P / L : Contraindicated in pregnancy and lactation
|| See TERMINOLOGY & ABBREVIATIONS ||
Perindopril erbumine / Indapamide tablet in following strength(s):
Perindopril erbumine / indapamide are indicated in the treatment of mild to moderate essential hypertension in patients for whom combination therapy is appropriate. This is not indicated for initial therapy. Patients in whom perindopril and indapamide are initiated simultaneously can develop symptomatic hypotension.
Patients should be titrated on the individual drugs. If the fixed combination represents the dosage determined by this titration, the use of Perindopril/Indapamide 4 mg/1.25 mg or Perindopril/Indapamide 8 mg/2.5 mg may prove to be more convenient in the management of patients. If during maintenance therapy dosage adjustment is necessary, it is advisable to use individual drugs.
|Dosage & Administration||
|Overdosage||Common adverse event in case of overdosage is hypotension, sometimes associated with nausea, vomiting, cramps, dizziness, sleepiness, mental confusion, oliguria which may progress to anuria (due to hypovolaemia). Salt and water disturbances (low sodium and potassium levels) may occur.
The first measures to be taken consist of rapid elimination of the product(s) ingested by gastric lavage and/or administration of activated charcoal, then restoring fluid and electrolyte balance in a specialised centre 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 IV infusion of isotonic saline may be given or any other method of volaemic expansion may be used. Perindoprilat, the active form of perindopril, can be dialysed.
This fixed combination is contraindicated in following situations.
Perindopril: Hypersensitivity to perindopril or to any other angiotensin-converting enzyme (ACE) inhibitor; history of angioedema (Quincke's oedema) associated with previous ACE inhibitor therapy; hereditary/idiopathic angioedema; 2nd and 3rd trimesters of pregnancy (see Use in pregnancy & lactation as follows).
|Pregnancy Category (FDA)||
Pregnancy Category D.
Use in pregnancy: Increased risk of birth defects, fetal and neonatal morbidity, and death when used throughout pregnancy. When used in pregnancy during the 2nd and 3rd trimesters, ACE inhibitors can cause injury and even death to the developing foetus.
|Adverse Drug Reaction(s)
Perindopril administration inhibits the renin-angiotensin aldosterone axis and tends to reduce the potassium loss caused by indapamide. Four percent (4%) of the patients on treatment with Perindopril/Indapamide combination 5 mg/1.25 mg and 6% of the patients on treatment with Perindopril/Indapamide combination 10 mg/2.5 mg experienced hypokalaemia (potassium level <3.4 mmol/L).
The following undesirable effects could be observed during treatment and ranked under the following frequency: 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 the Lymphatic System Disorders: Very Rare: Thrombocytopenia, leucopenia/neutropenia, agranulocytosis, aplastic anaemia, haemolytic anaemia.
Psychiatric Disorders: Uncommon: Mood or sleep disturbances.
Nervous System Disorders: Common: Paraesthesia, headache, dizziness, vertigo. Very Rare: Confusion.
Eye Disorders: Common: Visual disturbance.
Ear and Labyrinth Disorders: Common: Tinnitus.
Vascular Disorders: Common: Hypotension whether orthostatic or not.
Cardiac Disorders: Very Rare: Arrhythmia including bradycardia, ventricular tachycardia, atrial fibrillation, angina pectoris and myocardial infarction possibly secondary to excessive hypotension in high-risk patients.
Respiratory, Thoracic and Mediastinal Disorders: Common: A dry cough has been reported with the use of ACE inhibitors. It is characterised by its persistence and by its disappearance when treatment is withdrawn. An iatrogenic aetiology should be considered in the presence of this symptom. Dyspnoea. Uncommon: Bronchospasm. Very Rare: Eosinophilic pneumonia, rhinitis.
Hepatobiliary Disorders: Very Rare: Hepatitis either cytolytic or cholestatic. Not Known: In case of hepatic insufficiency, there is a possibility of onset of hepatic encephalopathy (see Contraindications and Precautions).
Skin and Subcutaneous Tissue Disorders: Common: Rash, pruritus, maculopapular eruptions. Uncommon: Angioedema of the face, extremities, lips, mucous membranes, tongue, glottis and/or larynx, urticaria. Hypersensitivity reactions, mainly dermatological, in subjects with a predisposition to allergic and asthmatic reactions. Purpura, possible aggravation of preexisting acute disseminated lupus erythematosus. Very Rare: Erythema multiforme, toxic epidermic necrolysis, Stevens-Johnson syndrome. Cases of photosensitivity reactions have been reported.
Musculoskeletal, Connective Tissue and Bone 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: Potassium depletion with particularly serious reduction in levels of potassium in some at risk populations; reduced sodium levels with hypovolaemia causing dehydration and orthostatic hypotension. Increase in uric acid levels and in blood glucose levels during treatment. Slight increase in urea and in plasma creatinine levels, reversible when treatment is stopped. This increase is more frequent in cases of renal artery stenosis, arterial hypertension treated with diuretics, renal insufficiency. Increased levels of potassium, usually transitory.
Rare: Raised plasma calcium levels.
|Drug Interactions||Increased risk of lithium toxicity. May cause and potentiate orthostatic hypotension when used with alcohol, barbiturates, neuroleptics, narcotics or other antihypertensives. Increased risk of acute renal insufficiency in dehydrated patients when used with systemic NSAIDs or high dose salicylates. May increase risk of hypoglycaemia in patients on concurrent treatment with hypoglycaemic sulfonamides/insulin. Concurrent use with baclofen may potentiate antihypertensive effect. May reduce antihypertensive effect when used with corticosteroids or tetracosactide. Increased risk of hyperkalaemia when used with potassium-sparing diuretics or potassium supplements. May increase hypotensive effect of certain anaesthetic drugs. Increased risk of leucopenia when used with allopurinol, immunosuppressants, procainamide or systemic corticosteoids. Additive hypotensive effect when used with other antihypertensives.
|Warnings||Angiotensin-Converting Enzyme (ACE) Inhibitors: ACE inhibitors have been shown to be strongly foetotoxic in animal studies. Recently available data indicate that ACE inhibitors can cause foetal and neonatal morbidity, and mortality when administered to a pregnant woman. The use of these agents during pregnancy is not recommended.
Common to Perindopril and Indapamide: Lithium: The combination of lithium, and the combination of perindopril and indapamide is usually not recommended.
Perindopril: Neutropenia/Agranulocytosis: 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, periodical monitoring of white blood cell counts is advised and patients should be instructed to report any sign of infection (eg, sore throat, fever).
Hypersensitivity/Angioedema: Angioedema of the face, extremities, lips, tongue, glottis and/or larynx has been reported rarely in patients receiving treatment with ACE 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 oedema may be fatal. Where there is involvement of the tongue, glottis or larynx, likely to cause airway obstruction, appropriate therapy, which may include SC adrenaline solution 1:1000 (0.3-0.5 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 nonBlacks.
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 Desensitisation: There have been isolated reports of patients experiencing sustained, life-threatening anaphylactoid reactions while receiving ACE inhibitors during desensitisation treatment with hymenoptera (bees, wasps) venom. ACE inhibitors should be used with caution in allergic patients treated with desensitisation and avoided in those undergoing venom immunotherapy. However, these reactions could be prevented by temporary withdrawal of ACE inhibitor for at least 24 hrs before treatment in patients who require both ACE inhibitors and desensitisation.
Anaphylactoid Reactions During Low-Density Lipoprotein (LDL)-Apheresis:Rarely, patients receiving ACE inhibitors during LDL-apheresis with dextran sulphate have experienced life-threatening anaphylactoid reactions. These reactions can be avoided by temporarily withholding ACE inhibitor therapy for at least 24 hrs prior to each apheresis.
Haemodialysis Patients: Anaphylactoid reactions have been reported in patients dialysed with high-flux membranes (eg, 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.
Potassium-Sparing Diuretics, Potassium Salts: The combination of perindopril and potassium-sparing diuretics, potassium salts is usually not recommended.
Indapamide: When liver function is impaired, thiazide diuretics and thiazide-related diuretics may cause hepatic encephalopathy. Administration of indapamide should be stopped immediately if this occurs.
Photosensitivity: Cases of photosensitivity reactions have been reported with thiazides and thiazide-related diuretics (see Adverse Reactions). If photosensitivity reaction occurs during treatment, it is recommended to stop the treatment. If readministration of the diuretic is deemed necessary, it is recommended to protect exposed areas to the sun or to artificial UVA.
|Precaution||Common to Perindopril and Indapamide: Renal Impairment: In case of severe renal impairment (creatinine clearance <30 mL/min), treatment with Perindopril/Indapamide combination is contraindicated.
In case of moderate renal impairment (creatinine clearance <60 mL/min), treatment with Perindopril/Indapamide combination 10 mg/2.5 mg 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 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.
Perindopril/Indapamide combination is usually not recommended in case of bilateral renal artery stenosis or a single functioning kidney.
Hypotension, 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 the clinical signs of water and electrolyte depletion, which may occur with an intercurrent episode of diarrhoea 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 for continuation of treatment. After reestablishment 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.
Excipients: Perindopril/Indapamide combination 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 characterised by its persistence and by its disappearance when treatment is withdrawn. An iatrogenic aetiology 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.
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 salt and water depletion (strict sodium-free diet or prolonged diuretic treatment), in patients whose blood pressure was initially low, in cases of renal arterial stenosis, congestive heart failure or cirrhosis with oedema and ascites.
The blocking of this system with an ACE inhibitor may therefore cause a sudden drop in blood pressure, particularly at the time of the 1st administration and during the first 2 weeks of treatment, 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.
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 revascularisation. 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.
Treatment with Perindopril/Indapamide combination 10 mg/2.5 mg is not appropriate in patients with known or suspected renal artery stenosis because treatment should be started in a hospital setting at a dose lower than Perindopril/Indapamide combination 10 mg/2.5 mg.
If Perindopril/Indapamide combination 5 mg/1.25 mg 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 at Risk: 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 Beta-blockers in hypertensive patients with coronary insufficiency should not be stopped, the ACE inhibitor should be added to the Beta-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.
Anaemia: Anaemia has been observed in patients who have had a kidney transplant or have been undergoing dialysis. The reduction in haemoglobin levels is more apparent as initial values were high. This effect does not seem to be dose-dependent but may be linked to the mechanism of action of ACE inhibitors.
This reduction in haemoglobin is slight, occurs within 1-6 months and then remains stable. It is reversible when treatment is stopped. Treatment can be continued with regular haematological testing.
Surgery/Anaesthesia: ACE inhibitors can cause hypotension in cases of anaesthesia, especially when the anaesthetic 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: ACE inhibitors must be used with care 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 of marked elevations of hepatic enzymes should discontinue the ACE inhibitor, and receive appropriate medical follow-up (see Adverse Reactions).
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 (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. Hyperkalemia 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.
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.
Potassium Levels: Potassium depletion with hypokalaemia 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 oedema and ascites, coronary patients and patients with heart failure.
In such cases, hypokalaemia 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. Hypokalaemia, as with bradycardia, acts as a factor which favours the onset of severe rhythm disorders, in particular Torsade 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; this formula is suitable for male elderly and should be adapted for women by multiplying the result by 0.85.
Hypovolaemia, 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 Perindopril/Indapamide combination 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 Perindopril/Indapamide combination affects 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 children: Perindopril/Indapamide combination should not be used in children and adolescents as the efficacy and tolerability of perindopril in children and adolescents, alone or in combination, have not been established.
Use in the elderly: Renal function and potassium levels are 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.
|Storage||Store below 30°C.|
Mechanism of Action:
Perindopril/Indapamide combination:Perindopril/Indapamide combination produces additive synergy of the antihypertensive effects of perindopril and indapamide.
Characteristics of Antihypertensive Action: Perindopril/Indapamide combination: In hypertensive patients regardless of age, Perindopril/Indapamide combination exerts a dose-dependent antihypertensive effect on diastolic and systolic arterial pressure whilst supine or standing. This antihypertensive effect lasts for 24 hrs. The reduction in blood pressure is obtained <1 month without tachyphylaxis; stopping treatment has no rebound effect. During clinical trials, the concomitant administration of perindopril and indapamide produced antihypertensive effects of a synergic nature to each of the products administered alone.
Indapamide: Indapamide, as monotherapy, has an antihypertensive effect which lasts for 24 hrs. This effect occurs at doses at which the diuretic properties are minimal.
Perindopril/Indapamide combination: The co-administration of perindopril and indapamide does not change their pharmacokinetic properties by comparison to separate administration.
Preclinical Safety Data: The perindopril/indapamide combination has slightly increased toxicity than that of its components. Renal manifestations do not seem to be potentiated in the rat. However, the combination produces gastrointestinal toxicity in the dog and the toxic effects on the mother seem to be increased in the rat (compared to perindopril). Nonetheless, these adverse effects are shown at dose levels corresponding to a very marked safety margin by comparison to the therapeutic doses used.
Perindopril: In the chronic oral toxicity studies (rats and monkeys), the target organ is the kidney, with reversible damage.
Indapamide: The highest doses administered orally to different animal species (40-8000 times the therapeutic dose) have shown an exacerbation of the diuretic properties of indapamide. The major symptoms of poisoning during acute toxicity studies with indapamide administered IV or intraperitoneally were related to the pharmacological action of indapamide ie, bradypnoea and peripheral vasodilation. Indapamide has been tested negative concerning mutagenic and carcinogenic properties.
|ATC Classification||C03BA11 - indapamide; Belongs to the class of low-ceiling sulfonamide diuretics. Used to promote excretion of urine.
C09AA04 - perindopril; Belongs to the class of ACE inhibitors. Used in the treatment of cardiovascular disease.
|Brand Name||Manufacturer/Marketer||Composition||Dosage Form||Pack Size & Price|
|COVERSYL Plus||Servier Bangladesh Operation||Indapamide 1.25mg+ Perindopril erbumine 4mg||Tablet||30's: 630.00 IP|
|Indapril 2||Incepta Pharmaceuticals Limited||0.625 mg of Indapamide+ 2 mg of Perindopril Erbumine||Tablet||10x3's:MRP 210 Tk|
|Indapril 4||Incepta Pharmaceuticals Limited||1.25 mg of Indapamide+ 4 mg of Perindopril Erbumine||Tablet||4x5's:MRP 240 Tk|
|INOPIL Plus||Delta Pharma Limited||Indapamide 1.25mg+ Perindopril erbumine 4mg||Tablet||20's: 160.00 MRP|
|PENDORIL Plus 2||Renata Limited||Indapamide 0.625mg+ Perindopril erbumine 2mg||Tablet||10's: 80.30 MRP|
|PENDORIL Plus 4||Renata Limited||Indapamide 1.25mg+ Perindopril erbumine 4mg||Tablet||10's: 130.50 MRP|
|PERINDAL 2+||Opsonin Pharma Limited||Indapamide 0.625mg+ Perindopril erbumine 2mg||Tablet||30's: 210.00 MRP|
|PERINDAL 4+||Opsonin Pharma Limited||Indapamide 1.25mg+ Perindopril erbumine 4mg||Tablet||20's: 240.00 MRP|
|REPRES PLUS||Square Pharmaceuticals Ltd.||Indapamide 1.25mg + Perindopril Erbumine 4mg||Tablet||2x10's: 241.80 MRP|
|| See Brand Manufacturer's Prescribing Information |||| Back to top ||