Bioprexum

Perindopril arginine.

Bioprexum 5 mg contains perindopril 3.395 mg corresponding to perindopril arginine 5 mg. It also contains lactose monohydrate 72.58 mg.
Bioprexum 10 mg contains perindopril 6.79 mg corresponding to perindopril arginine 10 mg. It also contains lactose monohydrate 145.16 mg.
Each tablet also contains the following excipients: Core: Lactose monohydrate, magnesium stearate, maltodextrin, hydrophobic colloidal silica and sodium starch glycolate (type A). Film-Coating: Glycerol, hypromellose, copper chlorophyllin (not 2.5 mg), macrogol 6000, magnesium stearate and titanium dioxide.
Bioprexum 5-mg tablet can be divided into equal halves.

Pharmacotherapeutic Group: ACE inhibitor, plain. ATC Code: C09AA04.
Pharmacology: Pharmacodynamics: Perindopril is an inhibitor of the enzyme that converts angiotensin I into angiotensin II [angiotensin-converting enzyme (ACE)]. The converting enzyme, or kinase, is an exopeptidase that allows conversion of angiotensin I into the vasoconstrictor angiotensin II as well as causing the degradation of the vasodilator bradykinin into an inactive heptapeptide. Inhibition of ACE results in a reduction of angiotensin II in the plasma, which leads to increased plasma renin activity (by inhibition of the negative feedback of renin release) and reduced secretion of aldosterone. Since ACE inactivates bradykinin, inhibition of ACE also results in an increased activity of circulating and local kallikrein-kinin systems (and thus also activation of the prostaglandin system). It is possible that this mechanism contributes to the blood pressure-lowering action of ACE inhibitors and is partially responsible for certain of their side effects (eg, cough).
Perindopril acts through its active metabolite, perindoprilat. The other metabolites show no inhibition of ACE activity in vitro.
Hypertension: Perindopril is active in all grades of hypertension: Mild, moderate, severe; a reduction in systolic and diastolic blood pressures in both supine and standing positions 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 a rule, while the glomerular filtration rate (GFR) is usually unchanged. The antihypertensive activity is maximal between 4 and 6 hrs after a single dose and is sustained for at least 24 hrs: Trough effects are about 87-100% of peak effects.
The decrease in blood pressure occurs rapidly. In responding patients, normalisation is achieved within a month and persists without the occurrence of tachyphylaxis.
Discontinuation of treatment does not lead to a 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 ratio of small arteries.
An adjunctive therapy with a thiazide-diuretic produces an additive-type of synergy. The combination of an ACE inhibitor and a thiazide also decreases the risk of hypokalaemia induced by the diuretic treatment.
Heart Failure: Perindopril reduces cardiac work by a decrease in pre- and afterload. Studies in patients with heart failure have demonstrated decreased left and right ventricular filling pressures, reduced total peripheral vascular resistance, increased cardiac output and improved cardiac index.
In comparative studies, the 1st administration of perindopril arginine 2.5 mg to patients with mild to moderate heart failure was not associated with any significant reduction of blood pressure as compared to placebo.
Patients with Stable Coronary Artery Disease: The EUROPA trial was a multicentre, international, randomised, double-blind, placebo-controlled clinical trial lasting 4 years.
Twelve thousand two hundred and eighteen (12,218) patients >18 years were randomised to perindopril tert-butylamine 8 mg (equivalent to perindopril arginine 10 mg) (n=6110) or placebo (n=6108).
The trial population had evidence of coronary artery disease with no evidence of clinical signs of heart failure. Overall, 90% of the patients had a previous myocardial infarction and/or a previous coronary revascularisation. Most of the patients received the study medication on top of conventional therapy including platelet inhibitors, lipid-lowering agents and β-blockers.
The main efficacy criterion was the composite of cardiovascular mortality, nonfatal myocardial infarction and/or cardiac arrest with successful resuscitation. The treatment with perindopril tert-butylamine 8 mg (equivalent to perindopril arginine 10 mg) once daily resulted in a significant absolute reduction in the primary endpoint of 1.9% [relative risk reduction (RRR) of 20%, 95% CI (9.4; 28.6); p<0.001].
In patients with a history of myocardial infarction and/or revascularisation, an absolute reduction of 2.2% corresponding to a RRR of 22.4% [95% CI (12.0; 31.6); p<0.001] in the primary endpoint was observed by comparison to placebo.
Pharmacokinetics: After oral administration, the absorption of perindopril is rapid and the peak concentration is achieved within 1 hr. The plasma half-life of perindopril is equal to 1 hr.
Perindopril is a prodrug. Twenty-seven percent (27%) of the administered perindopril dose reaches the bloodstream as the active metabolite perindoprilat. In addition to active perindoprilat, perindopril yields 5 metabolites, all inactive. The peak plasma concentration of perindoprilat is achieved within 3-4 hrs.
As ingestion of food decreases conversion to perindoprilat, hence bioavailability, perindopril arginine should be administered orally in a single daily dose in the morning before a meal.
It has been demonstrated a linear relationship between the dose of perindopril and its plasma exposure.
The volume of distribution is approximately 0.2 L/kg for unbound perindoprilat. Protein-binding of perindoprilat to plasma proteins is 20%, principally to ACE, but is concentration-dependent.
Perindoprilat is eliminated in the urine and the terminal half-life of the unbound fraction is approximately 17 hrs, resulting in steady-state within 4 days.
Elimination of perindoprilat is decreased in the elderly and also in patients with heart or renal failure. Dosage adjustment in renal insufficiency is desirable depending on the degree of impairment (creatinine clearance).
Dialysis clearance of perindoprilat is equal to 70 mL/min.
Perindopril kinetics are modified in patients with cirrhosis. Hepatic clearance of the parent molecule is reduced by half. However, the quantity of perindoprilat formed is not reduced and therefore, no dosage adjustment is required (see Dosage & Administration and Precautions).
Toxicology: Preclinical Safety Data: In the chronic oral toxicity studies (rats and monkeys), the target organ is the kidney, with reversible damage.
No mutagenicity has been observed in in vitro or in vivo studies.
Reproduction toxicology studies (rats, mice, rabbits and monkeys) showed no sign of embryotoxicity or teratogenicity. However, ACE inhibitors, as a class, have been shown to induce adverse effects on late foetal development, resulting in foetal death and congenital effects in rodents and rabbits. Renal lesions and an increase in peri- and postnatal mortality have been observed.
No carcinogenicity has been observed in long-term studies in rats and mice.

Treatment of hypertension and symptomatic heart failure.
Stable Coronary Artery Disease: Reduction of risk of cardiac events in patients with history of myocardial infarction and/or revascularisation.

The dose should be individualised according to the patient profile (see Precautions) and blood pressure response.
Hypertension: Bioprexum may be used in monotherapy or in combination with other classes of antihypertensive therapy. Recommended Dose: 5 mg once daily in the morning.
Patients with a strongly activated renin-angiotensin-aldosterone system (in particular, renovascular hypertension, salt- and/or volume-depletion, cardiac decompensation or severe hypertension) may experience an excessive drop in blood pressure following the initial dose. A starting dose of 2.5 mg is recommended in such patients and the initiation of treatment should take place under medical supervision. The dose may be increased to 10 mg once daily after 1 month of treatment.
Symptomatic hypotension may occur following initiation of therapy with Bioprexum; this is more likely in patients who are being treated concurrently with diuretics. Caution is therefore recommended since these patients may be volume- and/or salt-depleted.
If possible, the diuretic should be discontinued 2-3 days before beginning therapy with Bioprexum (see Precautions).
Hypertensive Patients in Whom the Diuretic Cannot be Discontinued: Therapy with Bioprexum should be initiated 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. If required, diuretic therapy may be resumed.
Elderly: Treatment should be initiated at a dose of 2.5 mg which may be progressively increased to 5 mg after 1 month, then to 10 mg if necessary depending on renal function.
Symptomatic Heart Failure: It is recommended that Bioprexum, generally associated with a nonpotassium-sparing diuretic and/or digoxin and/or a β-blocker, be introduced under close medical supervision with a recommended starting dose of 2.5 mg taken in the morning. This dose may be increased after 2 weeks to 5 mg once daily if tolerated. The dose adjustment should be based on the clinical response of the individual patient.
In severe heart failure and in other patients considered to be at high risk (patients with impaired renal function and a tendency to have electrolyte disturbances, patients receiving simultaneous treatment with diuretics and/or treatment with vasodilating agents), treatment should be initiated under careful supervision (see Precautions).
Patients at high risk of symptomatic hypotension eg, patients with salt depletion with or without hyponatraemia, patients with hypovolaemia or patients who have been receiving vigorous diuretic therapy, should have these conditions corrected, if possible, prior to therapy with Bioprexum. Blood pressure, renal function and serum potassium should be monitored closely, both before and during treatment with Bioprexum (see Precautions).
Stable Coronary Artery Disease: Initially 5 mg once daily for 2 weeks, then increased to 10 mg once daily, depending on renal function and provided that the 5 mg dose is well tolerated.
Elderly: Elderly patients should receive 2.5 mg once daily for 1 week, then 5 mg once daily the next week, before increasing the dose up to 10 mg once daily depending on renal function. The dose should be increased only if the previous lower dose is well tolerated.
Renal Impairment: Dosage in patients with renal impairment should be based on creatinine clearance (CrCl).
CrCl ≥60 mL/min: 5 mg/day, >30 to <60 mL/min: 2.5 mg/day, >15 to <30 mL/min: 2.5 mg every other day.
Haemodialysed Patients* (CrCl <15 mL/min): 2.5 mg on the day of dialysis.
*Dialysis clearance of perindoprilat is 70 mL/min. For patients on haemodialysis, the dose should be taken after dialysis.
Hepatic Impairment: No dosage adjustment is necessary in patients with hepatic impairment (see Pharmacokinetics under Actions and Precautions).
Administration: It is recommended that Bioprexum be taken once daily in the morning before a meal.

Symptoms: Limited data are available for overdosage in humans. Symptoms associated with overdosage of ACE inhibitors may include hypotension, circulatory shock, electrolyte disturbances, renal failure, hyperventilation, tachycardia, palpitations, bradycardia, dizziness, anxiety and cough.
Treatment: The recommended treatment of overdosage is IV infusion of 0.9% sodium chloride 9 mg/mL solution. If hypotension occurs, the patient should be placed in the shock position. If available, treatment with angiotensin II infusion and/or IV catecholamines may also be considered. Perindopril may be removed from the general circulation by haemodialysis (see Precautions). Pacemaker therapy is indicated for therapy-resistant bradycardia. Vital signs, serum electrolytes and creatinine concentrations should be monitored continuously.

Known hypersensitivity to perindopril, to any of the excipients of Bioprexum or to any other ACE inhibitor; history of angioedema associated with previous ACE inhibitor therapy; hereditary or idiopathic angioedema; 2nd and 3rd trimesters of pregnancy (see Use in pregnancy & lactation under Precautions).

Stable Coronary Artery Disease: If an episode of unstable angina pectoris (major or not) occurs during the 1st month of perindopril treatment, a careful appraisal of the benefit/risk should be performed before treatment continuation.
Hypotension: ACE inhibitors may cause a fall in blood pressure. Symptomatic hypotension is seen rarely in uncomplicated hypertensive patients and is more likely to occur in patients who have been volume-depleted eg, by diuretic therapy, dietary salt restriction, dialysis, diarrhoea or vomiting, or who have severe renin-dependent hypertension (see Adverse Reactions and Interactions). In patients with symptomatic heart failure, with or without associated renal insufficiency, symptomatic hypotension has been observed. This is most likely to occur in those patients with more severe degrees of heart failure, as reflected by the use of high doses of loop diuretics, hyponatraemia or functional renal impairment. In patients at increased risk of symptomatic hypotension, initiation of therapy and dose adjustment should be closely monitored (see Dosage & Administration and Adverse Reactions). Similar considerations apply to patients with ischaemic heart or cerebrovascular disease in whom an excessive fall in blood pressure could result in a myocardial infarction or cerebrovascular accident.
If hypotension occurs, the patient should be placed in the supine position and if necessary, should receive an IV infusion of 0.9% sodium chloride 9 mg/mL solution. A transient hypotensive response is not a contraindication to further doses, which can be given usually without difficulty once the blood pressure has increased after volume expansion.
In some patients with congestive heart failure who have normal or low blood pressure, additional lowering of systemic blood pressure may occur with Bioprexum.
This effect is anticipated and is usually not a reason to discontinue treatment. If hypotension becomes symptomatic, a reduction of dose or discontinuation of Bioprexum may be necessary.
Aortic and Mitral Valve Stenosis/Hypertrophic Cardiomyopathy: As with other ACE inhibitors, Bioprexum should be given with caution to patients with mitral valve stenosis and obstruction in the outflow of the left ventricle eg, aortic stenosis or hypertrophic cardiomyopathy.
Renal Impairment: In cases of renal impairment (CrCl <60 mL/min), the initial perindopril dosage should be adjusted according to the patient's CrCl (see Dosage & Administration) and then as a function of the patient's response to treatment. Routine monitoring of potassium and creatinine are part of normal medical practice for these patients (see Adverse Reactions).
In patients with symptomatic heart failure, hypotension following the initiation of therapy with ACE inhibitors may lead to some further impairment in renal function. Acute renal failure, usually reversible, has been reported in this situation.
In some patients with bilateral renal artery stenosis or stenosis of the artery to a solitary kidney, who have been treated with ACE inhibitors, increases in blood urea and serum creatinine, usually reversible upon discontinuation of therapy, have been seen. This is especially likely in patients with renal insufficiency. If renovascular hypertension is also present, there is an increased risk of severe hypotension and renal insufficiency. In these patients, treatment should be started under close medical supervision with low doses and careful dose titration. Since treatment with diuretics may be a contributory factor to the above, they should be discontinued and renal function should be monitored during the 1st weeks of Bioprexum therapy.
Some hypertensive patients with no apparent preexisting renal vascular disease have developed increases in blood urea and serum creatinine, usually minor and transient, especially when Bioprexum has been given concomitantly with a diuretic. This is more likely to occur in patients with preexisting renal impairment. Dosage reduction and/or discontinuation of the diuretic and/or Bioprexum may be required.
Haemodialysis Patients: Anaphylactoid reactions have been reported in patients dialysed with high-flux membranes and treated concomitantly with an ACE inhibitor. In these patients, consideration should be given to using a different type of dialysis membrane or different class of antihypertensive agent.
Kidney Transplantation: There is no experience regarding the administration of Bioprexum in patients with a recent kidney transplantation.
Hypersensitivity/Angioedema: Angioedema of the face, extremities, lips, mucous membranes, tongue, glottis and/or larynx has been reported rarely in patients treated with ACE inhibitors, including Bioprexum (see Adverse Reactions). This may occur at any time during therapy.
In such cases, Bioprexum should promptly be discontinued and appropriate monitoring should be initiated and continued until complete resolution of symptoms has occurred. In those instances where swelling was confined to the face and lips, the condition generally resolved without treatment, although antihistamines have been useful in relieving symptoms.
Angioedema associated with laryngeal oedema may be fatal. Where there is involvement of the tongue, glottis or larynx, likely to cause airway obstruction, emergency therapy should be administered promptly. This may include the administration of adrenaline and/or the maintenance of a patent airway. The patient should be under close medical supervision until complete and sustained resolution of symptoms has occurred.
Patients with a history of angioedema unrelated to ACE inhibitor therapy may be at increased risk of angioedema while receiving an ACE inhibitor (see Contraindications).
Intestinal angioedema has been reported rarely 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 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 Low-Density Lipoproteins (LDL) Apheresis: Rarely, patients receiving ACE inhibitors during LDL apheresis with dextran sulphate have experienced life-threatening anaphylactoid reactions. These reactions were avoided by temporarily withholding ACE inhibitor therapy prior to each apheresis.
Anaphylactic Reactions During Desensitisation: Patients receiving ACE inhibitors during desensitisation treatment (eg, hymenoptera venom) have experienced anaphylactoid reactions. In the same patients, these reactions have been avoided when the ACE inhibitors were temporarily withheld, but they reappeared upon inadvertent rechallenge.
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 (see Adverse Reactions).
Neutropenia/Agranulocytosis/Thrombocytopenia/Anaemia: Neutropenia/agranulocytosis, thrombocytopenia and anaemia have been reported in patients receiving ACE inhibitors. In patients with normal renal function and no other complicating factors, neutropenia occurs rarely. Perindopril should be used with extreme caution in patients with collagen vascular disease, immunosuppressant therapy, treatment with allopurinol or procainamide, or a combination of these complicating factors, especially if there is preexisting impaired renal function. Some of these patients developed serious infections, which in a few instances did not respond to intensive antibiotic therapy. If perindopril is used in such patients, periodic monitoring of white blood cell counts is advised and patients should be instructed to report any sign of infection (eg, sore throat, fever).
Race: ACE inhibitors cause a higher rate of angioedema in Blacks than in non-Blacks. As with other ACE inhibitors, perindopril may be less effective in lowering blood pressure in Blacks than in non-Blacks, possibly because of a higher prevalence of low-renin states in the black hypertensive population.
Cough: Cough has been reported with the use of ACE inhibitors. Characteristically, the cough is non-productive, persistent and resolves after discontinuation of therapy. ACE inhibitor-induced cough should be considered as part of the differential diagnosis of cough.
Surgery/Anaesthesia: In patients undergoing major surgery or during anaesthesia with agents that produce hypotension, Bioprexum may block angiotensin II formation secondary to compensatory renin release. The treatment should be discontinued 1 day prior to the surgery. If hypotension occurs and is considered to be due to this mechanism, it can be corrected by volume expansion.
Hyperkalaemia: Elevations in serum potassium have been observed in some patients treated with ACE inhibitors, including perindopril. Risk factors for the development of hyperkalaemia include those with renal insufficiency, worsening of renal function, >70 years, diabetes mellitus, intercurrent events, in particular dehydration, acute cardiac decompensation, metabolic acidosis and concomitant use of potassium-sparing diuretics (eg, spironolactone, eplerenone, triamterene or amiloride), potassium supplements or potassium-containing salt substitutes; or those patients taking other drugs associated with increases in serum potassium (eg, heparin). The use of potassium supplements, potassium-sparing diuretics or potassium-containing salt substitutes particularly in patients with impaired renal function may lead to a significant increase in serum potassium. Hyperkalaemia can cause serious, sometimes fatal arrhythmias. If concomitant use of the previously-mentioned agents is deemed appropriate, they should be used with caution and with frequent monitoring of serum potassium (see Interactions).
Diabetic Patients: In diabetic patients treated with oral antidiabetic agents or insulin, glycaemic control should be closely monitored during the 1st month of treatment with an ACE inhibitor (see Interactions).
Lithium: The combination of lithium and perindopril is generally not recommended (see Interactions).
Potassium-Sparing Diuretics, Potassium Supplements or Potassium-Containing Salt Substitutes: The combination of perindopril and potassium-sparing diuretics, potassium supplements or potassium-containing salt substitutes is generally not recommended (see Interactions).
Excipients: Due to the presence of lactose, patients with rare hereditary problems of galactose intolerance, glucose-galactose malabsorption, or the Lapp-lactase deficiency should not take this medicinal product.
Effects on the Ability to Drive or Operate Machinery: Bioprexum has no direct influence on the ability to drive and use machines but individual reactions related to low blood pressure may occur in some patients, particularly at the start of treatment or in combination with another antihypertensive medication.
As a result, the ability to drive or operate machinery may be impaired.
Use in pregnancy & lactation: The use of ACE inhibitors is not recommended during the 1st trimester of pregnancy. The use of ACE inhibitors is contraindicated during the 2nd and 3rd trimesters of pregnancy.
Epidemiological evidence regarding the risk of teratogenicity following exposure to ACE inhibitors during the 1st trimester of pregnancy has not been conclusive; however, a small increase in risk cannot be excluded. Unless continued ACE inhibitor therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with ACE inhibitors should be stopped immediately and, if appropriate, alternative therapy should be started.
Exposure to ACE inhibitor therapy during the 2nd and 3rd trimesters is known to induce human foetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia) (see Toxicology under Actions). Should exposure to ACE inhibitor have occurred from the 2nd trimester of pregnancy, ultrasound check of renal function and skull is recommended. Infants whose mothers have taken ACE inhibitors should be closely observed for hypotension (see Contraindications).
Because no information is available regarding the use of Bioprexum during breastfeeding, Bioprexum is not recommended and alternative treatments with better established safety profiles during breastfeeding are preferable, especially while nursing a newborn or pre-term infant.
Use in children and adolescents <18 years: Efficacy and safety of use in children and adolescents have not been established. Therefore, use in children and adolescents is not recommended.

The use of ACE inhibitors is not recommended during the 1st trimester of pregnancy. The use of ACE inhibitors is contraindicated during the 2nd and 3rd trimesters of pregnancy.
Epidemiological evidence regarding the risk of teratogenicity following exposure to ACE inhibitors during the 1st trimester of pregnancy has not been conclusive; however, a small increase in risk cannot be excluded. Unless continued ACE inhibitor therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with ACE inhibitors should be stopped immediately and, if appropriate, alternative therapy should be started.
Exposure to ACE inhibitor therapy during the 2nd and 3rd trimesters is known to induce human foetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia) (see Toxicology under Actions). Should exposure to ACE inhibitor have occurred from the 2nd trimester of pregnancy, ultrasound check of renal function and skull is recommended. Infants whose mothers have taken ACE inhibitors should be closely observed for hypotension (see Contraindications).
Because no information is available regarding the use of Bioprexum during breastfeeding, Bioprexum is not recommended and alternative treatments with better established safety profiles during breastfeeding are preferable, especially while nursing a newborn or pre-term infant.

The following adverse reactions have been observed during treatment with perindopril and ranked under the following frequencies: Very common (1/10); common (1/100, <1/10); uncommon (1/1000, <1/100); rare (1/10,000, <1/1000); very rare (<1/10,000); not known (cannot be estimated from the available data).
Blood and Lymphatic System Disorders: Decreases in haemoglobin and haematocrit, thrombocytopenia, leucopenia/neutropenia and cases of agranulocytosis or pancytopenia, have been reported very rarely. In patients with a congenital deficiency of G6PDH, very rare cases of haemolytic anaemia have been reported (see Precautions).
Metabolism and Nutrition Disorders: Not Known: Hypoglycaemia (see Precautions and Interactions).
Psychiatric Disorders: Uncommon: Mood or sleep disturbances.
Nervous System Disorders: Common: Headache, dizziness, vertigo, paraesthesia. Very Rare: Confusion.
Eye Disorders: Common: Visual disturbance.
Ear and Labyrinth Disorders: Common: Tinnitus.
Cardiac Disorders: Very Rare: Arrhythmia, angina pectoris and myocardial infarction, possibly secondary to excessive hypotension in high-risk patients (see Precautions).
Vascular Disorders: Common: Hypotension and effects related to hypotension. Very Rare: Stroke, possibly secondary to excessive hypotension in high-risk patients (see Precautions). Not Known: Vasculitis.
Respiratory, Thoracic and Mediastinal Disorders: Common: Cough, dyspnoea. Uncommon: Bronchospasm. Very Rare: Eosinophilic pneumonia, rhinitis.
Gastrointestinal Disorders: Common: Nausea, vomiting, abdominal pain, dysgeusia, dyspepsia, diarrhoea, constipation. Uncommon: Dry mouth. Very Rare: Pancreatitis.
Hepatobiliary Disorders: Very Rare: Hepatitis either cytolytic or cholestatic (see Precautions).
Skin and Subcutaneous Tissue Disorders: Common: Rash, pruritus. Uncommon: Angioedema of face, extremities, lips, mucous membranes, tongue, glottis and/or larynx, urticaria (see Precautions). Very Rare: Erythema multiforme.
Musculoskeletal and Connective Tissue Disorders: Common: Muscle cramps.
Renal and Urinary Disorders: Uncommon: Renal insufficiency. Very Rare: Acute renal failure.
Reproductive System and Breast Disorders: Uncommon: Impotence.
General Disorders and Administration Site Conditions: Common: Asthenia. Uncommon: Sweating.
Investigations: Increases in blood urea and plasma creatinine, hyperkalaemia reversible on discontinuation may occur, especially in the presence of renal insufficiency, severe heart failure and renovascular hypertension. Elevation of liver enzymes and serum bilirubin have been reported rarely.
Clinical Trials: During the randomised period of the EUROPA study, only serious adverse events were collected. Few patients experienced serious adverse events: 16 (0.3%) of the 6122 perindopril patients and 12 (0.2%) of the 6107 placebo patients. In the perindopril-treated patients, hypotension was observed in 6 patients, angioedema in 3 patients and sudden cardiac arrest in 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.

Diuretics: Patients on diuretics and especially those who are volume- and/or salt-depleted, may experience excessive reduction in blood pressure after initiation of therapy with an ACE inhibitor. The possibility of hypotensive effects can be reduced by discontinuation of the diuretic, by increasing volume or salt intake prior to initiating therapy with low and progressive doses of perindopril.
Potassium-Sparing Diuretics, Potassium Supplements or Potassium-Containing Salt Substitutes: Although serum potassium usually remains within normal limits, hyperkalaemia may occur in some patients treated with perindopril. Potassium-sparing diuretics (eg, spironolactone, triamterene or amiloride), potassium supplements, or potassium-containing salt substitutes may lead to significant increases in serum potassium. Therefore, the combination of perindopril with the previously-mentioned drugs is not recommended (see Precautions). If concomitant use is indicated because of demonstrated hypokalaemia, they should be used with caution and with frequent monitoring of serum potassium.
Lithium: Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with ACE inhibitors. Concomitant use of thiazide diuretics may increase the risk of lithium toxicity and enhance the already increased risk of lithium toxicity with ACE inhibitors. Use of perindopril with lithium is not recommended, but if the combination proves necessary, careful monitoring of serum lithium levels should be performed (see Precautions).
Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) Including Aspirin ≥3 g/day: When ACE inhibitors are administered simultaneously with NSAIDs (ie, acetylsalicylic acid at anti-inflammatory dosage regimens, COX-2 inhibitors and nonselective NSAIDs), attenuation of the antihypertensive effect may occur. Concomitant use of ACE inhibitors and NSAIDs may lead to an increased risk of worsening of renal function, including possible acute renal failure and an increase in serum potassium, especially in patients with poor preexisting renal function. The combination should be administered with caution, especially in the elderly. Patients should be adequately hydrated and consideration should be given to monitoring renal function after initiation of concomitant therapy and periodically thereafter.
Antihypertensive Agents and Vasodilators: Concomitant use of these agents may increase the hypotensive effects of perindopril. Concomitant use with nitroglycerin and other nitrates, or other vasodilators, may further reduce blood pressure.
Antidiabetic Agents: Epidemiological studies have suggested that concomitant administration of ACE inhibitors and antidiabetic medicines (insulins, oral hypoglycaemic agents) may cause an increased blood-glucose lowering effect with risk of hypoglycaemia. This phenomenon appeared to be more likely to occur during the 1st weeks of combined treatment and in patients with renal impairment.
Tricyclic Antidepressants/Antipsychotics/Anaesthetics: Concomitant use of certain anaesthetic medicinal products, tricyclic antidepressants and antipsychotics with ACE inhibitors may result in further reduction of blood pressure (see Precautions).
Sympathomimetics: Sympathomimetics may reduce the antihypertensive effects of ACE inhibitors.
Acetylsalicylic Acid, Thrombolytics, β-Blockers, Nitrates: Perindopril may be used concomitantly with acetylsalicylic acid (when used as a thrombolytic), thrombolytics, β-blockers and/or nitrates.
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 perindopril.
Incompatibilities: Not applicable.

Keep the container tightly closed. Protect from moisture.
Shelf-Life: 3 years.

ACE Inhibitors/Direct Renin Inhibitors

C09AA04 - perindopril ; Belongs to the class of ACE inhibitors. Used in the treatment of cardiovascular disease.

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