Perindopril Erbumine (perindopril erbumine 8 mg) Dailymed

When used in pregnancy, ACE inhibitors can cause injury and even death to the developing fetus. When pregnancy is detected, perindopril erbumine tablets should be discontinued as soon as possible. See

When used in pregnancy, ACE inhibitors can cause injury and even death to the developing fetus. When pregnancy is detected, perindopril erbumine tablets should be discontinued as soon as possible. See WARNINGS: Fetal/Neonatal Morbidity and Mortality.

Oral administration of perindopril erbumine tablets results in its rapid absorption with peak plasma concentrations occurring at approximately 1 hour. The absolute oral bioavailability of perindopril is about 75%. Following absorption, approximately 30 to 50% of systemically available perindopril is hydrolyzed to its active metabolite, perindoprilat, which has a mean bioavailability of about 25%. Peak plasma concentrations of perindoprilat are attained 3 to 7 hours after perindopril administration. 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%. (See PRECAUTIONS: Food Interaction .) With 4, 8 and 16 mg doses of perindopril erbumine tablets, 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. Perindopril exhibits multiexponential pharmacokinetics following oral administration. The mean half-life of perindopril associated with most of its elimination is approximately 0.8 to 1.0 hours. At very low plasma concentrations of perindopril (<3 ng/mL), there is a prolonged terminal elimination half-life, similar to that seen with other ACE inhibitors, that results from slow dissociation of perindopril from plasma/tissue ACE binding sites. Perindopril does not accumulate with a once-a-day multiple dosing regimen. Mean total body clearance of perindopril is 219 to 362 mL/min and its mean renal clearance is 23.3 to 28.6 mL/min. Perindopril is extensively metabolized following oral administration, with only 4 to 12% of the dose recovered unchanged in the urine. Six metabolites resulting from hydrolysis, glucuronidation and cyclization via dehydration have been identified. These include the active ACE inhibitor, perindoprilat (hydrolyzed perindopril), perindopril and perindoprilat glucuronides, dehydrated perindopril and the diastereoisomers of dehydrated perindoprilat. In humans, hepatic esterase appears to be responsible for the hydrolysis of perindopril. The active metabolite, perindoprilat, also exhibits multiexponential pharmacokinetics following the oral administration of perindopril erbumine tablets. Formation of perindoprilat is gradual with peak plasma concentrations occurring between 3 and 7 hours. The subsequent decline in plasma concentration shows an apparent mean half-life of 3 to 10 hours for the majority of the elimination, with a prolonged terminal elimination half-life of 30 to 120 hours resulting from slow dissociation of perindoprilat from plasma/tissue ACE binding sites. During repeated oral once-daily dosing with perindopril, perindoprilat accumulates about 1.5 to 2.0 fold and attains steady state plasma levels in 3 to 6 days. The clearance of perindoprilat and its metabolites is almost exclusively renal. Approximately 60% of circulating perindopril is bound to plasma proteins, and only 10 to 20% of perindoprilat is bound. Therefore, drug interactions mediated through effects on protein binding are not anticipated. At usual antihypertensive dosages, little radioactivity (<5% of the dose) was distributed to the brain after administration of 14C-perindopril to rats. Radioactivity was detectable in fetuses and in milk after administration of 14C-perindopril to pregnant and lactating rats. Elderly Patients: Plasma concentrations of both perindopril and perindoprilat in elderly patients (>70 yrs) are approximately twice those observed in younger patients, reflecting both increased conversion of perindopril to perindoprilat and decreased renal excretion of perindoprilat. (See PRECAUTIONS: Geriatric Use .) Heart Failure Patients: Perindoprilat clearance is reduced in congestive heart failure patients, resulting in a 40% higher dose interval AUC. (See DOSAGE AND ADMINISTRATION .) Patients with Renal Insufficiency: With perindopril erbumine doses of 2 to 4 mg, perindoprilat AUC increases with decreasing renal function. At creatinine clearances of 30 to 80 mL/min, AUC is about double that of 100 mL/min. When creatinine clearance drops below 30 mL/min, AUC increases more markedly. In a limited number of patients studied, perindopril dialysis clearance ranged from 41.7 to 76.7 mL/min (mean 52.0 mL/min). Perindoprilat dialysis clearance ranged from 37.4 to 91.0 mL/min (mean 67.2 mL/min). (See DOSAGE AND ADMINISTRATION .) Patients with Hepatic Insufficiency: The bioavailability of perindoprilat is increased in patients with impaired hepatic function. Plasma concentrations of perindoprilat in patients with impaired liver function were about 50% higher than those observed in healthy subjects or hypertensive patients with normal liver function. Pharmacodynamics and Clinical Effects: Stable Coronary Artery Disease The EURopean trial On reduction of cardiac events with Perindopril in stable coronary Artery disease (EUROPA) was a multicenter, randomized, double-blind and placebo-controlled study conducted in 12,218 patients who had evidence of stable coronary artery disease without clinical heart failure. Patients had evidence of coronary artery disease documented by previous myocardial infarction more than 3 months before screening, coronary revascularization more than 6 months before screening, angiographic evidence of stenosis (at least 70% narrowing of one or more major coronary arteries), or positive stress test in men with a history of chest pain. After a run-in period of 4 weeks during which all patients received perindopril 2 mg to 8 mg, the patients were randomly assigned to perindopril 8 mg once daily (n=6,110) or matching placebo (n=6,108). The mean follow-up was 4.2 years. The study examined the long-term effects of perindopril on time to first event of cardiovascular mortality, nonfatal myocardial infarction, or cardiac arrest in patients with stable coronary artery disease. The mean age of patients was 60 years; 85% were male, 92% were taking platelet inhibitors, 63% were taking β blockers, and 56% were taking lipid-lowering therapy. The EUROPA study showed that perindopril significantly reduced the relative risk for the primary endpoint events (Table 1). This beneficial effect is largely attributable to a reduction in the risk of non-fatal myocardial infarction. This beneficial effect of perindopril on the primary outcome was evident after about one year of treatment (Figure 1). Table 1. Primary Endpoint and Relative Risk Reduction RRR: relative risk reduction; MI: myocardial infarction Perindopril (N = 6,110) Placebo (N = 6,108) RRR (95% CI) P Combined Endpoint Cardiovascular mortality, non-fatal MI or cardiac arrest 488 (8.0%) 603 (9.9%) 20% (9 to 29) 0.0003 Component Endpoint Cardiovascular mortality Non-fatal MI Cardiac arrest 215 (3.5%) 295 (4.8%) 6 (0.1%) 249 (4.1%) 378 (6.2%) 11 (0.2%) 14% (-3 to 28) 22% (10 to 33) 46% (-47 to 80) 0.107 0.001 0.22 The outcome was similar across all predefined subgroups by age, underlying disease or concomitant medication (Figure 2).                                                 Figure 1. Time to First Occurrence of Primary Endpoint          Figure 2. Beneficial Effect of Perindopril Treatment on Primary Endpoint in Predefined Subgroups Size of squares proportional to the number of patients in that group. Dashed line indicates overall relative risk. Hypertension In placebo-controlled studies of perindopril monotherapy (2 to 16 mg q.d.) in patients with a mean blood pressure of about 150/100 mm Hg, 2 mg had little effect, but doses of 4 to 16 mg lowered blood pressure. The 8 and 16 mg doses were indistinguishable, and both had a greater effect than the 4 mg dose. The magnitude of the blood pressure effect was similar in the standing and supine positions, generally about 1 mm Hg greater on standing. In these studies, doses of 8 and 16 mg per day gave supine, trough blood pressure reductions of 9 to 15/5 to 6 mm Hg. When once-daily and twice-daily dosing were compared, the B.I.D. regimen was generally slightly superior, but by not more than about 0.5 to 1 mm Hg. After 2 to 16 mg doses of perindopril, the trough mean systolic and diastolic blood pressure effects were approximately equal to the peak effects (measured 3 to 7 hours after dosing.). Trough effects were about 75 to 100% of peak effects. When perindopril was given to patients receiving 25 mg HCTZ, it had an added effect similar in magnitude to its effect as monotherapy, but 2 to 8 mg doses were approximately equal in effectiveness. In general, the effect of perindopril occurred promptly, with effects increasing slightly over several weeks. In hemodynamic studies carried out in animal models of hypertension, blood pressure reduction after perindopril administration was accompanied by a reduction in peripheral arterial resistance and improved arterial wall compliance. In studies carried out in patients with essential hypertension, the reduction in blood pressure was accompanied by a reduction in peripheral resistance with no significant changes in heart rate or glomerular filtration rate. An increase in the compliance of large arteries was also observed, suggesting a direct effect on arterial smooth muscle, consistent with the results of animal studies. Formal interaction studies of perindopril erbumine tablets have not been carried out with antihypertensive agents other than thiazides. Limited experience in controlled and uncontrolled trials coadministering perindopril erbumine tablets with a calcium channel blocker, a loop diuretic or triple therapy (beta-blocker, vasodilator and a diuretic), does not suggest any unexpected interactions. In general, ACE inhibitors have less than additive effects when given with beta-adrenergic blockers, presumably because both work in part through the renin angiotensin system. A controlled pharmacokinetic study has shown no effect on plasma digoxin concentrations when coadministered with perindopril erbumine tablets. (See PRECAUTIONS: Drug Interactions .) In uncontrolled studies in patients with insulin-dependent diabetes, perindopril did not appear to affect glycemic control. In long-term use, no effect on urinary protein excretion was seen in these patients. The effectiveness of perindopril erbumine tablets was not influenced by sex and it was less effective in blacks than in nonblacks. In elderly patients (≥60 years), the mean blood pressure effect was somewhat smaller than in younger patients, although the difference was not significant.

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.

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, patent ductus arteriosus, and other structural cardiac malformations, as well as neurological malformations, have been reported following exposure to ACE inhibitors during the first trimester of pregnancy. When patients become pregnant, physicians should make every effort to discontinue the use of perindopril erbumine 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, perindopril erbumine 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 cynomolgus 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.

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 perindopril erbumine 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 perindopril erbumine 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 perindopril erbumine tablets. In U.S. controlled clinical trials, 1.4% of the patients receiving perindopril erbumine 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 perindopril erbumine tablets. (See PRECAUTIONS: 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, perindopril erbumine 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, perindopril erbumine 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 exposure to ACE inhibitors during pregnancy. Discuss other treatment options with women planning to become pregnant. Women who do become pregnant while on an ACE inhibitor (including perindopril erbumine) should be asked to stop the medication and contact their physician as soon as possible.

Pregnancy Categories D. (See .)

Pregnancy Categories D. (See WARNINGS: Fetal/Neonatal Morbidity and Mortality .)

Milk of lactating rats contained radioactivity following administration C-perindopril. It is not known whether perindopril is secreted in human milk. Because many drugs are secreted in human milk, caution should be exercised when perindopril erbumine tablets are given to nursing mothers.

Milk of lactating rats contained radioactivity following administration 14C-perindopril. It is not known whether perindopril is secreted in human milk. Because many drugs are secreted in human milk, caution should be exercised when perindopril erbumine tablets are given to nursing mothers.