Perindopril Arginine/ Indapamide

Registered South African indications:

• Hypertension
  - Mild to moderate (2.5/0.625 (mg) & 5/1.25 (mg))
  - In patients already controlled on the individual components at the same dosages, and in patients not adequately controlled on monotherapy of the individual components (10/2.5 (mg)) 

Registered South African contraindications

Perindopril Arginine/ Indapamide

• Hypersensitivity to any of the excipients
• Perindopril arginine/ indapamide should not be given to patients with Addison’s disease
• Due to the lack of sufficient therapeutic experience, perindopril arginine/ indapamide should not be used in:
  • Dialysis patients
  • Patients with untreated decompensated heart failure

Perindopril Arginine

• Hypersensitivity to the active ingredient or any of the excipients in this combination product
• A history of angioedema related to previous therapy with ACE inhibitors or angiotensin receptor blockers (ARBs): these patients must never again be given these medicines
• Hereditary/idiopathic angioedema
• Hypertrophic obstructive cardiomyopathy (HOCM)
• Severe renal impairment (creatinine clearance below 30 ml/min)
• Bilateral renal artery stenosis
• Renal artery stenosis in patients with a single kidney
• Aortic stenosis
• Concomitant therapy with potassium-sparing diuretics (such as spironolactone, triamterene, amiloride, potassium salts)
• Porphyria
• Lithium therapy: concomitant administration with perindopril arginine/indapamide may lead to toxic blood concentration of lithium
• Concomitant use of perindopril arginine/Indapamide with aliskiren 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
• Pregnancy
• Lactation
• In patients with elevated serum levels of potassium

Indapamide

• Hypersensitivity to indapamide or to any other sulphonamides
• Severe renal impairment (creatinine clearance below 30 ml/min)
• Hepatic encephalopathy
• Severe hepatic impairment
• Hypokalaemia
• As a general rule, the use of Perindopril Arginine/Indapamide is inadvisable in combination with non antidysrhythmic agents causing torsades de pointes
• Lactation

Contraindications registered in other jurisdictions

Perindopril Arginine/ Indapamide

• Hypersensitivity to any of the excipients 
• Due to the lack of sufficient therapeutic experience, perindopril arginine/ indapamide should not be used in:
  • Dialysis patients
  • Patients with untreated decompensated heart failure

Perindopril Arginine

• Hypersensitivity to the active substance or to any other ACE inhibitor
• History of angioedema (Quincke's oedema) associated with previous ACE inhibitor therapy
• Hereditary/idiopathic angioedema
• Second and third trimesters of pregnancy
• Concomitant use of perindopril arginine/ indapamide with aliskiren-containing products in patients with diabetes mellitus or renal impairment (GFR < 60 ml/min/1.73 m²)
• Concomitant use with sacubitril/valsartan therapy. perindopril arginine/ indapamide must not be initiated earlier than 36 hours after the last dose of 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

Indapamide

• Hypersensitivity to the active substance or to any other sulfonamides
• Severe renal impairment (creatinine clearance below 30 ml/min)
• Hepatic encephalopathy
• Severe hepatic impairment
• Hypokalaemia

• First trimester of pregnancy (Recommendations in other jurisdictions)
• Breastfeeding  (Recommendations in other jurisdictions)
• Mild renal impairment (10/2.5 (mg)) (South African recommendations)
• Moderate renal impairment (5/1.25 (mg))
• Mild to moderate hepatic impairment
• Elderly
• Dual blockade of renin-angiotensin-aldosterone system
• Collagen vascular disease
• Immunosuppressant therapy
• Desensitization with hymenoptera venom
• Black patients
• Haemodialysis with high flux membranes
• LDL aphoresis
• Hypotension
• Bilateral renal artery stenosis
• Single functioning kidney
• Diabetes mellitus
• Galactose intolerance
• Water depletion
• Electrolyte depletion
• Congestive cardiac failure
• Cirrhosis
• Atherosclerosis
• Surgery
• Aortic or mitral valve stenosis
• QT prolongation or risk factors thereof 
• Hyperuricaemic patients
• Athletes
• Risk factors for acute angle-closure glaucoma
• Lapp lactase deficiency
• Glucose-galactose malabsorption

Forms avail. in SA and covered in this monograph: fct

South African registered indications and dosages

Hypertension
- Mild to moderate

Perindopril Arginine/ Indapamide
2.5/0.625 (mg)
5/1.25 (mg)

• Oral (fct): Initial: 1 tab, daily preferably taken in the morning and before a meal

- In patients already controlled on the individual components at the same dosages, and in patients not adequately controlled on monotherapy of the individual components

10/2.5 (mg)

• Oral (fct): Initial: 1 tab, daily preferably taken in the morning and before a meal

When possible individual dose titration with the components is recommended

If blood pressure is not controlled with the after 1 month of treatment with the 2.5/0.625 (mg), the dose can be doubled

The 5/1.25 (mg) film-coated tablet should be used when blood pressure is not adequately controlled on the lowest dosage of the fixed combination. When clinically appropriate, direct change from monotherapy to 5/1.25 (mg) film-coated tablet may be considered

Not established for use in children and adolescents

Pregnancy

South African recommendations

• Contraindicated
• The use of perindopril arginine/ indapamide is contraindicated during pregnancy. Pregnant women should be informed of the potential hazards to the foetus and must not take this combination product during pregnancy
• 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 perindopril arginine/ indapamide should be stopped and if appropriate, alternative therapy should be started
• Foetal exposure to ACE-inhibitors during the first trimester of pregnancy has been reported to be associated with an increased risk of malformations of the cardiovascular (atrial and/or ventricular septal defect, pulmonic stenosis, patent ductus arteriosus) and central nervous system (microcephaly spina bifida) and of kidney malformations. Perindopril arginine/ indapamide passes through the placenta and can be presumed to cause disturbances in foetal blood pressure regulatory mechanisms
• Oligohydramnios as well as hypotension, oliguria and anuria in new-borns, have been reported after administration of perindopril arginine/ indapamide during the second and third trimester. Cases of defective skull ossification have been observed. Prematurity and low birth mass can occur
• Linked to indapamide: Prolonged exposure to thiazides during the third 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 hypoglycaemia and thrombocytopenia in neonates have been reported following exposure near term

Recommendations in other jurisdictions

• First trimester of pregnancy: Caution
• Second and third trimesters of pregnancy: Contraindicated
• Given the effects of the individual components in this combination product on pregnancy and lactation, this combination product is not recommended during the first trimester of pregnancy and it is contraindicated during the second and third trimesters of pregnancy
• Linked to perindopril: 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. 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. Exposure to ACE inhibitor therapy during the second and third trimesters is known to induce human foetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia). 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 foeto-placental ischaemia 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

South African recommendations

• Contraindicated
• Perindopril: It is not known whether perindopril is excreted into human breast milk
• Indapamide: There is insufficient information on the excretion of indapamide/metabolites in human milk. Indapamide is closely related to thiazide diuretics which have been associated with a decrease or suppression of milk lactation during breastfeeding. Hypersensitivity to sulphonamide-derived medicines and hypokalaemia might occur. Indapamide is contraindicated during breastfeeding

Recommendations in other jurisdictions

• Caution; not recommended
• Perindopril arginine/ indapamide is not recommended during lactation. A decision should therefore be made whether to discontinue nursing or to discontinue treatment taking account the importance of this therapy for the mother
• Linked to perindopril: Because no information is available regarding the use of perindopril during breast-feeding, perindopril is not recommended and alternative treatments with better established safety profiles during breast-feeding 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 hypokalaemia might occur. A risk to the newborns/infants cannot be excluded. Indapamide is closely related to thiazide diuretics which have been associated, during breast-feeding, with decrease or even suppression of milk lactation. Indapamide is not recommended during breast-feeding

Fertility

Recommendations below are applicable to South Africa and other jurisdictions

• Reproductive toxicity studies showed no effect on fertility in female and male rats. No effects on human fertility are anticipated

South African recommendations

5/1.25 (mg)

• Mild (CrCl ≥60ml/min): No dose adjustment recommended
  Usual medical follow-up will include frequent monitoring of creatinine and potassium
• Moderate (CrCl 30-60ml/min): Caution; dose adjustment recommended
  It is recommended to start treatment with the adequate dosage of the free combination
• Severe (CrCl<30ml/min): Contraindicated
• Bilateral renal artery stenosis and renal artery stenosis in patients with a single kidney: Contraindicated

10/2.5 (mg)

• Mild: Caution; no dose adjustment recommended
  Usual medical follow-up will include frequent monitoring of creatinine and potassium
• Moderate to severe (CrCl<60ml/min): Contraindicated
• Bilateral renal artery stenosis and renal artery stenosis in patients with a single kidney: Contraindicated

Recommendations in other jurisdictions

5/1.25 (mg)

• Mild (CrCl≥60ml/min): No dose adjustment recommended
  Usual medical follow-up will include frequent monitoring of creatinine and potassium
• Moderate (CrCl 30-60ml/min): Caution; dose adjustment recommended
  It is recommended to start treatment with the adequate dosage of the free combination
• Severe (CrCl<30ml/min): Contraindicated

Recommendations below are applicable to South Africa and other jurisdictions

• Mild to moderate: Caution; no dose adjustment recommended
• Severe: Contraindicated

Recommendations below are applicable to South Africa and other jurisdictions

• Caution; no dose adjustment recommended
  Treatment should be initiated after considering blood pressure response and renal function
  The lower strength of this combination should preferably be considered

Perindopril

• Lithium
• Baclofen
• NSAIDs including acetylsalicylic acid ≥ 3g/day
• Imipramine-like antidepressants
• Neuroleptics
• Sacubitril/valsartan
• Racecadotril
• mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus)
• Gliptins (e.g., linagliptin, saxagliptin, sitagliptin, vildagliptin)
• Aliskiren
• Extracorporeal treatments
• Angiotensin-receptor blockers
• Estramustine
• Potassium-sparing diuretics (e.g., triamterene, amiloride)
• Potassium salts
• Antidiabetic agents (insulin, oral hypoglycaemic agents)
• Non-potassium-sparing diuretics
• Eplerenone
• Spironolactone
• Vasodilators
• Allopurinol
• Cytostatic or immunosuppressive agents
• Heparins
• Ciclosporin
• Tacrolimus
• Trimethoprim
• Cotrimoxazole
• Systemic corticosteroids
• Procainamide
• Anaesthetic drugs
• Sympathomimetics
• Gold

Indapamide

• Torsades de pointes inducing drugs
• Class Ia antiarrhythmic agents
• Quinidine
• Hydroquinidine
• Disopyramide
• Class III antiarrhythmic agents
• Amiodarone
• Dofetilide
• Ibutilide
• Bretylium
• Sotalol
• Some antipsychotics
• Phenothiazines
• Chlorpromazine
• Cyamemazine
• Levomepromazine
• Thioridazine
• Trifluoperazine
• Benzamides
• Amisulpride
• Sulpiride
• Sultopride
• Tiapride
• Butyrophenones
• Droperidol
• Haloperidol
• Pimozide
• Bepridil
• Cisapride
• Diphemanil
• Erythromycin IV
• Halofantrine
• Mizolastine
• Moxifloxacin
• Pentamidine
• Sparfloxacin
• Vincamine IV
• Methadone
• Astemizole
• Terfenadine
• Potassium-lowering drugs
• Amphotericin B (IV route)
• Glucocorticoids and mineralocorticoids (systemic route)
• Stimulant laxatives
• Digitalis preparations
• Allopurinol
• Potassium-sparing diuretics
• Amiloride
• Spironolactone
• Triamterene
• Metformin
• Iodinated contrast media
• Calcium (salts)
• Ciclosporin
• Tacrolimus
• Corticosteroids
• Tetracosactide (systemic route)

• Blood pressure
• Blood urea nitrogen (BUN)
• Serum creatinine and electrolytes
• Hepatic function (baseline and as clinically indicated)

Specific cases may require

• Uric acid
• Glucose
• Urea (when there is coadministration of potassium-containing agents or drugs associated with increase in serum potassium, or other RAAS inhibitors)
• If patient has collagen vascular disease and/or kidney impairment, periodically monitor complete blood count (CBC) with differential

Perindopril arginine/ indapamide is a combination of perindopril arginine salt, an angiotensin converting enzyme inhibitor, and indapamide, a chlorosulfamoyl 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.

Perindopril arginine
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.

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.

COMBINATION PREPARATIONS

Perindopril/ Indapamide

Tablet 2mg/0.625mg

• Acesyl Co (Thebe)
• Preterax (Servier)
• Spec-Perindopril Plus (Specpharm)

Tablet 5mg/1.25mg

• Coversyl Plus (Servier) originator
• Prexum Plus (Biogaran)
• Trexeva Plus 5/1.25 (Teva Pharmaceuticals)

Tablet 10mg/2.5mg

• Bio Coversyl Plus (Servier) originator
• BioPrexum Plus (Biogaran)
• Prexum 2,5 Plus (Biogaran)