Perindopril Tert-Butylamine/ Indapamide

Registered South African indications:

• Essential hypertension
  - In patients where blood pressure is not adequately controlled and where a fixed combination is considered more appropriate than monotherapy

Should a woman become pregnant while receiving perindopril tert-butylamine/ indapamide, the treatment must be stopped promptly and switched to a different class of antihypertensive medicine

 

Registered South African contraindications

Perindopril Tert-Butylamine/ Indapamide

• Hypersensitivity to the active ingredient or any of the excipients in this combination product
• Hypersensitivity to any other ACE inhibitors or sulphonamides
• Severe renal function impairment (CrCl less than 30ml/min)
• Due to the lack of sufficient therapeutic experience, this treatment should not be used in dialysis patients and patients with untreated decompensated cardiac failure

Perindopril Tert-Butylamine

• A history of angioedema (for example Quincke’s oedema) related to previous therapy with ACE inhibitors or angiotensin receptor blockers (ARBs). These patients must never again be given these medicine
• Hereditary or idiopathic angioedema
• Hypertrophic obstructive cardiomyopathy (HOCM)
• 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 and amiloride
• Porphyria
• Lithium therapy: Concomitant administration with perindopril tert-butylamine/ indapamide may lead to toxic blood concentrations of lithium
• The concomitant use of perindopril tert-butylamine/ indapamide with renin inhibitors, such as aliskiren is contraindicated in patients with diabetes mellitus or renal impairment (GFR < 60ml/min/1.73 m²)
• Concomitant use with sacubitril/valsartan. Perindopril tert-butylamine/ 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
• Concomitant use of fluoroquinolones with ACE-inhibitors/Renin angiotensin receptor blockers is contraindicated in patients with moderate to severe renal failure (CrCl ≤ 30ml/min) and in elderly patients
• Significant bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney
• Pregnancy
• Breastfeeding

Indapamide

• Hepatic encephalopathy
• Severe hepatic impairment
• Hypokalaemia
• As a general rule, this medicine is inadvisable in combination with non antidysrhythmic agents causing torsades de pointes
• Breastfeeding 

• Moderate renal impairment
• 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: tab

South African registered indications and dosages

Essential hypertension
- In patients where blood pressure is not adequately controlled and where a fixed combination is considered more appropriate than monotherapy

Perindopril Tert-Butylamine/ Indapamide
4/1.25 (mg)
8/2.5 (mg)

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

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The dosage regimen is dependent on the individual requirements of the patient and is at the discretion of the medical doctor

Not established for use in children and adolescents

Pregnancy

South African recommendations

• Contraindicated

Linked to perindopril

• Pregnant women should be informed of the potential hazards to the foetus and must not take perindopril tert-butylamine/ indapamide 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 tert-butylamine/ 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 tert-butylamine/ indapamide passes through the placenta and can cause disturbance in foetal blood pressure regulatory mechanisms
• Oligohydramnios as well as hypotension, oliguria and anuria in newborns have been reported after administration of ACE-inhibitors in the second and third trimester. Cases of defective skull ossification have been observed. Prematurity and low birth mass can occur
• Should exposure to ACE-inhibitor 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

• 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

Breastfeeding

South African recommendations

• Contraindicated

Linked to perindopril

• Because no information is available regarding the use of perindopril during breastfeeding, perindopril is not recommended

Linked to indapamide

• Indapamide is contraindicated during breastfeeding

Fertility

South African recommendations

• No effect on reproductive performance or fertility is anticipated

South African recommendations

• Mild (CrCl >60ml/min): No dose adjustment recommended
  Usual medical follow-up will include frequent monitoring of creatinine and potassium2
• Moderate (CrCl 30-60ml/min): Caution; dose adjustment recommended
  It is recommended to start the treatment with only one of the constituents
• Severe (CrCl<30ml/min): Contraindicated

South African recommendations

• Mild to moderate: Caution; no information available
• Severe: Contraindicated

South African recommendations

• Caution; dose adjustment recommended
  It is recommended to start the treatment with only one of the constituents

Infections and infestations

Less frequent

• Rhinitis

Blood and lymphatic system disorders

Less frequent

• Eosinophilia
• Agranulocytosis
• Aplastic anaemia
• Pancytopenia
• Leukopenia
• Neutropenia
• Haemolytic anaemia
• Thrombocytopenia

Immune system disorders

Frequent

• Hypersensitivity (reactions, mainly dermatological, in subjects with a predisposition to allergic and asthmatic reactions)

Metabolism and nutrition disorders

Less frequent

• Hypoglycaemia
• Hyperkalaemia, reversible on discontinuation
• Hyponatraemia
• Hypercalcaemia

Frequency unknown

• Potassium depletion with hypokalaemia (particularly serious in certain high risk populations) 

Psychiatric disorders

Less frequent

• Altered mood
• Sleep disorder
• Confusion

Nervous system disorders

Frequent

• Dizziness
• Headache
• Paraesthesia
• Dysgeusia

Less frequent

• Somnolence
• Syncope
• Stroke possibly secondary to excessive hypotension in high-risk patients

Frequency unknown

• Possibility of onset of hepatic encephalopathy in case of hepatic insufficiency

Eye disorders

Frequent

• Vision disturbance

Frequency unknown

• Myopia
• Blurred vision

Ear and labyrinth disorders

Frequent

• Vertigo
• Tinnitus

Cardiac disorders

Less frequent

• Palpitations
• Tachycardia
• Angina pectoris
• Dysrhythmia (including bradycardia, ventricular tachycardia, atrial fibrillation)
• Myocardial infarction possibly secondary to excessive hypotension in high-risk patients

Frequency unknown

• Torsade de pointes (potentially fatal)

Vascular disorders

Frequent

• Hypotension (and effects related to hypotension)

Less frequent

• Vasculitis

Frequency unknown

• Raynaud’s phenomenon

Respiratory, thoracic and mediastinal disorders

Frequent

• Cough
• Dyspnoea

Less frequent

• Bronchospasm
• Eosinophilic pneumonia

Gastrointestinal disorders

Frequent

• Abdominal pain
• Constipation
• Diarrhoea
• Dyspepsia
• Nausea
• Vomiting

Less frequent

• Dry mouth
• Pancreatitis

Hepatobiliary disorders

Less frequent

• Hepatitis
• Abnormal hepatic function

Skin and subcutaneous tissue disorders

Frequent

• Pruritus
• Rash
• Rash maculo-papular

Less frequent

• Urticaria
• Angioedema
• Purpura
• Hyperhidrosis
• Photosensitivity reaction
• Pemphigoid
• Psoriasis aggravation
• Erythema multiforme
• Toxic epidermal necrolysis
• Stevens Johnson syndrome

Musculoskeletal, connective tissue and bone disorders

Frequent

• Muscle cramps

Less frequent

• Arthralgia
• Myalgia

Frequency unknown

• Possible worsening of pre-existing acute disseminated lupus erythematosus

Renal and urinary disorders

Less frequent

• Renal insufficiency
• Acute renal failure

Reproductive system and breast disorders

Less frequent

• Erectile dysfunction

General disorders and administrative site conditions

Frequent

• Asthenia

Less frequent

• Chest pain
• Malaise
• Peripheral oedema
• Pyrexia
• Fatigue

Investigations

Less frequent

• Increased blood urea
• Increased blood creatinine
• Increased blood bilirubin
• Increased hepatic enzyme
• Decreased haemoglobin and decreased haematocrit

Frequency unknown

• Increased blood glucose
• Increased blood uric acid
• Electrocardiogram QT prolonged

Injury, poisoning and procedural complications

Less frequent

• Fall

Additional adverse reactions

Less frequent

• Syndrome of Inappropriate Antidiuretic Hormone secretion (SIADH)

Linked to Perindopril Tert-Butylamine/ Indapamide

• Lithium
• Baclofen
• Non-steroidal anti-inflammatory drugs (NSAIDs)
• High-dose salicylates (including aspirin ≥ 3 g/day)
• COX-2 inhibitors
• Imipramine-like (tricyclic) antidepressants
• Neuroleptics

Linked to Perindopril

• Renin inhibitors (dual blockade) 
• Aliskiren
• Agents inducing hyperkalaemia
• Potassium salts or potassium containing salt substitutes
• Potassium-sparing diuretics
• Spironolactone
• Triamterene
• ACE-inhibitors
• Angiotensin-II receptor antagonists
• NSAIDs
• Heparins
• Immunosuppressant agents
• Ciclosporin
• Tacrolimus
• Trimethoprim
• Sacubitril/valsartan
• Fluoroquinolones
• Estramustine
• Co-trimoxazole (trimethoprim/sulfamethoxazole)
• Potassium supplements
• Antidiabetic medicines
• Insulin
• Hypoglycaemic sulphonamides 
• Non-potassium-sparing diuretics
• Eplerenone
• Antihypertensive medicines and vasodilators
• Nitroglycerin and other nitrates
• Allopurinol
• Cytostatic or immunosuppressive medicines
• Systemic corticosteroids
• Procainamide
• Anaesthetic medicines
• Gliptins
• Linagliptin
• Saxagliptin
• Sitagliptin
• Vildagliptin 
• Sympathomimetics
• mTOR inhibitors
• Sirolimus
• Everolimus
• Temsirolimus 
• Racecadotril

Linked to Indapamide

• Anti-dysrhythmic agents which produce torsades de pointes
• Class IA antidysrhythmic agents
• Quinidine
• Hydroquinidine
• Disopyramide
• Amiodarone
• Sotalol
• Class III antidysrhythmic agents
• Dofetilide
• Ibutilide
• Bretylium
• Some neuroleptics
• 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 agents
• Amphotericin B
• Glucocorticoids and mineralocorticoids
• Tetracosactide
• Stimulant laxatives
• Digitalis preparations
• Allopurinol
• Potassium-sparing diuretics
• Amiloride
• Spironolactone
• Triamterene
• Metformin
• Iodinated contrast media
• Calcium salts
• Ciclosporin
• Tacrolimus

Other interactions

• Extracorporeal treatments
  - High-flux membranes (e.g. polyacrylonitril membranes) and low density lipoprotein apheresis with dextran sulphate 
• Gold

• 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 tert-butylamine/ indapamide produces an added synergy of the antihypertensive effects of the two components.

Perindopril
Perindopril acts through its active metabolite, perindoprilat by inhibiting angiotensin converting enzyme 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 rennin 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 other metabolites of perindopril are inactive.

Indapamide
Indapamide, [N-(3-sulphamoyl-4-chlorobenzamido) 2-methyl indoline] is an indole derivative of chlorosulphonamide with an antihypertensive action. It has an extra renal antihypertensive action resulting in a decrease in vascular hyper-reactivity and a reduction in total peripheral and arteriolar resistance. This action is thought to be due to the inhibition of transmembrane ionic influx, essentially calcic, and the stimulation of synthesis of the vasodilatory hypotensive prostaglandin PGE₂. There is also a direct renal diuretic action. Prolonged use of indapamide has been shown to be associated with a reduction in left ventricular mass in hypertensive patients.

COMBINATION PREPARATIONS

Perindopril Tert-Butylamine/ Indapamide

Tablet 4mg/1.25mg

• Acesyl Co (Akacia)
• Ariprel Plus (Arrow)
• Ciplasyl Plus (Zydus)
• Circator Plus (Biogaran)
• Coversyl Plus (Servier) originator
• Pearinda Plus (Pharma Dynamics)
• Perincopril Co Unicorn (Servier)
• Prexum Plus (Biogaran)
• Spec-Perindopril Plus (Specpharm)
• Vectoryl Plus (Biogaran)