İHALE DÜNYASI
İHALE DÜNYASI
Perindopril erbumine tablets are the tert-butylamine salt of perindopril, the ethyl ester of a non-sulfhydryl angiotensin-converting enzyme (ACE) inhibitor. Perindopril erbumine is chemically described as (2S,3?S,7?S)-1-[(S)-N-[(S)-1-Carboxy-butyl]alanyl]hexahydro-2-indolinecarboxylic acid, 1-ethyl ester, compound with tert-butylamine (1:1). Its molecular formula is C 19 H 32 N 2 O 5 C 4 H 11 N. Its structural formula is: Perindopril erbumine is a white, crystalline powder with a molecular weight of 368.47 (free acid) or 441.61 (salt form). It is freely soluble in water (60% w/w), alcohol and chloroform. Perindopril is the free acid form of perindopril erbumine, is a pro-drug and metabolized in vivo by hydrolysis of the ester group to form perindoprilat, the biologically active metabolite. Perindopril erbumine tablets are available in 2 mg, 4 mg and 8 mg strengths for oral administration. In addition to perindopril erbumine, each tablet contains the following inactive ingredients: hydrophobic colloidal silica, lactose monohydrate, magnesium stearate and microcrystalline cellulose. Perindopril erbumine structural formula
Stable Coronary Artery Disease Perindopril erbumine tablets are indicated in patients with stable coronary artery disease to reduce the risk of cardiovascular mortality or non-fatal myocardial infarction. Perindopril erbumine tablets can be used with conventional treatment for management of coronary artery disease, such as antiplatelet, antihypertensive or lipid-lowering therapy. Hypertension Perindopril erbumine tablets are indicated for the treatment of patients with essential hypertension. Perindopril erbumine tablets may be used alone or given with other classes of antihypertensives, especially thiazide diuretics. When using perindopril erbumine tablets, consideration should be given to the fact that another angiotensin converting enzyme inhibitor (captopril) has caused agranulocytosis, particularly in patients with renal impairment or collagen vascular disease. Available data are insufficient to determine whether perindopril erbumine tablets has a similar potential. (See WARNINGS .) In considering use of perindopril erbumine tablets, it should be noted that in controlled trials ACE inhibitors have an effect on blood pressure that is less in black patients than in nonblacks. In addition, it should be noted that black patients receiving ACE inhibitor monotherapy have been reported to have a higher incidence of angioedema compared to nonblacks. (See WARNINGS : Head and Neck Angioedema .)
Stable Coronary Artery Disease In patients with stable coronary artery disease, perindopril erbumine tablets should be given at an initial dose of 4 mg once daily for 2 weeks, and then increased as tolerated, to a maintenance dose of 8 mg once daily. In elderly patients (>70 yrs), perindopril erbumine tablets should be given as a 2 mg dose once daily in the first week, followed by 4 mg once daily in the second week and 8 mg once daily for maintenance dose if tolerated. Hypertension Use in Uncomplicated Hypertensive Patients: In patients with essential hypertension, the recommended initial dose is 4 mg once a day. The dosage may be titrated upward until blood pressure, when measured just before the next dose, is controlled or to a maximum of 16 mg per day. The usual maintenance dose range is 4 to 8 mg administered as a single daily dose. perindopril erbumine tablets may also be administered in two divided doses. When once-daily dosing was compared to twice-daily dosing in clinical studies, the B.I.D. regimen was generally slightly superior, but not by more than about 0.5 to 1.0 mm Hg. Use in the Elderly Patients: As in younger patients, the recommended initial daily dosage of perindopril erbumine tablets for the elderly (>65 years) is 4 mg daily, given in one or two divided doses. The daily dosage may be titrated upward until blood pressure, when measured just before the next dose, is controlled, but experience with perindopril erbumine tablets is limited in the elderly at doses exceeding 8 mg. Dosages above 8 mg should be administered with caution and under close medical supervision. (See PRECAUTIONS : Geriatric Use .) Use in Concomitant Diuretics: If blood pressure is not adequately controlled with perindopril alone, a diuretic may be added. In patients currently being treated with a diuretic, symptomatic hypotension occasionally can occur following the initial dose of perindopril. To reduce likelihood of such reaction, the diuretic should, if possible, be discontinued 2 to 3 days prior to the beginning of perindopril erbumine tablets therapy. (See WARNINGS .) Then, if blood pressure is not controlled with perindopril erbumine tablets alone, the diuretic should be resumed. If the diuretic cannot be discontinued, an initial dose of 2 to 4 mg daily in one or in two divided doses should be used with careful medical supervision for several hours and until blood pressure has stabilized. The dosage should then be titrated as described above. (See WARNINGS and PRECAUTIONS : Drug Interactions .) After the first dose of perindopril erbumine tablets, the patient should be followed closely for the first two weeks of treatment and whenever the dose of perindopril erbumine tablets and/or diuretics is increased (See WARNINGS and PRECAUTIONS , Drug Interactions .) In patients who are currently being treated with a diuretic, symptomatic hypotension occasionally can occur following the initial dose of perindopril erbumine tablets. To reduce the likelihood of hypotension, the dose of diuretic, if possible, can be adjusted which may diminish the likelihood of hypotension. The appearance of hypotension after the initial dose of perindopril erbumine tablets does not preclude subsequent careful dose titration with the drug, following effective management of the hypotension. Dose Adjustment in Renal Impairment Kinetic data indicate that perindoprilat elimination is decreased in renally impaired patients, with a marked increase in accumulation when creatinine clearance drops below 30 mL/min. In such patients (creatinine clearance <30 mL/min), safety and efficacy of perindopril erbumine tablets have not been established. For patients with lesser degrees of impairment (creatinine clearance above 30 mL/min), the initial dosage should be 2 mg/day and dosage should not exceed 8 mg/day due to limited clinical experience. During dialysis, perindopril is removed with the same clearance as in patients with normal renal function.
Perindopril erbumine tablets are contraindicated in patients known to be hypersensitive to this product or to any other ACE inhibitor. Perindopril erbumine tablets are also contraindicated in patients with a history of angioedema related to previous treatment with an ACE inhibitor.
Hypertension Perindopril erbumine tablets have been evaluated for safety in approximately 3,400 patients with hypertension in U.S. and foreign clinical trials. Perindopril erbumine tablets were in general well tolerated in the patient populations studied, the side effects were usually mild and transient. Although dizziness was reported more frequently in placebo patients (8.5%) than in perindopril patients (8.2%), the incidence appeared to increase with an increase in perindopril dose. The data presented here are based on results from the 1,417 perindopril erbumine tablets -treated patients who participated in the U.S. clinical trials. Over 220 of these patients were treated with perindopril erbumine tablets for at least one year. In placebo-controlled U.S. clinical trials, the incidence of premature discontinuation of therapy due to adverse events was 6.5% in patients treated with perindopril erbumine tablets and 6.7% in patients treated with placebo. The most common causes were cough, headache, asthenia and dizziness. Among 1,012 patients in placebo-controlled U.S. trials, the overall frequency of reported adverse events was similar in patients treated with perindopril erbumine tablets and in those treated with placebo (approximately 75% in each group). 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. Of these adverse events, those considered possibly or probably related to study drug are shown in the last two columns. Table 2. Frequency of Adverse Events (%) All Adverse Events Possibly - or Probably - Related Adverse Events Perindopril n=789 Placebo n=223 Perindopril n=789 Placebo n=223 Cough 12.0 4.5 6.0 1.8 Back Pain 5.8 3.1 0.0 0.0 Sinusitis 5.2 3.6 0.6 0.0 Viral Infection 3.4 1.6 0.3 0.0 Upper Extremity Pain 2.8 1.4 0.2 0.0 Hypertonia 2.7 1.4 0.2 0.0 Dyspepsia 1.9 0.9 0.3 0.0 Fever 1.5 0.5 0.3 0.0 Proteinuria 1.5 0.5 1.0 0.5 Ear Infection 1.3 0.0 0.0 0.0 Palpitation 1.1 0.0 0.9 0.0 Of these, cough was the reason for withdrawal in 1.3% of perindopril and 0.4% of placebo patients. While dizziness was not reported more frequently in the perindopril group (8.2%) than in the placebo group (8.5%), it was clearly increased with dose, suggesting a causal relationship with perindopril. Other commonly reported complaints (1% or greater), regardless of causality, include: headache (23.8%), upper respiratory infection (8.6%), asthenia (7.9%), rhinitis (4.8%), low extremity pain (4.7%), diarrhea (4.3%), edema (3.9%), pharyngitis (3.3%), urinary tract infection (2.8%), abdominal pain (2.7%), sleep disorder (2.5%), chest pain (2.4%), injury, paresthesia, nausea, rash (each 2.3%), seasonal allergy, depression (each 2.0%), abnormal ECG (1.8%), ALT increase (1.7%), tinnitus, vomiting (each 1.5%), neck pain, male sexual dysfunction (each 1.4%), triglyceride increase, somnolence (each 1.3%), joint pain, nervousness, myalgia, menstrual disorder (each 1.1%), flatulence and arthritis (each 1.0%), but none of those was more frequent by at least 1% on perindopril than on placebo. Depending on the specific adverse event, approximately 30 to 70% of the common complaints were considered possibly or probably related to treatment. Stable Coronary Artery Disease Perindopril has been evaluated for safety in EUROPA, a double-blind, placebo-controlled study in 12,218 patients with stable coronary artery disease. The overall rate of discontinuation was about 22% on drug and placebo. The most common medical reasons for discontinuation that were more frequent on perindopril than placebo were cough, drug intolerance and hypotension. Below is a list (by body system) of adverse experiences reported in 0.3 to 1% of patients in U.S. placebo-controlled studies in hypertensive patients without regard to attribution to therapy. Less frequent but medically important adverse events are also included; the incidence of these events is given in parentheses. Body as a Whole: malaise, pain, cold/hot sensation, chills, fluid retention, orthostatic symptoms, anaphylactic reaction, facial edema, angioedema (0.1%). Gastrointestinal: constipation, dry mouth, dry mucous membrane, appetite increased, gastroenteritis. Respiratory: posterior nasal drip, bronchitis, rhinorrhea, throat disorder, dyspnea, sneezing, epistaxis, hoarseness, pulmonary fibrosis (<0.1%). Urogenital: vaginitis, kidney stone, flank pain, urinary frequency, urinary retention. Cardiovascular: hypotension, ventricular extrasystole, myocardial infarction, vasodilation, syncope, abnormal conduction, heart murmur, orthostatic hypotension. Endocrine: gout. Hematology: hematoma, ecchymosis. Musculoskeletal: arthralgia, myalgia. CNS: migraine, amnesia, vertigo, cerebral vascular accident (0.2%). Psychiatric: anxiety, psychosexual disorder. Dermatology: sweating, skin infection, tinea, pruritus, dry skin, erythema, fever blisters, purpura (0.1%). Special Senses: conjunctivitis, earache. Laboratory: potassium decrease, uric acid increase, alkaline phosphatase increase, cholesterol increase, AST increase, creatinine increase, hematuria, glucose increase. When perindopril erbumine tablets was given concomitantly with thiazide diuretics, adverse events were generally reported at the same rate as those for perindopril erbumine tablets alone, except for a higher incidence of abnormal laboratory findings known to be related to treatment with thiazide diuretics alone ( e.g. , increases in serum uric acid, triglycerides and cholesterol and decreases in serum potassium). Potential Adverse Effects Reported with ACE Inhibitors: Other medically important adverse effects reported with other available ACE inhibitors include: cardiac arrest, eosinophilic pneumonitis, neutropenia/agranulocytosis, pancytopenia, anemia (including hemolytic and aplastic), thrombocytopenia, acute renal failure, nephritis, hepatic failure, jaundice (hepatocellular or cholestatic), symptomatic hyponatremia, bullous pemphigoid, pemphigus, acute pancreatitis, falls, psoriasis, exfoliative dermatitis and a syndrome which may include: arthralgia/arthritis, vasculitis, serositis, myalgia, fever, rash or other dermatologic manifestations, a positive ANA, leukocytosis, eosinophilia or an elevated ESR. Many of these adverse effects have also been reported for perindopril. Fetal/Neonatal Morbidity and Mortality: See WARNINGS : Fetal/Neonatal Morbidity and Mortality . Clinical Laboratory Test Findings Hypertension Hematology, clinical chemistry and urinalysis parameters have been evaluated in U.S. placebo-controlled trials. In general, there were no clinically significant trends in laboratory test findings. Hyperkalemia: In clinical trials, 1.4% of the patients receiving perindopril erbumine tablets and 2.3% of the patients receiving placebo showed serum potassium levels greater than 5.7 mEq/L. (See PRECAUTIONS .) BUN/Serum Creatinine Elevations: Elevations, usually transient and minor, of BUN and serum creatinine have been observed. In placebo-controlled clinical trials, the proportion of patients experiencing increases in serum creatinine were similar in the perindopril erbumine tablets and placebo treatment groups. Rapid reduction of long-standing or markedly elevated blood pressure by any anti-hypertensive therapy can result in decreases in the glomerular filtration rate and, in turn, lead to increases in BUN or serum creatinine. (See PRECAUTIONS .) Hematology: Small decreases in hemoglobin and hematocrit occur frequently in hypertensive patients treated with perindopril erbumine tablets, but are rarely of clinical importance. In controlled clinical trials, no patient was discontinued from therapy due to the development of anemia. Leukopenia (including neutropenia) was observed in 0.1% of patients in U.S. clinical trials (See WARNINGS .) Liver Function Tests: Elevations in ALT (1.6% perindopril erbumine tablets vs 0.9% placebo) and AST (0.5% perindopril erbumine tablets vs 0.4% placebo) have been observed in U.S placebo-controlled clinical trials. The elevations were generally mild and transient and resolved after discontinuation of therapy.
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 perindopril erbumine tablets) may be subject to a variety of adverse reactions, some of them serious. Head and Neck Angioedema: Angioedema involving the face, extremities, lips, tongue, glottis and/or larynx has been reported in patients treated with ACE inhibitors, including perindopril erbumine tablets (0.1% of patients treated with perindopril erbumine tablets in U.S. clinical trials). In such cases, perindopril erbumine 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. 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. Intestinal angioedema should be included 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. Hypotension: Like other ACE inhibitors, perindopril erbumine tablets can cause symptomatic hypotension. Perindopril erbumine tablets have 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 perindopril erbumine 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, perindopril erbumine 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 perindopril erbumine 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. Perindopril erbumine 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 perindopril erbumine tablets are insufficient to show whether perindopril erbumine 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, 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/m 2 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. --- BOXED WARNING: USE IN PREGNANCY 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 .
Diuretics: Patients on diuretics, and especially those started recently, may occasionally experience an excessive reduction of blood pressure after initiation of perindopril erbumine tablets therapy. 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. If diuretics cannot be interrupted, close medical supervision should be provided with the first dose of perindopril erbumine tablets, for at least two hours and until blood pressure has stabilized for another hour. (See WARNINGS and DOSAGE AND ADMINISTRATION .) The rate and extent of perindopril absorption and elimination are not affected by concomitant diuretics. The bioavailability of perindoprilat was reduced by diuretics, however, and this was associated with a decrease in plasma ACE inhibition. Potassium Supplements and Potassium-Sparing Diuretics: Perindopril erbumine tablets may increase serum potassium because of its potential to decrease aldosterone production. Use of potassium-sparing diuretics (spironolactone, amiloride, triamterene and others), potassium supplements or other drugs capable of increasing serum potassium (indomethacin, heparin, cyclosporine and others) can increase the risk of hyperkalemia. Therefore, if concomitant use of such agents is indicated, they should be given with caution and the patient's serum potassium should be monitored frequently. Lithium: Increased serum lithium and symptoms of lithium toxicity have been reported in patients receiving concomitant lithium and ACE inhibitor therapy. These drugs should be coadministered with caution and frequent monitoring of serum lithium concentration is recommended. Use of a diuretic may further increase the risk of lithium toxicity. 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 perindropil erbumine tablets. Digoxin: A controlled pharmacokinetic study has shown no effect on plasma digoxin concentrations when co-administered with perindopril erbumine tablets, but an effect of digoxin on the plasma concentration of perindopril/perindoprilat has not been excluded. Gentamicin: Animal data have suggested the possibility of interaction between perindopril and gentamicin. However, this has not been investigated in human studies. Co-administration of both drugs should proceed with caution. Food Interaction: Oral administration of perindopril erbumine tablets with food does not significantly lower the rate or extent of perindopril absorption relative to the fasted state. However, the extent of biotransformation of perindopril to the active metabolite, perindoprilat, is reduced approximately 43%, resulting in a reduction in the plasma ACE inhibition curve of approximately 20%, probably clinically insignificant. In clinical trials, perindopril was generally administered in a non-fasting state.
