplasia.S. ACEON® Tablets has been associated with hypotension in 0. the patient should be placed immediately in a supine position and. Neutropenia/Agranulocytosis: Another ACE inhibitor. dietary salt restriction. 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. Fetal/Neonatal Morbidity and Mortality: ACE inhibitors can cause fetal and neonatal morbidity and death when administered to pregnant women. with or without associated renal insufficiency.inhibitor. oligohydramnios in this setting has been associated with fetal limb contractures. including hypotension. captopril. presumably resulting from decreased fetal renal function. In patients at risk of excessive hypotension. When pregnancy is detected. diarrhea or vomiting.3% of uncomplicated hypertensive patients in U. 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. Several dozen cases have been reported in the world literature. placebo-controlled trials. has been shown to cause agranulocytosis and bone marrow depression. craniofacial deformation and hypoplastic lung development. and rarely with acute renal failure and death. Volume and/or salt depletion should be corrected before initiating therapy with ACEON® Tablets. as a result of prolonged diuretic therapy. Anaphylactoid reactions have also been reported in patients undergoing low-density lipoprotein apheresis with dextran sulfate absorption. anuria. . If excessive hypotension occurs. if necessary. ACEON® Tablets therapy should be started under very close medical supervision. rarely in uncomplicated patients but more frequently in patients with renal impairment.

50 times (in rabbits) and 17 times (in monkeys) the maximum recommended human dose (assuming a 50 kg adult). can theoretically be removed from the neonatal circulation by these means. 670 times (in rats). physicians should make every effort to discontinue the use of ACEON® Tablets as soon as possible. no alternative to ACE inhibitors will be found. rabbits and cynomolgus monkeys. 3. the mothers should be apprised of the potential hazards to their fetuses. a non-stress test (NST) or biophysical profiling (BPP) may be appropriate. On a mg/kg basis. In these rare cases. Contraction stress testing (CST). The mechanism of this syndrome is not understood. 150 times (in rabbits) and 50 times (in monkeys) the maximum recommended human dose. however. have been reported following exposure to ACE inhibitors during the first trimester of pregnancy. On a mg/m2 basis. PRECAUTIONS General: Impaired Renal Function: As a consequence of inhibiting the renin-angiotensin-aldosterone system. Patients and physicians should be aware. Hepatic Failure: Rarely. If oliguria occurs. but limited experience has not shown that such removal is central to the treatment of these infants. Exchange transfusion or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function. ACEON® Tablets should be discontinued unless it is considered life-saving for the mother. If oligohydramnios is observed. the doses used in these studies were 6 times (in mice). intrauterine growth retardation. attention should be directed toward support of blood pressure and renal perfusion.750 times (in rats). . When patients become pregnant. Rarely (probably less often than once in every thousand pregnancies). and serial ultrasound examinations should be performed to assess the intra-amniotic environment. No teratogenic effects of perindopril were seen in studies of pregnant rats. patent ductus arteriosus. and other structural cardiac malformations. Infants with histories of in utero exposure to ACE inhibitors should be closely observed for hypotension.Prematurity. as well as neurological malformations. mice. Perindopril. that oligohydramnios may not appear until after the fetus has sustained irreversible injury. oliguria and hyperkalemia. depending upon the week of pregnancy. Patients receiving ACE inhibitors who develop jaundice or marked elevations of hepatic enzymes should discontinue the ACE inhibitor and receive appropriate medical follow-up. these multiples are 60 times (in mice). ACE inhibitors have been associated with a syndrome that starts with cholestatic jaundice and progresses to fulminant hepatic necrosis and (sometimes) death. which crosses the placenta. changes in renal function may be anticipated in susceptible individuals.

where renal function may depend on the activity of the renin-angiotensin-aldosterone system. In such patients. Some hypertensive patients without apparent pre-existing renal vascular disease have developed increases in blood urea nitrogen and serum creatinine.4% of the patients receiving ACEON® Tablets and 2. usually minor and transient. especially following the first dose. ACE inhibitor-induced cough should be considered in the differential diagnosis of cough.3% of patients receiving placebo showed increased serum potassium levels to greater than 5. always resolving after discontinuation of therapy. In some cases. Risk factors for the development of hyperkalemia include renal insufficiency. potassium supplements and/or potassiumcontaining salt substitutes. discontinuation of either or both drugs may be necessary. can occur with ACE inhibitor therapy. Experience with ACE inhibitors suggests that these increases are usually reversible upon discontinuation of the drug.7 mEq/L. controlled clinical trials. Patients should be told to report immediately signs or . the diuretic or both may be required. cough was present in 12% of perindopril patients and 4. and rarely with acute renal failure and/or death. increases in blood urea nitrogen and serum creatinine may occur. 1. Hypotension attributable to this mechanism can be corrected by volume expansion. Most cases were isolated single values that did not appear clinically relevant and were rarely a cause for withdrawal. diabetes mellitus and the concomitant use of agents such as potassium-sparing diuretics.5% of patients given placebo. including ACEON® Tablets.) Cough: Presumably due to the inhibition of the degradation of endogenous bradykinin.S. (See PRECAUTIONS: Drug Interactions. (See DOSAGE AND ADMINISTRATION) Hyperkalemia: Elevations of serum potassium have been observed in some patients treated with ACE inhibitors. ACEON® Tablets may block angiotensin II formation that would otherwise occur secondary to compensatory renin release. if at all. In U. treatment with ACE inhibitors. including laryngeal edema. Evaluation of hypertensive patients should always include an assessment of renal function. Information for Patients: Angioedema: Angioedema. Surgery/Anesthesia: In patients undergoing surgery or during anesthesia with agents that produce hypotension. Drugs associated with increases in serum potassium should be used cautiously. with ACEON® Tablets. including ACEON® Tablets.Hypertensive Patients with Congestive Heart Failure: In patients with severe congestive heart failure. Hypertensive Patients with Renal Artery Stenosis: In hypertensive patients with unilateral or bilateral renal artery stenosis. Reduction of dosages of ACEON® Tablets. persistent nonproductive cough has been reported with all ACE inhibitors. In controlled trials with perindopril. renal function should be monitored during the first few weeks of therapy. may be associated with oliguria and/or progressive azotemia. These increases are more likely to occur in patients treated concomitantly with a diuretic and in patients with pre-existing renal impairment.

The bioavailability of perindoprilat was reduced by diuretics..g. tongue. hoarseness or difficulty in swallowing or breathing) and to take no more drug before consulting a physician. (See WARNINGS and DOSAGE AND ADMINISTRATION) The rate and extent of perindopril absorption and elimination are not affected by concomitant diuretics. however. heparin. if concomitant use of such agents is indicated. and this was associated with a decrease in plasma ACE inhibition. lips. ACEON® Tablets should be discontinued and a physician consulted. The possibility of hypotensive effects can be minimized by either discontinuing the diuretic or increasing the salt intake prior to initiation of treatment with perindopril. close medical supervision should be provided with the first dose of ACEON® Tablets. triamterene and others). . Patients should be told that if fainting occurs. for at least two hours and until blood pressure has stabilized for another hour. Drug Interactions: Diuretics: Patients on diuretics. diarrhea or vomiting can lead to an excessive fall in blood pressure in association with ACE inhibitor therapy. sore throat. patients should be cautioned that lightheadedness can occur.symptoms suggesting angioedema (swelling of face. Therefore. Neutropenia: Patients should be told to report promptly any indication of infection (e. If diuretics cannot be interrupted. eyes. extremities. fever) which could be a sign of neutropenia. All patients should be cautioned that inadequate fluid intake or excessive perspiration. Hyperkalemia: Patients should be advised not to use potassium supplements or salt substitutes containing potassium without a physician's advice. Women who do become pregnant while on an ACE inhibitor (including ACEON®) should be asked to stop the medication and contact their physician as soon as possible. Discuss other treatment options with women planning to become pregnant. may occasionally experience an excessive reduction of blood pressure after initiation of ACEON® Tablets therapy. amiloride. potassium supplements or other drugs capable of increasing serum potassium (indomethacin. Potassium Supplements and Potassium-Sparing Diuretics: ACEON® Tablets may increase serum potassium because of its potential to decrease aldosterone production. Pregnancy: Female patients of childbearing age should be told about the consequences of exposure to ACE inhibitors during pregnancy. and especially those started recently. Use of potassiumsparing diuretics (spironolactone. Symptomatic Hypotension: As with any antihypertensive therapy. cyclosporine and others) can increase the risk of hyperkalemia. especially during the first few days of therapy and that it should be reported promptly. they should be given with caution and the patient's serum potassium should be monitored frequently.

perindopril was generally administered in a non-fasting state.) Nursing Mothers: Milk of lactating rats contained radioactivity following administration14Cperindopril. It is not known whether perindopril is secreted in human milk. TK ± mouse lymphoma assay. Mutagenesis. but an effect of digoxin on the plasma concentration of perindopril/perindoprilat has not been excluded. including the Ames test. Impairment of Fertility: Carcinogenesis: No evidence of carcinogenic effect was observed in studies in rats and mice when perindopril was administered at dosages up to 20 times (mg/kg) or 2 to 4 times (mg/m2) the maximum proposed clinical doses (16 mg/day) for 104 weeks. probably clinically insignificant. resulting in a reduction in the plasma ACE inhibition curve of approximately 20%. perindoprilat. the extent of biotransformation of perindopril to the active metabolite. Gentamicin: Animal data have suggested the possibility of interaction between perindopril and gentamicin. Pregnancy: Pregnancy Category D. and hypotension) have been reported rarely in patients on therapy with injectable gold (sodium aurothiomalate) and concomitant ACE Inhibitor therapy including ACEON®. Carcinogenesis. . this has not been investigated in human studies. cultured human lymphocytes. In clinical trials. Mutagenesis: No genotoxic potential was detected for ACEON® Tablets. caution should be exercised when ACEON® Tablets is given to nursing mothers. However. Because many drugs are secreted in human milk. Gold: Nitritoid reactions (symptoms include facial flushing. These drugs should be coadministered with caution and frequent monitoring of serum lithium concentration is recommended. Impairment of Fertility: There was no meaningful effect on reproductive performance or fertility in the rat given up to 30 times (mg/kg) or 6 times (mg/m2) the proposed maximum clinical dosage of ACEON® Tablets during the period of spermatogenesis in males or oogenesis and gestation in females. However. nausea. is reduced approximately 43%. vomiting. Coadministration of both drugs should proceed with caution. mouse and rat micronucleus tests and Chinese hamster bone marrow assay. Digoxin: A controlled pharmacokinetic study has shown no effect on plasma digoxin concentrations when coadministered with ACEON® Tablets.Lithium: Increased serum lithium and symptoms of lithium toxicity have been reported in patients receiving concomitant lithium and ACE inhibitor therapy. the Saccharomyces cerevisiae D4 test. (See WARNINGS: Fetal/Neonatal Morbidity and Mortality. Use of a diuretic may further increase the risk of lithium toxicity. Food Interaction: Oral administration of ACEON® Tablets with food does not significantly lower the rate or extent of perindopril absorption relative to the fasted state. perindoprilat and other metabolites in various in vitro and in vivo investigations.

clinical trials. although the difference was not significant. headache. it was clearly increased with dose.5% in patients treated with ACEON® Tablets and 6. patients. the incidence of premature discontinuation of therapy due to adverse events was 6. associated with perindopril.7% in patients treated with placebo. The data presented here are based on results from the 1.S.2%). Falls and fall-related events may be exacerbated by the central nervous system effects of dizziness and syncope as well as the symptomatic hypotension. Of these adverse events. Although dizziness was reported more frequently in placebo patients (8. In placebo-controlled U. Geriatric Use: The mean blood pressure effect of perindopril was somewhat smaller in patients over 60 than in younger patients. Experience with ACEON® Tablets in elderly patients at daily doses exceeding 8 mg is limited. No adverse effects were clearly increased in older patients with the exception of dizziness and possibly rash.S. clinical trials. those considered possibly or probably related to study drug are shown in the last two columns. the overall frequency of reported adverse events was similar in patients treated with ACEON® Tablets and in those treated with placebo (approximately 75% in each group).417 ACEON® Tablets-treated patients who participated in the U. While dizziness was not reported more frequently in the perindopril group (8. Perindopril should be used with caution when administered to elderly patients who are at an increased risk for falls due to age.Pediatric Use: Safety and effectiveness of ACEON® Tablets in pediatric patients have not been established. the incidence appeared to increase with an increase in perindopril dose. Plasma concentrations of both perindopril and perindoprilat were increased in elderly patients compared to concentrations in younger patients. and foreign clinical trials. Other commonly reported complaints (1% or greater). ACEON® Tablets was in general well-tolerated in the patient populations studied.400 patients with hypertension in U.2%) than in the placebo group (8. The most common causes were cough.S.5%). their underlying disease and/or their concurrent use of medications(s) associated with falls.S. . Among 1. the side effects were usually mild and transient. regardless of causality. suggesting a causal relationship with perindopril. asthenia and dizziness. ADVERSE REACTIONS Hypertension ACEON® (perindopril erbumine) Tablets has been evaluated for safety in approximately 3. including orthostatic.012 patients in placebo-controlled U. trials. Adverse events that occurred in 1% or greater of the patients and that were more common for perindopril than placebo by at least 1% (regardless of whether they were felt to be related to study drug) are shown in the first two columns below.5%) than in perindopril patients (8. Over 220 of these patients were treated with ACEON® Tablets for at least one year.

asthenia (7. heart murmur. ventricular extrasystole. placebo-controlled study in 12. vertigo. orthostatic symptoms.1%). fluid retention. kidney stone.4%). male sexual dysfunction (each 1.S.8%). chills. pharyngitis (3. upper respiratory infection (8. Urogenital: vaginitis. somnolence (each 1.2%). drug intolerance and hypotension. cerebral vascular accident (0. pulmonary fibrosis (<0. psychosexual disorder.218 patients with stable coronary artery disease. orthostatic hypotension. dry mucous membrane. diarrhea (4. paresthesia. depression (each 2%). rhinitis (4. bronchitis.1%). myocardial infarction. nausea. low extremity pain (4.include: headache (23. Respiratory: posterior nasal drip. syncope. approximately 30 to 70% of the common complaints were considered possibly or probably related to treatment. myalgia. . abnormal conduction.3%). Depending on the specific adverse event. angioedema (0. pain. ALT increase (1. the incidence of these events is given in parentheses.9%). urinary frequency. joint pain. injury. rash (each 2.1%). Endocrine: gout. Stable Coronary Artery Disease Perindopril has been evaluated for safety in EUROPA. The overall rate of discontinuation was about 22% on drug and placebo. Hematology: hematoma.3%). sneezing. appetite increased.8%). urinary tract infection (2. seasonal allergy. flank pain. placebo-controlled studies in hypertensive patients without regard to attribution to therapy.5%).5%). CNS: migraine. Musculoskeletal: arthralgia. Gastrointestinal: constipation. but none of those was more frequent by at least 1% on perindopril than on placebo.6%). ecchymosis. Cardiovascular: hypotension. cold/hot sensation.3 to 1% of patients in U.3%). nervousness. dry mouth. sleep disorder (2.7%). Body as a Whole: malaise. vasodilation.7%). abnormal ECG (1. throat disorder. hoarseness. vomiting (each 1. Psychiatric: anxiety. dyspnea. Below is a list (by body system) of adverse experiences reported in 0. The most common medical reasons for discontinuation that were more frequent on perindopril than placebo were cough. gastroenteritis.8%). triglyceride increase. anaphylactic reaction.7%). menstrual disorder (each 1. amnesia.4%).3%). edema (3. urinary retention. Less frequent but medically important adverse events are also included. rhinorrhea. chest pain (2. flatulence and arthritis (each 1%). neck pain. tinnitus.8%). epistaxis. abdominal pain (2.9%). a double-blind. myalgia. facial edema.

vasculitis. jaundice (hepatocellular or cholestatic).g. fever blisters. alkaline phosphatase increase. a positive ANA. eosinophilia or an elevated ESR. bullous pemphigoid. increases in serum uric acid. falls. acute renal failure. pancytopenia. glucose increase. exfoliative dermatitis and a syndrome which may include: arthralgia/arthritis.. thrombocytopenia.Dermatology: sweating. except for a higher incidence of abnormal laboratory findings known to be related to treatment with thiazide diuretics alone (e. eosinophilic pneumonitis. triglycerides and cholesterol and decreases in serum potassium). pruritus. acute pancreatitis. purpura (0. fever. Many of these adverse effects have also been reported for perindopril. adverse events were generally reported at the same rate as those for ACEON® Tablets alone. serositis. tinea. rash or other dermatologic manifestations. Special Senses: conjunctivitis. myalgia. nephritis. anemia (including hemolytic and aplastic). earache. Laboratory: potassium decrease. uric acid increase. creatinine increase. erythema. cholesterol increase. . When ACEON® Tablets was given concomitantly with thiazide diuretics. leukocytosis. skin infection. psoriasis. Potential Adverse Effects Reported with ACE Inhibitors: Other medically important adverse effects reported with other available ACE inhibitors include: cardiac arrest. symptomatic hyponatremia. neutropenia/agranulocytosis.1%). hematuria. dry skin. hepatic failure. AST increase. pemphigus.