Perindopril - Indapamide combination

 

PCI / LCI : Contraindicated in pregnancy and lactation

Molecule Info

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Content

Perindopril erbumine / Indapamide tablet in following strength(s): 

  • Perindopril/Indapamide 2 mg/0.625 mg
  • Perindopril/Indapamide 4 mg/1.25 mg
  • Perindopril/Indapamide 8 mg/2.5 mg
The fixed dose combination is individualized and adjusted on patient requirement. All the above strengths may not be available in the market. Strength of  5 mg/1.25 mg and  10 mg/2.5 mg may also available in some other markets.
Indication(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.
The safety and efficacy of Perindopril/Indapamide 2 mg/0.625 mg / Perindopril/Indapamide 4 mg/1.25 mg / Perindopril/Indapamide 8 mg/2.5 mg in renovascular hypertension and in congestive heart failure have not been established and therefore, their use in this condition is not recommended.

General
In using Perindopril/Indapamide 2 mg/0.625 mg / Perindopril/Indapamide 4 mg/1.25 mg / Perindopril/Indapamide 8 mg/2.5 mg, consideration should be given to the risk of angioedema.

Geriatrics (> 65 years of age)
Although the blood pressure response and safety profile of Perindopril/Indapamide 2 mg/0.625 mg / Perindopril/Indapamide 4 mg/1.25 mg / Perindopril/Indapamide 8 mg/2.5 mg in patients over 65 years old were comparable to those of the younger adult patients, greater sensitivity of some elderly patients cannot be ruled out.
Pediatrics
The safety and effectiveness of Perindopril/Indapamide 2 mg/0.625 mg / Perindopril/Indapamide 4 mg/1.25 mg / Perindopril/Indapamide 8 mg/2.5 mg in children have not been established. Its use in this age group, therefore, is not recommended.

Dosage & Administration

Dosing considerations
Dosage of Perindopril erbumine/indapamide must be individualized and adjustment is required in the elderly, and in case of renal impairment. Perindopril/Indapamide 8 mg/2.5 mg are not for initial therapy and the dose should be determined by titration of the individual components.
Recommended Dose and Dosage Adjustment
Initiation of therapy requires consideration of recent antihypertensive drug treatment, the extent of blood pressure elevation and salt restriction. The dosage of other antihypertensive agents being used with Perindopril/Indapamide 2 mg/0.625 mg, Perindopril/Indapamide 4 mg/1.25 mg or Perindopril/Indapamide 8 mg/2.5 mg may need to be adjusted. The presence of food in the astrointestinal tract reduces the bioavailability of perindoprilat.
One Perindopril/Indapamide 2 mg/0.625 mg (perindopril erbumine/indapamide) tablet per day as a single dose, to be taken orally, preferably in the morning. In case of uncontrolled blood pressure the dose may be increased to two tablets of Perindopril/Indapamide 2 mg/0.625 mg as a single dose or one tablet of Perindopril/Indapamide 4 mg/1.25 mg. Once the patient has been successfully titrated with the individual components, one tablet per day of Perindopril/Indapamide 4 mg/1.25 mg or Perindopril/Indapamide 8 mg/2.5 mg may be substituted if the titrated doses and dosing schedule can be achieved by the fixed combination.

::The elderly
Treatment should be initiated after considering blood pressure response and renal function.

::Renal impairment
In patients with severe renal impairment (creatinine clearance below 30 ml/min), all dosages are contraindicated.

In patients with moderate renal impairment (creatinine clearance 30-60 ml/min), Perindopril/Indapamide 8 mg/2.5 mg is contraindicated and it is recommended to start treatment with Perindopril/Indapamide 2 mg/0.625 mg / Perindopril/Indapamide 4 mg/1.25 mg with the adequate dosage of the combination of the individual components. Caution should be exercised especially in the elderly patients as greater sensitivity in the elderly cannot be ruled out.
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 levels.

In patients whose renal function may depend on the activity of the renin-angiotensin-aldosterone system, such as patients with bilateral renal artery stenosis, unilateral renal artery stenosis to a solitary kidney, or severe congestive heart failure, treatment with agents that inhibit this system has been associated with oliguria, progressive azotemia, and rarely, acute renal failure and/or death. In susceptible patients, concomitant diuretic use may further increase risk


Missed Dose
If a dose is missed, a double dose should not be taken, but just carry on with the next dose at the normal time.

Administration
It is recommended that Perindopril/Indapamide 2 mg/0.625 mg, Perindopril/Indapamide 4 mg/1.25 mg, Perindopril/Indapamide 8 mg/2.5 mg be taken once daily, preferably in the morning before a meal.

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.
Contraindications

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).
Indapamide: Hypersensitivity to indapamide or to any other sulphonamides; severe renal impairment (creatinine clearance <30 mL/min); hepatic encephalopathy; severe hepatic impairment; hypokalaemia.
As a general rule, indapamide is inadvisable in combination with non-antiarrhythmic agents causing Torsade de pointes and lactation (see Use in pregnancy & lactation as follows). 
Perindopril/Indapamide combination: Hypersensitivity to any of the excipients of Perindopril/Indapamide combination.
Perindopril/Indapamide combination 8 mg/2.5 mg: Moderate renal impairment (creatinine clearance <60 mL/min).
Due to the lack of sufficient therapeutic experience, Perindopril/Indapamide combination should not be used in dialysis patients; patients with untreated decompensated heart failure.

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.
When pregnancy is detected, Perindopril/Indapamide combination should be discontinued as soon as possible.
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.
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, retardation of skull ossification) and neonatal toxicity (renal failure, hypotension, hyperkalaemia).
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.
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 foeto-placental ischaemia and growth retardation. Moreover, rare cases of hypoglycemia and thrombocytopenia in neonates have been reported following exposure near term.
Used in lactation: Perindopril/Indapamide combination is contraindicated in lactation.
Use of perindopril is not recommended during breastfeeding.
Indapamide is excreted in human milk. It is closely related to thiazide diuretics which have been associated, during breastfeeding, with decrease or even suppression of milk lactation. Hypersensitivity to sulfonamide-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 therapy for the mother.

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.
Anaemia has been reported with ACE inhibitors in specific circumstances (patients who have had kidney transplants, patients undergoing haemodialysis).

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.
Gastrointestinal Disorders: Common: Constipation, dry mouth, nausea, vomiting, dysgeusia, dyspepsia, diarrhoea, epigastric pain, anorexia, abdominal pain, taste disturbance. Very Rare: Pancreatitis.

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.
Pharmacology

Pharmacodynamics: 

Mechanism of Action:

Perindopril/Indapamide combination:Perindopril/Indapamide combination produces additive synergy of the antihypertensive effects of perindopril and indapamide.
Perindopril: Perindopril is an inhibitor of the ACE 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 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 preload) and 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: Indapamide is a sulfonamide 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.

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.
PICXEL, a multicenter, randomised, double-blind active-controlled study, has assessed on echocardiography the effect of perindopril/indapamide combination on left ventricular hypertrophy (LVH) versus enalapril monotherapy.
In PICXEL, hypertensive patients with LVH [defined as left ventricular mass index (LVMI) >120 g/m2 in males and >100 g/m2 in females] were randomised either to perindopril tert-butylamine 2 mg (equivalent to perindopril arginine 2.5 mg)/indapamide 0.625 mg or to enalapril 10 mg once a day for a 1-year treatment. The dose was adapted according to blood pressure control, up to perindopril tert-butylamine 8 mg (equivalent to perindopril arginine 10 mg) and indapamide 2.5 mg or enalapril 40 mg once a day. Only 34% of the subjects remained treated with perindopril tert-butylamine 2 mg (equivalent to perindopril arginine 2.5 mg)/indapamide 0.625 mg (versus 20% with enalapril 10 mg).
At the end of treatment, LVMI had decreased significantly more in the perindopril/indapamide group (-10.1 g/m2) than in the enalapril group (-1.1 g/m2) in the all-randomised patients population. The between group difference in LVMI change was -8.3 [95% CI (-11.5,-5), p<0.0001].
A better effect on LVMI was reached with higher perindopril/indapamide doses than those licensed for perindopril perindopril arginine 2.5 mg/indapamide 0.625 mg and Perindopril/Indapamide combination 5 mg/1.25 mg.
Regarding blood pressure, the estimated mean between-group differences in the randomised population were -5.8 mm Hg [95% CI (-7.9, -3.7), p<0.0001] for systolic blood pressure and -2.3 mm Hg [95% CI (-3.6,-0.9), p=0.0004] for diastolic blood pressure, respectively, in favour of the perindopril/indapamide group.
Perindopril: Perindopril is active in all grades of hypertension: Mild to moderate or severe. A reduction in systolic and diastolic arterial pressure is observed in the lying and standing position.
The antihypertensive activity after a single dose is maximal at between 4 and 6 hrs and is maintained over 24 hrs.
There is a high degree of residual blocking of ACE at 24 hrs, approximately 80%.
In patients who respond, normalised blood pressure is reached after 1 month and is maintained without tachyphylaxis.
Withdrawal of treatment has no rebound effect on hypertension.
Perindopril has vasodilatory properties and restores elasticity of the main arterial trunks, corrects histomorphometric changes in resistance arteries and produces a reduction in LVH.
If necessary, the addition of a thiazide diuretic leads to an additive synergy.
The combination of an ACE inhibitor with a thiazide diuretic decreases the hypokalaemia risk associated with the diuretic 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.
Its antihypertensive action is proportional to an improvement in arterial compliance and a reduction in total and arteriolar peripheral vascular resistance.
Indapamide reduces LVH.
When the dose of thiazide diuretics and thiazide-related diuretics is exceeded, the antihypertensive effect reaches a plateau, whereas the adverse effects continue to increase. If the treatment is ineffective, the dose should not be increased.
Furthermore, it has been shown that in the short-, mid- and long-term in hypertensive patients, indapamide has no effect on lipid metabolism (triglycerides, LDL-cholesterol and HDL-cholesterol), and on carbohydrate metabolism, even in diabetic hypertensive patients.

Pharmacokinetics: 

Perindopril/Indapamide combination: The co-administration of perindopril and indapamide does not change their pharmacokinetic properties by comparison to separate administration.
Perindopril: 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 salt should be administered orally in a single daily dose in the morning before a meal.
A linear relationship has been demonstrated 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).
Indapamide: Indapamide is rapidly and completely absorbed from the digestive tract.
The peak plasma level is reached in humans approximately 1 hr after oral administration of Perindopril/Indapamide combination. Plasma protein-binding is 79%.
The elimination half-life is between 14 hrs and 24 hrs (average 18 hrs). Repeated administration does not produce accumulation. Elimination is mainly in the urine (70% of the dose) and faeces (22%) in the form of inactive metabolites.
The pharmacokinetics are unchanged in patients with renal insufficiency.

Toxicology: 

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.
Preclinical studies performed separately with perindopril and indapamide did not show genotoxic, carcinogenic, or teratogenic potential.

Perindopril: 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 fetal development, resulting in fetal 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.

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/Product Info


Total Products : 9         
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
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