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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.
