BIOPREXUN?® 10 mg Perindopril arginine ‘COMPOSITION (One fm-coated tablet contains 6.780 mg perindopril coresponding to 10 mg perindopril arginine, ‘THERAPEUTIC INDICATIONS ‘+ Hypertension + Stable coronary artery cisease. Treatment of stable coronary artery disease in patients wih a history of myocardial infarction andlor revascularisation. Perindopril should be used with standard treatment for management of Coronary artery cisease. POSOLOGY AND METHOD OF ADMINISTRATION Posology ‘The dose should be individualised according to the patient profile (see section “Special Warnings and Precautions for Use’) and blood pressure response. Hypertension BIOPREXUM 10 mg may be used in monotherapy or in combination with other classes of ‘antihypertensive therapy (see sections "Contraindicalons’, “Special warnings and precautions for Use", “Interaction with other medicinal products and other forms of inferacion’, and "Pharmacodynamic properties") ‘The recommended starting dose is 5 mg given once dally in the morning, Patients with a strongly activated renin-angiotensin-aldosterone system (in particular, renovascular hypertension, salt andlor volume depletion, cardiac decompensation or severe hypertension) may ‘experience an excessive drop in blood pressure following the inal dose. A starting dose of 2.5 mq Is recommended in such patients and the inibation of treatment should take place under medical supenision ‘The dose may be increased to 10 mg once dally after one month of treatment ‘Symptomatic hypotension may occur following intiaton of therapy with BIOPREXUM 10 mg: this is ‘more likely in patients who are being treated concurrently with diuretics. Caution is therefore recommended since these patients may be volume andlor salt depleted. If possible, the dluretic should be ciscontinued 2 to 3 days before beginning therapy with [BIOPREXUM 10 mg (see section ‘Special Warnings and Precautions for Use"), In hypertensive patients in whom the diuretic cannot be discontinued, therapy with BIOPREXUM should be inated with a 2.5 mg dose. Renal function and serum potassium should be monitored, ‘The subsequent dosage of BIOPREXUM should be adjusted according to Blood pressure response. I required, diuretic therapy may be resumed. In elderly patients treatment should be initiated at a dose of 2.5 mg which may be progressively Increased to § mg affer one month then to 10 mg if necessary depending on renal funetion (ee table below), 1 BIOPREXUM should be introduced at a dose of 5 mg once daly for two weeks, then increased to 10 mg once dally. depencing on renal function and provided thatthe 5 mg dose is well tolerated Elderly patients should receive 2.5 mg once daily for one week, then 5 mg once dally the next week, before increasing the dose up fo 10 mg once dally depending on renal functon (see Table 1 "Dosage adjustment in renal impaiment), The dose should be increased only i the previous lower dose is wel tolerated,‘Special population: Patients with renal impairment Dosage in patients with renal impairment should be based on creatinine clearance as outlined in table 1 below Table 1: Dosage adjustment in renal impairment Creatinine clearance (mlinin) | Recommended dose Cin 60 Smaperday 30 Cen < 60 2:5mgper day 1870 years), clabetes melts, intercurrent events, in Particular dehydration, acute cardiac decompensation, metabolic acidosis and concomitant use of Potassium-sparing diuretics (@.9. spironolactone, eplerenane, tamlerene, or amiloride), potassium Supplements or potassium-containing salt substitutes, or thase patients taking other drugs associated with increases in serum potassium (e.g. heparin). The use of potassium supplements, Potassium-sparing diuretics, or potassium-contalning salt substitutes. particularly in patents with impaired renal function may lead toa signifcant increase in serum potassium. Hyperkalaemia can ‘cause serous, sometimes fatal arhythmias. If concomitant use of the above-mentioned agents is ‘deemed appropriate, hey should be used with caution and with frequent monitoring of serum potassium (See section interaction with other medicinal products and other forms of interaction). Diabetic patents In diabetic patients treated with oral antidiabetic agents or insulin, glycaemic control should be closely monitored during the fist month of reatment with an ACE inhibitor (see section “interactions with ther medicinal products and other forms of interaction’) Lata The combination of thium and perindopril is generally not recommended (see section “interactions with ofter medicinal products and other forms of interaction”) Potassium sparin m. Jaining salt substiutes “The combination of perindopril and potassium sparing drugs, potassium supplements or potassium- containing salt substitutes is generally not recommended (see section “Interactons with other ‘macicinal products and other forms of interaction’) | Dual blockade ofthe renin-angiotensin-aldosteront ‘There is evidence that the concomitant use of ACE-nhibilors, angiotensin ll receptor blockers or | alskren increases the risk of hypotension, hyperkalaemia and decreased renal function (including ‘acute renal failure). Dual blockade of RAAS trough the combined use of ACE-iahbitor, “angiotensin Il receptor blockers or aliskiren is therefore nat recommended (see sections “interaction ‘with other medicinal products and other forms of interaction’, and “Pharmacodynamic properties”). If dual blockade therapy is considered absolutely necessary, this should only occur under specialist ‘supervision and subject to frequent close monitoring of renal function, electrlytes. and blood pressure. ‘ACE-inhibitors and angiotensin Il receptor blockers should not be used concomitantly in patents ‘with diabetic nephropathy.Preanancr ACE nhibtors should not be insted during pregnancy. Unless continued ACE inhibitor therapy is Considered essential, patients planning pregnancy shoud be changed to altemative ant hypertensive treatments which have an estabished safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with ACE inhibitors should be stopped immediately. and, if propriate, altemaive therapy should be started (see sections. “Contvaindications” and “interactions with other medicinal products and other forms of interaction’) Excipients ue to the presence of lactose, patients with rare hereditary problems of galactose intolerance, dlucose-galactose malabsorpion, oF the Lapp lactase deficiency should not take this medicinal Product INTERACTION WITH OTHER MEDICINAL PRODUCTS AND OTHER FORMS OF INTERACTION Clinica wal data has shown that dual blockade ofthe renin-angiotensin-aldosterone-eystem (RAS) through the combined use of ACE-inhbitors, angiotensin Il receptor blockers or alskiren is associated with 3 higher frequency of adverse events such as hypotension, hyperkalaemia and decreased renal function (including acute renal failure) compared tothe use ofa single RAAS-acing agent (see sections ‘Contraincications, “Special warnings ang precautions for use’, and "Pharmacodynamic properties”) ‘Some drugs or therapeutic classes may increase the occurrence of hyperkalaemia: aliskiren, potassium salts, potassium-sparing diuretics, ACE inhibitors, angiotensiml receptors antagonist, NSAIDs, hoparine, immunasuppressant agents such as ciclosporin or tacrolimus, trimethopeim, The Combination ofthese drugs increases the sk of hypeskalaemia, Concomitent use contra-indicated (see section contraindications): Alskien: In diabetic or impaired renal patients, risk of hyperkalemia, worsening of renal function and cardiovascular morbidity and moray increase, Concomitant use not recommended (see section special warnings and special precautions for sel: Aliskien {In patients other than diabetic of impaired renal patens, risk of hyperkalaemia, worsening of renal function and cardiovascular morbidity and morally Increase, ‘Concomitant therapy with ACE inhibitor and anglotensin-recepter blocker thas been reported in the iterature that in patients with established atherosclerotic disease, heart failure, or with diabetes with end organ damage, concomitant therapy with ACE. inhibitor and angiotonsinrecoptor blocker is associated with a higher frequency of hypotension, syncope, hhyperkalaemia, and worsening renal function (Including acute renal failure) as compared to use of single renin-angiotensin-aldosterone system agent. Dual blockade (@.g, by combining an ACE- Intvbitor with an angiotensin Il receptor antagonist) shoul be limited to individually defined cases with close monitoring f renal function, potassium levels, and blood pressure. Estamustine: Fisk of increased adverse effects such as angioneurotc oedema (angioedema). Racecadoti AACE inhibitors (e.g. perindopril) are known to cause angioedema. This risk may be elevated when Used concomitantly with racecadotil (a drug used against acute iarrer Ri i lemstoinus Patients taking concomitant mTOR inhibitors therapy may be at increased risk for angloedema (see section ‘Special wamings and special precautions for use’). Potassium-sparing diuretics e.g. viemterene, amiloride...) potassium (salts) Hyperkalsemia (potentialy lethal), especially in conjunction with renal impairment (additive hhyperkalaemic effects) ‘The combination of perindopril with the above-mentioned drugs is not recommended (see section special warnings and precautions for use). If concomitant use is nonetheless indicated, they should be used with caution and with frequent monitoring of serum potassium. For use of spironolactone in heart fale, see below. uth: Reversible increases in serum lithium concentrations and toxicity have been reported during ‘concomitant administration of lithium with ACE inhibitors Use of perindopell with ithium ts not recommended, but if the combination proves necessary, careful monitoring of serum lithium levels, ‘should be performed (soe section “Special warrings and precautions for use") Concomitant use which requires special care: Antgiabetc agents (insulin, oral hypoalycaemic agents) Epidemiological studies nave suggested that concomitant administration of ACE inhibitors and“antidiabetic medicines (insulins, oral hypogiyeaenie agents) may cause an iereased blood glucose lowering effect with risk of hypoglyeaemia. This phenomenon appeared to be more likely {0 occur during the frst weeks of combined treatment and in patients with renal impairment. Bacofen: increased antihypertensive effect. Monitor blood pressure and adapt anthypertensive dosage) if necessary. ‘Non-potassium sparing diuretics: Patients on duretcs, and especially those who are volume andor salt depleted, may experien ‘excessive reduction in blood pressure aftr ination of therapy wth an ACE inhibitor. The possbil ‘of hypotensive effects can be reduced by discontinuation of the diuretic, by increasing volume or sat Intake prior to inating therapy with low and progressive doses of perindopril In arterial hypertension, when prior diuretic therapy can have caused saltvolume depletion, either diuretic must be discontinued before inating the ACE inhibitor, in which case a non- potassium sparing duretc can be thereaterrenvodiced or the ACE inion must belied wih law ‘dosage and progressively increased. in durtereoted congestive hear faiur, the ACE lbtor shoud be inated at avery low dosage, possibly after reducing the dosage of the associated non-patassium-sparing curetic. In all cases, feral function (creatinine levels) must be monitored during the frst few weeks of ACE inhibitor therapy, Potassiun-sparing diuretics (eplerenone, sirona ‘With epierenone or spironolactone at doses between 12,5 mg to 60 mg by day and with low doses of ACE inhibitors: In the treatment of class IFIV heart failure (NYHA) with an ejection fraction <40%, and previously ‘weated with ACE inhibitors and loop diuretics, risk of hyperkalaemia, potentially lea, especialy in ‘case of ron-observance of the prescription recommendations on this combination. Before inating the combination, check the absence of hyperkalaemia and renal impairment. ‘A-close monitoring of the kalaemia and creatinemia Is recommended in the frst month of the treatment once a week at the beginning and, monthly thereafter. Now: steroigalantnfiam ucts (NSAIDs) including asprin > 3 aida ‘When ACE-inhibitors are administered simuitaneously wih non-steroidal antiinflammatory drugs (\. acetyisalicyic acid at antiinflammatory dosage regimens, COX-2 inhibitors and non-selective NSAIDS), attenuation ofthe antinypertensive effect may occur, Concomitant use of ACE-iahibitors and NSAIDs may lead to an increased risk of worsening of renal function, including possible acute renal failure, and an increase in serum potassium, especialy n patents wth poor pre-existing renal function. The combination should be administered with caution, especialy in the elderly. Patients should adequately hydrated and consideration should be given to monitoring renal function after initation pt ‘concomitant therapy, and periodically thereafter. Concomitant use which requires some care: ‘Anthyoert r Concomitant use ofthese agents may increase the hypotensive effects of perindopril. Concomitant use with nitrogycerin and other nitrates, or other vasodilators, may futher reduce blood pressure, tinting (ue saxagiptine, sitagiptine, vidagiptine) Increased risk of angio-oedema, due to dipeptidy! peptidase IV (OPP-IV) decreased actvly by the aliptine, in patients co-treated with an ACE inhibitor Tes ti nisi u Concomitant use of certain. anaesthetic medicinal products, cycle antidepressants and antipsychotics with ACE inhibitors may result in further reducion of blood pressure (see section “Special wamings and precautions for use") ‘Sumpathomimetics: ‘Sympathomimetcs may reduce the antihypertensive effects of ACE inhibitor. Gals [Nititoid reactions (symptoms include facial fushing, nausea, vomiting and hypotension) have boon reported rarely in patients on therapy with injectable gold (sodium aurothiomalate) and =e ACE inhibitor therapy including perindopril FERTILITY, PREGNANCY AND LACTATION Pr ‘The use of AGE inhibitors Is not recommended during the fst vimester of pregnancy (eee section special wamings and precautions for use). The use of ACE inhibitors is conta-ndieated during the 2nd land 3rd trimester of pregnancy (see sections contraindication and special wamings and precautions for use), Epidemiological evidence regarding the risk of teratogenicity following exposure to ACE inhibitors uring the frst timester of pregnancy has not been conclusive; however a small increase in risk Cannot be excluded. Uniess continued ACE inhibitor therapy is considered essential, patents planning pregnancy should be changed to altematve ant-hypertensive treatments which have an established Safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with ACE. inhibitors should be stopped immediately, and, appropriate alternative therapy shouldbe startedTadiaion ‘Because no information is availabe regarding the use of Bioprexum during breastfeeding, Bioprexum is not recommended and aleriatve treatments vith beter established safety profiles during breast feeding are preferable, especially while nursing a newbom or preterm infant. Exposure to ACE inhibitor therapy during the second and thi trimesters is known to induce human foctotoxity (decreased renal function, aligohyéramnios, skull ossification retardation) and neonatal toxicity (renal falure, hypotension, hyperkalaemia) (see secton “Precinical safety data’). Should ‘exposure to ACE inhibitor have occurred from the second trimester of pregnancy, ulasound check ff renal functon and skull is recommended. Infants whose mothers have taken ACE Inhibitors should be closely observed for hypotension (see also sections “Contraindicatons” and “Special warnings and precautions for use") Lactation ‘Because no information is avalable regarding the use of Coversyt during breastfeeding, Coversy! is fot recommended and alternative treatments wih better established safety profiles during breat feeding are preferable, especially while nursing @ newborn or preterm infant. Ect: ‘There vas no effect on reproductive performance or fertiy EFFECTS ON ABILITY TO DRIVE AND USE MACHINES. Bloprexum has no direct influence on the abilty to dive and use machines but individual reactions related to low blood pressure may occur in some patients, particulary at the start of teatment or in Combination wth another antihypertensive medication, ‘AS a result the ability to drive or operate machinery may be impaired, UNDESIRABLE EFFECTS. 2. Summary of safety profile ‘The safety profile of perindopril consistent with the safety profile of ACE inhibitors: ‘The most frequent adverse events reported In dlinical tals and observed with perindopril are: dizziness, headache, paraesthesia, verigo, visual disturbances, tinnitus, hypotension, cough, ‘dyspnoea, abdominal pain, constipation, diarrhoea, dysgeusia, dyspepsia, nausea, vomiting, prt, ‘ash, muscle cramps, and asthenia. Tabula list of adverse reactions ‘The folowing undesirabie effects have been observed during cinical tials and/or post marketing use wth perindopal and ranked under the following frequency: Very common (21/10); common (21/100, <1/10); uncommon (21/1000, <1/109); rare (21/10000, 1/1000); very rare (<1/10000}; not known (cannot be estimated from the avalable data). MedDRA Undesirable Effects Frequency ‘Systom Organ Class Blood and the lymphatic | Eosinophia Uncommon” ‘System Disorders ‘granulocytosis oF pancyioperia Very rare Haemoglobin decreased and Very rare haematocrit decreased Leucopeniaineutroperia Very rare Haemolyic anaemia in patients witha | Very are ‘congenital deficiency of G-6POH (see ‘section ‘Special warnings and precautions for use") “Thrombocytopenia Very rare Metabolism and nutrition | Fypoglycaemia (see sections "Special | Uncommon” disorder \wamings and precautions for use" and “Interaction with other medicinal and ‘other forms of interaction’) Fyperkalaemia, reversible on ~Uneamman™ iscontnuation (see section "Special .wamings and precautions for use") Hyponatraemi Uncomment Paychiatrie disorders Mood disturbances ‘Uncommon Sleep disorder ‘Uncommon Nervous system disorders | Dizziness ‘Common Headache ‘Common Paraosthesia ‘Common Vertigo ‘Common ‘Semnolenee Uncomment ‘Syncope ‘Uneomman”™ Confusion Very rare | Eye Disorders Visual disturbances ‘Common ar and labyrinth disorders | Tinnitus ‘CommonCardiac disorders Palpitations ‘Uncommon* I Tachycardia Uncommon* Angina pectoris (see section “Special Very rare ‘warnings and precautions for use”) Arrythmia Very rare Myocardial infarction, possibly Very rare secondary to excessive hypotension in high risk patients (see section “Special ‘warnings and precautions for use”) Vascular disorders | Hypotension (and effects related to Common hypotension) Vasculitis ‘Uncommon Stroke possibly secondary to excessive | Very rare hypotension in high-risk patients (see section “Special warnings and precautions for use”) Repirator, drat | Cough Common dere et | Drones Common Broshospesm Uncommon Eoinophili reunoni ra ini Verve Gastrointestinal | Abdominal pai Common eee Constipation Common | Diahes Common | | Dyson Common Dyspepsia, Common Nawses Common Voming Common Dry mouth _ Uncommon Pancreat Very ee Tiepasbitary | Hepa citer cyte erates | Veryre disorders (see section “Special warnings and _ precautions for use”) skin soa | Pai Connon Satncon te [ya - — Urticaria (see section “Special ‘Uncommon ‘warnings and precautions for use”) Angioedema of face, extremities, lips, | Uncommon ‘mucous membranes, tongue, glottis, and/or larynx (see section “Special ‘warnings and precautions for use” Photosensitivity reactions Uncommon* Pemphigoid Uncommon* Hyperhydrosis Uncommon Psoriasis aggravation Rare* Erythema multiforme Very rare NS er eeeMusculoskeletal and | Muscle cramps Common connective tissue disorders Arthralgia Uncommon* Myalgia Uncommon* Renal and urinary | Renal insufficiency ‘Uncommon disorders ‘Acute renal failure Very rare Reproductive system and | Erectile dysfunction ‘Uncommon, breast disorders General disorders and | Asthenia ‘Common ‘administration ste Chest pain ‘Uncommon* Malaise Uncommon* edema peripheral Uncommon* Pyrexia __| Uncommon* investigations Blood urea increased ‘Uncommon* Blood creatinine increased ‘Uncommon* Blood bilirubin increased Rare Hepatic enzyme increased Rare Injury, poisoning _and | Fall ‘Uncommon* procedural complications * Frequency calouated from cinial Was for adverse events dlected from spontaneous report (GlnicaL tials: During the randomised period of the EUROPA study, only serious adverse events were collected. Few patients experienced serious adverse events: 16 (0.5%) of the 6122 perindoprl patients and 12 (0.2%) Of the 6107 placebo patients. In perindopri-treated patients, hypotension was observed in 6 patients, ‘angioedema in 3 patients and sudden cardiac arrestin 1 patient. More patients withdrew for cough, hypotension or other intolerance on perindopril than on placebo, 6.0% (n=366) versus 2.1% (n=129} respectively. Reporting of suspected adverse reaction: Reporting suspected adverse reactions aller authorisation of the medicinal product is important. It allows continued monitoring of the benefirsk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via PUSAT FARMAKOVIGILANS- BPOM: Tip. O21-4245459, 021-4244755 Ext. 111, Fax. 021-4243605, 021-42885408; Email pv- ‘Senler@pom.go id andlor ndonesia-MESO-BadanPOM@notmail com. ovERDOSE Limited data are avaliable for overdosage in humans. Symptoms associated with overdosage of ACE. Inhibitors may include hypotension, circulatory shock, electrolyte disturbances, renal failure, hhyperventiation, tachycardia, palpitations, bradycardia, dizziness, arty, and cough The recommended treatment of overdosage Is Intravenous infusion of sodium chloride 9 mail (0.5%) soluton. If ypotension occurs, the patient should be placed inthe shock positon I avaiable, lweatment with angiotensin Infusion andlor intravenous catecholamines may also be considered, Perindopril may be removed from the general circulation by haemodialysis (see "Special Warnings and Precautions for Use). Pacemaker therapy Is indicated for therapy-esistant bradycardia. Vital Signs, serum electrolytes and creatinine concentrations should be monitored continuously. PHARMACOLOGICAL PROPERTIES Pharmacodynamic properties Pharmacotherapeutic group: ACE inhibitors, plan, ATC code: CO9A AD Mechanism of action Perindopril is an inhibitor of the enzyme that converts angiotensin | into angiotensin I! (Angiotensin Converting Enzyme ACE). The converting enzyme, or kinase, is an exopeptidase that allows, Conversion of angiotensin | into the vasoconstrictor angiotensin Il as well as causing the degradation Of the vasodilator bradykinin into an inactive heptapeptide. Inhibition of ACE results ina reduction of angiotensin Il in the plasma, which leads to Increased plasma renin actvly (by inhibition of the egative feedback of renin release) and reduced secration of aldosterone. Since ACE inactivates bradykinin, inhibition of ACE also results in an increased activity of circulating land local kalikrein-kinin systems (and thus also activation ofthe prostaglandin system). It's possible that this mechanism contributes to the blood pressure-owering action of ACE inhibitors and is Parlay cesponsible for carta oftheir side effects (2.9. cOUgh). Perindopril acts through is active metabolite, perindopilat. The other metabolites show no inhibiton OF ACE activity in vite.Glinieal efficacy and safety Hypertension Perindopril is acive in all grades of hypertension: mid, moderate, severe: a reduction in systolic and diastolic blood pressures in both supine and standing postions is observed Perindopril reduces. peripheral vascular resistance, leading to blood pressure reduction. AS a ‘consequence, peripheral blood flow increases, with no effect on heart rate, Renal blood flow increases as are, while the glomeruarfitaton rae (GFR) is usually unchanged, ‘The antihypertensive activity is maximal between 4 and 6 hours after a single dose and ls sustained for at east 24 hours: rough effets are about 87-100 % of peak elects, ‘The decrease in blood pressure occurs rapidly. In responding patients, normalisation is achleved ‘within a month and persists without the occurrence of tachyphylan, Discontinuation of treatment does not lead toa rebound effect Perindopril reduces left ventricular hypertrophy. In man, perindopril has been confirmed to demonstrate vasodilatory properties. It improves large artery elasticity and decreases the media: lumen rato of small arteries. ‘An adjunctive therapy witha thiazide diuretic produces an adeitve-ype of synergy. The combination | fof an ACE inhibitor and a thiazide also decreases the risk of hypokalaemia Induoed by the duretc treatment. Patents with stable coron ‘The EUROPA study was a multicent clinical tal lasting 4 years, “Twelve thousand two hundred and eighteen (12218) patonts aged over 18 were randomised to 8 mg) perindopril tert-butylamine (equivalent to 10 mg perindopril arginine) (n=6110) or placebo (n=6108). ‘The tial population had evidence of coronary artery disease with no evidence of clinical signs of heart failure. Overal, 90% of the patents had a previous myocardal Infarction and/or a previous coronary revasculrisation, Most ofthe patients received the study medication ontop of conventional therapy including platelet inhibitors, pi lowering agents and beta-blockers ‘The main efficacy criterion was the composite of cardiovascular mortally, non fatal myocardial Infarction andor cardiac arrest with successful resuscitation. The treatment with 8 mg perindopril ter- butylamine (equivalent to 10 mg perindopril arginine) once daly resulted in a significant absolute reduction in the primary endpoint of 1.9% (relative risk reduction of 20%, O5%CI [9.4; 28.6] - 0.00") Inpatients with a history of myocardial infarction andlor revascularsation, an absolute reduction of 2.2% corresponding to a RRR of 22.4% (95%4Cl [12.0; 31.6] - p<0.001) in the primary endpoint was ‘observed by comparison to placebo. ilernational, randomised, double-blind, placebo-contrlled Paediatric use The safely and efficacy of perindopril in children and adolescents aged below 18 years have not been established, Inan open, non-comparative clinical study in 62 hypertensive children aged from 2 to 15 years with 2 glomerular fivaton rate > 30 mlimin/.73 m?, patents recelved perindopril with an average dose of B07 mgikgiday. The dose was individualised according to the patient profile and blood pressure response up to a maximum dose of 0.135 mghka/day. 59 patients completed the period of tree months, and 36 patients completed the extension period of| the study, 0. woe folowed atleast 24 months (iean study duration: 44 months). Sysioic and diastolic blood pressure remained stable from the inclusion to the last assessment in patients previously treated by other anthypertensive treatments, and decreased in naive patents. Nore han 75% of cron Mad stoic and data Bod pressure below the 95" pecenleat ih last assessment ‘The safety was consistent wih the known safety profile of perindopril Pharmacokinetic propertios, Absorption ‘ter oral administration, the absorption of perindopril is rapid and the peak concentrations achieved within 1 hour. The plasma halfife of perindopril is equal 01 hour Perindopril is a prodrug. Twenty seven percent of the administered perindopril dose reaches the bloodstream as the active metabolite perindopriat. In additon to active perindoprlat, perindopril yields five metabolites, all inactive, The peak plasma concentration of perindoprlat is achieved within 3to 4 hours {As ingestion of food decreases conversion to perindopiat, hence bioavailability, perindopril arginine ‘should be administered orally ina single dally ose inthe morning before a meal It has been demonstrated a linear relationship between the dose of perindopril and its plasma exposure. Distbuton ‘The volume of distibuton is approximately 0.2 Ukg for unbound perindopril. Protein binding of petindopriat to plasma protens Is 20%, princpaly to angiotensin convering enzyme, but Is | Eoncentration-dependent Elimination Petindopriat is eiminated inthe urine and the terminal half-ife of the unbound fraction is approximately 17 hours, esuling in steady-state within 4 daysErato ef pend decreased inthe eet, nd ton patents wea of eal ce, Docayo acgavant tr renal rnicnty we decree dopey on to Cems of impart (reatine aracs) Shays osrancn cf eeapit sequal to 70min Pesdep! ae ae mode’ in pales win ries: hepa cerance of he pret lease istadued ya Howaver, be quary of edopiat meds ot eauced ara eraor thsoge auestnent a eared (oe ae, econ "Posolgy ond ead of eomiovobor? and ‘Spoda naming and procauton fr ue Preclinical safety data In the chronic oral toxicity studies (rats and monkeys), the target organ isthe kidney, with reversible damage. No mutagenicity has been observed in vtto or in vivo studies. Reproduction toxicology studies (rats, mice, rabbits and monkeys) showed no sign of embryotoxcty or feratogenicity. However. angiotensin converting enzyme inhibitors asa class, have been shown to Induce adverse effecs on late fetal development, resulting in fetal death and congenital effects in Fedents and rabbits: renal lesions and an increase in peti and postnatal mortality have been observed. Fertility was not impaired eter in male or in female rats. No carcinagenicty has been observed in fang term studies in rats and mice, ‘STORAGE CONDITION Store under 30°C. Shot ite :3 years. PACKING Box of 1 plastic bottle of 30 tablets. Reg. No.: DK1163160061781 (ON PRESCRIPTION ONLY HARUS DENGAN RESEP DOKTER = Manufactured by —— Servier (reland) Industries Lt >= ‘Atow —Irland > SERVIER Registered by Les Laboratoires Servier PT Darya-Varia Laboratoria Tbk France Bogor - Indonesia Imported and Marketed by PT. Servier Indonesia Jakarta ~ Indonesia