Bi-Preterax

Bi-Preterax

perindopril + indapamide

Manufacturer:

Servier

Distributor:

Zuellig
Full Prescribing Info
Contents
Perindopril, indapamide.
Description
Each tablet contains 3.338 mg perindopril corresponding to 4 mg perindopril tert-butylamine and 1.25 mg indapamide.
Excipient with known effect: 61.55 mg lactose monohydrate.
Action
Pharmacology: Pharmacodynamics: Bi-Preterax is a combination of perindopril tert-butylamine salt, an angiotensin converting enzyme inhibitor, and indapamide, a chlorosulphamoyl diuretic. Its pharmacological properties are derived from those of each of the components taken separately, in addition to those due to the additive synergic action of the two products when combined.
Mechanism of action: Perindopril tert-butylamine + Indapamide (Bi-Preterax) produces an additive synergy of the antihypertensive effects of the two components.
Perindopril is an inhibitor of the angiotensin converting enzyme (ACE inhibitor) which converts angiotensin I to angiotensin II, a vasoconstricting substance; in addition, the enzyme stimulates the secretion of aldosterone by the adrenal cortex and stimulates the degradation of bradykinin, a vasodilatory substance, into inactive heptapeptides.
This results in: a reduction in aldosterone secretion; an increase in plasma renin activity, since aldosterone no longer exercises negative feedback; a reduction in total peripheral resistance with a preferential action on the vascular bed in muscle and the kidney, with no accompanying salt and water retention or reflex tachycardia, with chronic treatment.
The antihypertensive action of perindopril also occurs in patients with low or normal renin concentrations.
Perindopril acts through its active metabolite, perindoprilat. The other metabolites are inactive.
Perindopril reduces the work of the heart: by a vasodilatory effect on veins, probably caused by changes in the metabolism of prostaglandins: reduction in pre-load; by reduction of the total peripheral resistance: reduction in afterload.
Studies carried out on patients with cardiac insufficiency have shown: a reduction in left and right ventricular filling pressures; a reduction in total peripheral vascular resistance; an increase in cardiac output and an improvement in the cardiac index; an increase in regional blood flow in muscle.
Exercise test results also showed improvement.
Indapamide is a sulphonamide derivative with an indole ring, pharmacologically related to the thiazide group of diuretics. Indapamide inhibits the reabsorption of sodium in the cortical dilution segment. It increases the urinary excretion of sodium and chlorides and, to a lesser extent, the excretion of potassium and magnesium, thereby increasing urine output and having an antihypertensive action.
Pharmacokinetics: The co-administration of perindopril and indapamide does not change their pharmacokinetic properties by comparison to separate administration.
Linked to perindopril: After oral administration, the absorption of perindopril is rapid and the peak concentration is achieved within 1 hour. The plasma half-life of perindopril is equal to 1 hour. As ingestion of food decreases conversion to perindoprilat, hence bioavailability, perindopril tert-butylamine salt should be administered orally in a single daily dose in the morning before a meal.
The volume of distribution is approximately 0.2 l/kg for unbound perindoprilat. Protein binding of perindoprilat to plasma proteins is 20%, principally to angiotensin converting enzyme, but is concentration-dependent.
Perindopril is a prodrug. Twenty seven percent of the administered perindopril dose reaches the bloodstream as the active metabolite perindoprilat. In addition to active perindoprilat, perindopril yields five metabolites, all inactive. The peak plasma concentration of perindoprilat is achieved within 3 to 4 hours.
Perindoprilat is eliminated in the urine and the terminal half-life of the unbound fraction is approximately 17 hours, resulting in steady-state within 4 days. It has been demonstrated a linear relationship between the dose of perindopril and its plasma exposure.
Special populations: Elderly: Elimination of perindoprilat is decreased in the elderly, and also in patients with heart or renal failure.
Renal impairment: Dosage adjustment in renal insufficiency is desirable depending on the degree of impairment (creatinine clearance).
In case of dialysis: Dialysis clearance of perindoprilat is equal to 70 ml/min.
Cirrhosis: 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.
Linked to indapamide: Indapamide is rapidly and completely absorbed from the digestive tract.
The peak plasma level is reached in humans approximately one hour after oral administration of the product.
Plasma protein binding is 79 %.
The elimination half-life is between 14 and 24 hours (average 18 hours). Repeated administration does not produce accumulation. Elimination is mainly in the urine (70 % of the dose) and feces (22 %) in the form of inactive metabolites.
Special populations: Renal impairment: The pharmacokinetics are unchanged in patients with renal insufficiency.
Indications/Uses
This medicine is indicated for the treatment of essential hypertension. This fixed dose combination is not indicated for initial therapy.
Dosage/Direction for Use
One tablet per day as a single dose, preferably to be taken in the morning, and before a meal.
When possible, individual dose titration with the components is recommended. Perindopril tert-butylamine + Indapamide (Bi-Preterax) 4mg/1.25mg tablet should be used when blood pressure is not adequately controlled on Perindopril tert-butylamine + Indapamide (Preterax) 2mg/625mcg tablet (where available). When clinically appropriate, direct change from monotherapy to Perindopril tert-butylamine + Indapamide (Bi-Preterax) may be considered.
Elderly: Treatment should be initiated after considering blood pressure response and renal function.
Renal impairment: In severe renal impairment (creatinine clearance below 30 ml/min), treatment is contraindicated.
In patients with moderate renal impairment (creatinine clearance 30-60 ml/min), it is recommended to start treatment with the adequate dosage of the free combination.
In patients with creatinine clearance greater than or equal to 60 ml/min, no dose modification is required. Usual medical follow-up will include frequent monitoring of creatinine and potassium.
Hepatic impairment: In severe hepatic impairment, treatment is contraindicated.
In patients with moderate hepatic impairment, no dose modification is required.
Pediatric population: The safety and efficacy of perindopril tert-butylamine/indapamide in the pediatric population have not yet been established.
No data are available. Perindopril tert-butylamine + Indapamide (Bi-Preterax) should not be used in children and adolescents.
Missed Dose: It is important to take the medicine every day as regular treatment is more effective. However, if a dose of Perindopril tert-butylamine + Indapamide (Bi-Preterax) is forgotten, take the next dose at the usual time. Do not take a double dose to make up for a forgotten dose.
Stopping Treatment: As the treatment for high blood pressure is usually life-long, patient should discuss with the doctor before stopping this medicinal product.
Overdosage
Symptoms: The most likely adverse reaction in cases of overdose is hypotension, sometimes associated with nausea, vomiting, cramps, dizziness, sleepiness, mental confusion, oliguria which may progress to anuria (due to hypovolemia). Salt and water disturbances (low sodium levels, low potassium levels) may occur.
Management: The first measures to be taken consist of rapidly eliminating the product(s) ingested by gastric lavage and/or administration of activated charcoal, then restoring fluid and electrolyte balance in a specialized center until they return to normal.
If marked hypotension occurs, this can be treated by placing the patient in a supine position with the head lowered. If necessary an intravenous infusion of isotonic saline may be given, or any other method of volemic expansion may be used.
Perindoprilat, the active form of perindopril, can be dialyzed.
Contraindications
Linked to perindopril: Hypersensitivity to the active substance or to any other ACE inhibitor; History of angioedema (Quincke's edema) associated with previous ACE inhibitor therapy; Hereditary/idiopathic angioedema; Second and third trimesters of pregnancy; Concomitant use with aliskiren-containing products in patients with diabetes mellitus or renal impairment (GFR < 60 ml/min/1.73 m2); Concomitant use with sacubitril/valsartan; Extracorporeal treatments leading to contact of blood with negatively charged surfaces; significant bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney.
Linked to indapamide: Hypersensitivity to the active substance or to any other sulphonamides; Severe renal impairment (creatinine clearance below 30 ml/min); Hepatic encephalopathy; Severe hepatic impairment; Hypokalemia; As a general rule, this medicine is inadvisable in combination with non antiarrhythmic agents causing torsades de pointes; Lactation.
Linked to Perindopril tert-butylamine + Indapamide (Bi-Preterax): Hypersensitivity to any of the excipients; Due to the lack of sufficient therapeutic experience, should not be used in: Dialysis patients; Patients with untreated decompensated heart failure.
Special Precautions
Special warnings: Common to perindopril and indapamide: Lithium: The combination of lithium and the combination of perindopril and indapamide is usually not recommended.
Linked to perindopril: Dual blockade of the renin-angiotensin-aldosterone system (RAAS): There is evidence that the concomitant use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren increases the risk of hypotension, hyperkalemia and decreased renal function (including acute renal failure). Dual blockade of RAAS through the combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is therefore not recommended.
If dual blockade therapy is considered absolutely necessary, this should only occur under specialist supervision and subject to frequent close monitoring of renal function, electrolytes and blood pressure.
ACE-inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy.
Potassium-sparing drugs, potassium supplements or potassium-containing salt substitutes: The combination of perindopril and potassium-sparing drugs, potassium supplements or potassium-containing salt substitutes is usually not recommended.
Neutropenia/agranulocytosis/thrombocytopenia/anemia: Neutropenia/agranulocytosis, thrombocytopenia and anemia 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 pre-existing 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, periodical monitoring of white blood cell counts is advised and patients should be instructed to report any sign of infection (e.g. sore throat, fever).
Hypersensitivity/angioedema: Angioedema of the face, extremities, lips, tongue, glottis and/or larynx has been reported rarely in patients treated with angiotensin converting enzyme inhibitors, including perindopril. This may occur at any time during treatment. In such cases perindopril should be discontinued promptly and appropriate monitoring should be instituted to ensure complete resolution of symptoms prior to dismissing the patient. In those instances where swelling has been confined to the face and lips the condition generally resolved without treatment, although antihistamines have been useful in relieving symptoms.
Angioedema associated with laryngeal edema may be fatal. Where there is involvement of the tongue, glottis or larynx, likely to cause airway obstruction, appropriate therapy, which may include subcutaneous epinephrine solution 1:1000 (0.3 ml to 0.5 ml) and/or measures to ensure a patent airway, should be administered promptly.
Black patients receiving ACE inhibitors have been reported to have a higher incidence of angioedema compared to non-blacks.
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 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.
Concomitant use of mTOR inhibitors (e.g. sirolimus, everolimus, temsirolimus): Patients taking concomitant mTOR inhibitors (e.g. sirolimus, everolimus, temsirolimus) therapy may be at increased risk for angioedema (e.g. swelling of the airways or tongue, with or without respiratory impairment).
Anaphylactoid reactions during desensitization: There have been isolated reports of patients experiencing sustained, life-threatening anaphylactoid reactions while receiving ACE inhibitors during desensitization treatment with hymenoptera (bees, wasps) venom. ACE inhibitors should be used with caution in allergic patients treated with desensitization, and avoided in those undergoing venom immunotherapy. However these reactions could be prevented by temporary withdrawal of ACE inhibitor for at least 24 hours before treatment in patients who require both ACE inhibitors and desensitization.
Anaphylactoid reactions during LDL apheresis: Rarely, patients receiving ACE inhibitors during low density lipoprotein (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.
Hemodialysis patients: Anaphylactoid reactions have been reported in patients dialyzed with high-flux membranes (e.g., AN 69) and treated concomitantly with an ACE inhibitor. In these patients consideration should be given to using a different type of dialysis membrane or a different class of antihypertensive agent.
Use in Pregnancy: ACE inhibitors should not be initiated during pregnancy. Unless continued ACE inhibitor therapy is considered essential, patients planning pregnancy should be changed to alternative anti-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, if appropriate, alternative therapy should be started.
Linked to indapamide: Hepatic encephalopathy: When liver function is impaired, thiazide diuretics and thiazide-related diuretics may cause hepatic encephalopathy. Administration of the diuretic should be stopped immediately if this occurs.
Photosensitivity: Cases of photosensitivity reactions have been reported with thiazides and related thiazide diuretics. If photosensitivity reaction occurs during treatment, it is recommended to stop the treatment. If a re-administration of the diuretic is deemed necessary, it is recommended to protect exposed areas to the sun or to artificial UVA.
Precautions for use: Common to perindopril and indapamide: Renal impairment: In cases of severe renal impairment (creatinine clearance < 30 ml/min), treatment is contraindicated.
In certain hypertensive patients without pre-existing 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 one constituent only.
In these patients, usual medical follow-up will include frequent monitoring of potassium and creatinine, after two weeks of treatment and then every two 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.
The drug 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 pre-existing sodium depletion (in particular 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 intravenous 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 one of the constituents.
Potassium levels: The combination of perindopril and indapamide does not prevent the onset of hypokalemia 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.
Excipients: Perindopril tert-butylamine + Indapamide (Bi-Preterax) should not be administered to patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption.
Linked to perindopril: Cough: A dry cough has been reported with the use of angiotensin converting enzyme inhibitors. It is characterized by its persistence and by its disappearance when treatment is withdrawn. An iatrogenic etiology should be considered in the event of this symptom. If the prescription of an angiotensin converting enzyme inhibitor is still preferred, continuation of treatment may be considered.
Pediatric population: 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 angiotensin converting enzyme inhibitor may therefore cause, particularly at the time of the first administration and during the first two 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.
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.
Atherosclerosis: The risk of hypotension exists in all patients but particular care should be taken in patients with ischemic heart disease or cerebral circulatory insufficiency, with treatment being started at a low dose.
Renovascular hypertension: The treatment for renovascular hypertension is revascularization. Nonetheless, angiotensin converting enzyme inhibitors can be beneficial in patients presenting with renovascular hypertension who are awaiting corrective surgery or when such a surgery is not possible.
If Perindopril tert-butylamine + Indapamide (Bi-Preterax) 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.
Cardiac failure/severe cardiac insufficiency: In patients with severe cardiac insufficiency (grade IV), treatment should be started under medical supervision with a reduced initial dose. Treatment with beta-blockers in hypertensive patients with coronary insufficiency should not be stopped: the ACE inhibitor should be added to the beta-blocker.
Diabetic patients: 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.
The glycemia levels should be closely monitored in diabetic patients previously treated with oral antidiabetic drugs or insulin, namely during the first month of treatment with an ACE inhibitor.
Ethnic differences: As with other angiotensin converting enzyme 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 anesthesia, especially when the anesthetic administered is an agent with hypotensive potential.
It is therefore recommended that treatment with long-acting angiotensin converting enzyme inhibitors such as perindopril should be discontinued where possible one day before surgery.
Aortic or mitral valve stenosis/hypertrophic cardiomyopathy: ACE inhibitors should be used with caution in patient 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.
Hyperkalemia: Elevations in serum potassium have been observed in some patients treated with ACE inhibitors, including perindopril. Risk factors for the development of hyperkalemia 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 (e.g., spironolactone, eplerenone, triamterene, amiloride), potassium supplements or potassium-containing salt substitutes; or those patients taking other drugs associated with increases in serum potassium (e.g. heparins, other ACE inhibitors, angiotensin-II receptor antagonists, acetylsalicylic acid ≥ 3 g/day, COX-2 inhibitors and non-selective NSAIDs, immunosuppressant agents such as ciclosporin or tacrolimus, trimethoprim). 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. Hyperkalemia can cause serious, sometimes fatal arrhythmias. If concomitant use of the above-mentioned agents is deemed appropriate, they should be used with caution and with frequent monitoring of serum potassium.
Linked to indapamide: Water and electrolyte balance: Sodium levels: These should be tested before treatment is started, then at regular intervals. Reduction in sodium levels can be initially asymptomatic and regular testing is therefore essential. Testing should be more frequent in elderly and cirrhotic patients. Any diuretic treatment may cause hyponatremia, sometimes with very serious consequences. Hyponatremia with hypovolemia may be responsible of dehydration and orthostatic hypotension. Concomitant loss of chloride ions may lead to secondary compensatory metabolic alkalosis: the incidence and degree of this effect are slight.
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 such as 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 first measurement of plasma potassium levels should be carried out during the first 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 hyperuricemic 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, i.e. 220 µmol/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: clcr = (140 - age) x body weight/0.814 x plasma creatinine level with: age expressed in years; body weight in kg; 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 pre-existing renal impairment.
Athletes: Athletes should note that this product contains an active substance which may cause a positive reaction in doping tests.
Acute myopia and secondary angle-closure glaucoma: Sulfonamide, or sulfonamide derivative, drugs can cause an idiosyncratic reaction resulting in transient myopia and acute angle-closure glaucoma. Untreated acute angle-closure glaucoma can lead to permanent vision loss. The primary treatment is to discontinue drug intake as rapidly as possible. Prompt medical or surgical treatments may need to be considered if the intraocular pressure remains uncontrolled. Risk factors for developing acute angle-closure glaucoma may include a history of sulfonamide or penicillin allergy.
Driving and using machines: Neither the two active substances nor Perindopril tert-butylamine + Indapamide (Bi-Preterax) 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
Given the effects of the individual components in this combination product on pregnancy and lactation, it is not recommended during the first trimester of pregnancy, and is contraindicated during the second and third trimesters of pregnancy.
This product is contraindicated during lactation. A decision should therefore be made whether to discontinue nursing or to discontinue Perindopril tert-butylamine + Indapamide (Bi-Preterax) taking account the importance of this therapy for the mother.
Pregnancy: Linked to perindopril: The use of ACE inhibitors is not recommended during the first trimester of pregnancy. The use of ACE inhibitors is contraindicated during the second and third trimesters of pregnancy.
Epidemiological evidence regarding the risk of teratogenicity following exposure to ACE inhibitors during the first 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 anti-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, if appropriate, alternative therapy should be started.
Exposure to ACE inhibitor therapy during the second and third trimesters is known to induce human fetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalemia).
Should exposure to ACE inhibitors have occurred from the second 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.
Linked to indapamide: There are no or limited amount of data (less than 300 pregnancy outcomes) from the use of indapamide in pregnant women. Prolonged exposure to thiazide during the third trimester of pregnancy can reduce maternal plasma volume as well as uteroplacental blood flow, which may cause a feto-placental ischemia and growth retardation.
Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity.
As a precautionary measure, it is preferable to avoid the use of Indapamide during pregnancy.
Breastfeeding: Perindopril tert-butylamine + Indapamide (Bi-Preterax) is contraindicated during lactation.
Linked to perindopril: Because no information is available regarding the use of perindopril during breastfeeding, perindopril is not recommended and alternative treatments with better established safety profiles during breastfeeding are preferable, especially while nursing a newborn or preterm infant.
Linked to indapamide: There is insufficient information on the excretion of indapamide/metabolites in human milk. Hypersensitivity to sulfonamide-derived drugs and hypokalemia might occur. A risk to the newborns/infants cannot be excluded.
Indapamide is closely related to thiazide diuretics which have been associated, during breastfeeding, with decrease or even suppression of milk lactation.
Indapamide is contraindicated during breastfeeding.
Fertility: Common to perindopril and indapamide: Reproductive toxicity studies showed no effect on fertility in female and male rats. No effects on human fertility are anticipated.
Adverse Reactions
Like all medicines, Perindopril tert-butylamine + Indapamide (Bi-Preterax) can cause side effects, although not everybody gets them.
The following undesirable effects have been observed during clinical trials and/or post-marketing use and ranked under the following frequency: Very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1000, <1/100); rare (≥1/10000, <1/1000), very rare (<1/10000), not known (cannot be estimated from the available data). (See Tables A and B.)

Click on icon to see table/diagram/image


Click on icon to see table/diagram/image

Cases of SIADH (syndrome of inappropriate antidiuretic hormone secretion) have been reported with other ACE inhibitors. SIADH can be considered as a very rare but possible complication associated with ACE inhibitor therapy including perindopril.
Reporting of Adverse Drug Reaction: Seek medical attention immediately at the first sign of any adverse drug reaction.
Drug Interactions
Avoid with: Lithium, aliskiren in diabetic or impaired renal patients, potassium-sparing diuretics (e.g. triamterene, amiloride), potassium salts, estramustine, other antihypertensives (ACE inhibitors and angiotensin receptor blockers).
Special care with: other antihypertensives, including angiotensin II receptor blocker (ARB) or aliskiren or diuretics; potassium-sparing drugs used in the treatment of heart failure: eplerenone and spironolactone at doses between 12.5 mg to 50 mg per day; racecadotril; mTor inhibitors e.g. sirolimus, everolimus, temsirolimus; anesthetic medicines; iodinated contrast agent; moxifloxacin, sparfloxacin; methadone; procainamide; allopurinol; mizolastine, terfenadine or astemizole (antihistamines for hay fever or allergies); corticosteroids used to treat various conditions including severe asthma and rheumatoid arthritis; immunosuppressants used for the treatment of auto-immune disorders or following transplant surgery to prevent rejection (e.g. ciclosporin, tacrolimus); erythromycin by injection; halofantrine; pentamidine; injectable gold; vincamine; bepridil; medicines used for heart rhythm problems (e.g. quinidine, hydroquinidine, disopyramide, amiodarone, sotalol); cisapride, diphemanil; digoxin or other cardiac glycosides (for the treatment of heart problems); baclofen; antidiabetics such as insulin, metformin or gliptins; calcium including calcium supplements; stimulant laxatives (e.g. senna); non-steroidal anti-inflammatory drugs (e.g. ibuprofen) or high dose salicylates (e.g. aspirin); amphotericin B by injection; medicines for mental disorders such as depression, anxiety, schizophrenia (e.g. tricyclic antidepressants, neuroleptics (such as amisulpride, sulpiride, sultopride, tiapride, haloperidol, droperidol)); tetracosactide; trimethoprim; vasodilators including nitrates; heparin; medicines used for treatment of hypotension, shock or asthma (e.g. ephedrine, noradrenaline or adrenaline).
Interaction with food and drink: It is preferable to take Perindopril tert-butylamine + Indapamide (Bi-Preterax) before a meal.
Storage
Store at temperatures not exceeding 30°C.
ATC Classification
C09BA04 - perindopril and diuretics ; Belongs to the class of ACE inhibitors in combination with diuretics. Used in the treatment of cardiovascular disease.
Presentation/Packing
Tab (white, rod-shaped) 30's.
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