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Perindopril and Indapamide: Renal Impairment: In cases of severe renal impairment (CrCl <30 mL/min), treatment is contraindicated.
In certain hypertensive patients without preexisting apparent renal lesions and for whom renal blood tests show functional renal insufficiency, treatment should be stopped and possibly restarted either at a low dose or with 1 constituent only.
In these patients, usual medical follow-up will include frequent monitoring of potassium and creatinine, after 2 weeks of treatment and then every 2 months during therapeutic stability period. Renal failure has been reported mainly in patients with severe heart failure or underlying renal failure including renal artery stenosis.
Bioprexum Plus is usually not recommended in case of bilateral renal artery stenosis or a single functioning kidney.
Hypotension and Water and Electrolyte Depletion: There is a risk of sudden hypotension in the presence of preexisting sodium depletion (particularly in individuals with renal artery stenosis). Therefore systematic testing should be carried out for clinical signs of water and electrolyte depletion, which may occur with an intercurrent episode of diarrhea or vomiting. Regular monitoring of plasma electrolytes should be carried out in such patients.
Marked hypotension may require the implementation of an IV infusion of isotonic saline.
Transient hypotension is not a contraindication to continuation of treatment. After re-establishment of a satisfactory blood volume and blood pressure, treatment can be started again either at a reduced dose or with only 1 of the constituents.
Potassium Levels: The combination of perindopril and indapamide does not prevent the onset of hypokalaemia particularly in diabetic patients or in patients with renal failure. As with any antihypertensive agent containing a diuretic, regular monitoring of plasma potassium levels should be carried out.
Bioprexum Plus should not be administered to patients with rare hereditary problems of galactose intolerance, Lapp-lactase deficiency or glucose-galactose malabsorption.
Perindopril: Cough: A dry cough has been reported with the use of ACE inhibitors. It is characterized by its persistence and disappearance when treatment is withdrawn. An iatrogenic etiology should be considered in the event of this symptom. If the prescription of an ACE inhibitor is still preferred, continuation of treatment may be considered.
Patients with Known Atherosclerosis: The risk of hypotension exists in all patients but particular care should be taken in patients with ischaemic heart disease or cerebral circulatory insufficiency, with treatment being started at a low dose.
Renovascular Hypertension: The treatment for renovascular hypertension is revascularization. Nonetheless, ACE inhibitors can be beneficial in patients presenting with renovascular hypertension who are awaiting corrective surgery or when such a surgery is not possible.
If Bioprexum Plus is prescribed to patients with known or suspected renal artery stenosis, treatment should be started in a hospital setting at a low dose and renal function and potassium levels should be monitored, since some patients have developed a functional renal insufficiency which was reversed when treatment was stopped.
Other Populations: In patients with severe cardiac insufficiency (grade IV) or in patients with insulin-dependent diabetes mellitus (spontaneous tendency to increased levels of potassium), treatment should be started under medical supervision with a reduced initial dose. Treatment with β-blockers in hypertensive patients with coronary insufficiency should not be stopped, the ACE inhibitor should be added to the β-blocker.
Diabetic Patients: The glycaemia levels should be closely monitored in diabetic patients previously treated with oral antidiabetic drugs or insulin, namely during the 1st month of treatment with an ACE inhibitor.
Ethnic Differences: As with other ACE inhibitors, perindopril is apparently less effective in lowering blood pressure in Black people than in non-Blacks, possibly because of a higher prevalence of low-renin states in the Black hypertensive population.
Surgery/Anesthesia: Angiotensin-converting enzyme inhibitors can cause hypotension in cases of anaesthesia, especially when the anesthetic administered is an agent with hypotensive potential.
It is therefore recommended that treatment with long-acting ACE inhibitors eg, perindopril should be discontinued where possible 1 day before surgery.
Aortic or Mitral Valve Stenosis/Hypertrophic Cardiomyopathy: Angiotensin-converting enzymes inhibitors should be used with caution in patients with an obstruction in the outflow tract of the left ventricle.
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 Reaction).
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, age (>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).
Use in children and adolescents: The efficacy and tolerability of perindopril in children and adolescents, alone or in combination, have not been established.
Risk of Arterial Hypotension and/or Renal Insufficiency (In Cases of Cardiac Insufficiency, Water and Electrolyte Depletion, etc.): Marked stimulation of the renin-angiotensin-aldosterone system has been observed particularly during marked water and electrolyte depletions (strict sodium-free diet or prolonged diuretic treatment), in patients whose blood pressure was initially low, in cases of renal artery stenosis, congestive heart failure or cirrhosis with edema and ascites.
The blocking of this system with an ACE inhibitor may therefore cause, particularly at the time of the 1st administration and during the 1st 2 weeks of treatment, a sudden drop in blood pressure and/or an increase in plasma levels of creatinine, showing a functional renal insufficiency. Occasionally this can be acute in onset, although rare and with a variable time to onset. In such cases, the treatment should then be initiated at a lower dose and increased progressively.
Use in the elderly: Renal function and potassium levels should be tested before the start of treatment. The initial dose is subsequently adjusted according to blood pressure response, especially in cases of water and electrolyte depletion, in order to avoid sudden onset of hypotension.
Indapamide: Water and Electrolyte Balance: Sodium Levels: These should be tested before treatment is started, then at regular intervals. All diuretic treatment can cause a reduction in sodium levels, which may have serious consequences. Reduction in sodium levels can be initially asymptomatic and regular testing is therefore essential. Testing should be more frequent in elderly and cirrhotic patients (see Overdosage and Adverse Reaction).
Potassium Levels: Potassium depletion with hypokalemia is a major risk with thiazide diuretics and thiazide-related diuretics. The risk of onset of lowered potassium levels (<3.4 mmol/L) should be prevented in some high risk populations eg, elderly and/or malnourished subjects, whether or not they are taking multiple medications, cirrhotic patients with edema and ascites, coronary patients and patients with heart failure.
In such cases, hypokalemia increases the cardiac toxicity of cardiac glycosides and the risk of rhythm disorders.
Subjects presenting with a long QT interval are also at risk, whether the origin is congenital or iatrogenic. Hypokalemia, as with bradycardia, acts as a factor which favors the onset of severe rhythm disorders, in particular Torsades de pointes, which may be fatal.
In all cases, more frequent testing of potassium levels is necessary. The 1st measurement of plasma potassium levels should be carried out during the 1st week following the start of treatment.
If low potassium levels are detected, correction is required.
Calcium Levels: Thiazide diuretics and thiazide-related diuretics may reduce urinary excretion of calcium and cause a mild and transient increase in plasma calcium levels. Markedly raised levels of calcium may be related to undiagnosed hyperparathyroidism. In such cases, the treatment should be stopped before investigating the parathyroid function.
Blood Glucose: Monitoring of blood glucose is important in diabetic patients, particularly when potassium levels are low.
Uric Acid: Tendency to gout attacks may be increased in hyperuricaemic patients.
Renal Function and Diuretics: Thiazide diuretics and thiazide-related diuretics are only fully effective when renal function is normal or only slightly impaired (creatinine levels lower than approximately 25 mg/L ie, 220 micromol/L for an adult).
In the elderly, the value of plasma creatinine levels should be adjusted to take account of the age, weight and sex of the patient, according to the Cockroft formula:
CrCl = (140 - age) x body weight/0.814 x plasma creatinine level.
With age expressed in years, body weight in kg and plasma creatinine level in micromol/L. This formula is suitable for an elderly male and should be adapted for women by multiplying the result by 0.85.
Hypovolemia, resulting from the loss of water and sodium caused by the diuretic at the start of treatment, causes a reduction in glomerular filtration. It may result in an increase in blood urea and creatinine levels. This transitory functional renal insufficiency is of no adverse consequence in patients with normal renal function but may however worsen a preexisting renal impairment.
Athletes: Athletes should note that Bioprexum Plus contains an active substance which may cause a positive reaction in doping tests.
Effects on the Ability to Drive or Operate Machinery: Neither perindopril, indapamide nor Bioprexum Plus affect alertness 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: Perindopril: 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 (see Contraindications).
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 fetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia). (See Toxicology under Actions.)
Should exposure to ACE inhibitors 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).
Indapamide: Prolonged exposure to thiazide during the 3rd trimester of pregnancy can reduce maternal plasma volume as well as uteroplacental blood flow, which may cause a fetoplacental ischemia and growth retardation. Moreover, rare cases of hypoglycemia and thrombocytopenia in neonates have been reported following exposure near term.
Bioprexum Plus is contraindicated during lactation.
Use of perindopril is not recommended during breastfeeding.
Indapamide is excreted in human milk. Indapamide is closely related to thiazide diuretics which have been associated, during breastfeeding, with decrease or even suppression of milk lactation. Hypersensitivity to suphonamide-derived drugs, hypokalaemia and nuclear icterus might occur.
As with both drugs, serious adverse reactions might occur in nursing infants, a decision should be made whether to discontinue nursing or to discontinue therapy taking account the importance of this to the mother.
