Perindopril/ Indapamide/ Amlodipine

Registered South African indications:

• Substitution therapy for treatment of essential hypertension
  - In adult patients already controlled with amlodipine and the fixed dose combination perindopril/ indapamide, taken at the same dose levels as contained in perindopril/ indapamide/ amlodipine

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

 

Registered South African contraindications

• Hypersensitivity to the active ingredients or any of the excipients in this combination product
• Pregnancy
• Breastfeeding
• Moderate renal impairment (CrCl 30-60ml/min) for perindopril/ indapamide/ amlodipine doses containing 10/2.5 mg of perindopril/indapamide combination:
  - 10/2.5/5 (mg)
  - 10/2.5/10 (mg)
• Severe renal impairment (CrCl<30ml/min)
• Moderate to severe hepatic impairment (Child-Pugh Classes B&C)
• Porphyria
• 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 or idiopathic angioedema
• Hypertrophic obstructive cardiomyopathy (HOCM)
• Bilateral renal artery stenosis
• Renal artery stenosis in patients with a single kidney
• Aortic stenosis
• Dialysis patients
• Patients with untreated decompensated heart failure
• Hepatic encephalopathy
• Hypokalaemia
• Severe hypotension
• Shock, including cardiogenic shock
• Obstruction of the outflow-tract of the left ventricle (e.g. high-grade aortic stenosis)
• Haemodynamically unstable heart failure after acute myocardial infarction
• Extracorporeal treatments leading to contact of blood with negatively charged surfaces
• Coadministration of fluoroquinolones with ACE-inhibitors/ angiotensin receptor blockers is contraindicated in patients with moderate to severe renal impairment (CrCl≤30ml/min) and in elderly patients
• Coadministration with aliskiren-containing products in patients with diabetes mellitus or renal impairment (GFR <60ml/min/1.73m²)
• Coadministration with potassium-sparing diuretics such as spironolactone, triamterene and amiloride
• Coadministration with lithium may lead to toxic blood concentrations of lithium
• Coadministration with sacubitril/ valsartan, perindopril/ indapamide/ amlodipine must not be initiated earlier than 36 hours after the last dose of sacubitril/valsartan

South African recommendations

• Mild renal impairment (CrCl>60ml/min)
• Moderate renal impairment (CrCl 30-60ml/min)
  - 5/1.25/5 (mg)
  - 5/1.25/10 (mg)
• Mild hepatic impairment (Child-Pugh Class A)
• Elderly
• Diabetic nephropathy
• Individual or a combination of these complicating factors especially if there is pre-existing impaired renal function
  - Collagen vascular disease
  - Immunosuppressant therapy
  - Coadministration with allopurinol or procainamide
• Unilateral renal artery stenosis
• Black patients
• Patients with a history of angioedema unrelated to ACE-inhibitor therapy
• Allergic patients treated with desensitisation
• Patients undergoing venom immunotherapy
• Patients receiving low-density lipoprotein(LDL)-apheresis
• Primary hyperaldosteronism
• Heart failure
• Hypertensive patients without pre-existing apparent renal lesions and for whom renal blood tests are indicative of functional renal insufficiency
• Cardiac insufficiency
• Marked water and electrolyte depletion
  - Sodium-restricted diet
  - Prolonged diuretic treatment
  - Pre-existing sodium depletion
• Patients whose blood pressure was initially low
• Congestive heart failure
• Cirrhosis with oedema and ascites
• Ischaemic heart or cerebrovascular disease
• Diabetic patients
  - Insulin-dependent diabetes mellitus
• Risk factors for the development of hyperkalemia
  - Renal insufficiency
  - Worsening of renal function
  - Age (>70 years)
  - Diabetes mellitus
  - Intercurrent events, in particular, dehydration, acute cardiac decompensation, metabolic acidosis and concomitant use of potassium-sparing diuretics (e.g. spironolactone, eplerenone, triamterene, or amiloride)
  - Potassium supplements or potassium-containing salt substitutes or those patients taking other medications associated with increases in serum potassium (e.g. heparin, trimethoprim/ sulfamethoxazole)
• Malnourished patients
• Cirrhotic patients with oedema and ascites
• Coronary artery disease
• Long QT interval (congenital or iatrogenic)
• Bradycardia
• Cerebral circulatory insufficiency
• Renovascular hypertension
• Hypertensive crisis
• Heart failure NYHA class III and IV
• Surgery/ anaesthesia
• Hyperuricaemic patients
• Pre-existing systemic lupus erythematosus
• May impair ability to drive and operate machinery

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

South African registered indications and dosages

Substitution therapy for treatment of essential hypertension
- In adult patients already controlled with amlodipine and the fixed dose combination perindopril/ indapamide, taken at the same dose levels as contained in perindopril/ indapamide/ amlodipine

Perindopril/ Indapamide/ Amlodipine
5/1.25/5 (mg)
5/1.25/10 (mg)
10/2.5/5 (mg)
10/2.5/10 (mg)

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

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Not suitable for initial therapy. If a change of the posology is required, titration should be done with the individual components

Not established for use in children below 18 years

Pregnancy

South African recommendations

• Contraindicated
• Should a woman become pregnant while receiving perindopril/ indapamide/ amlodipine, the treatment must be stopped promptly and switched to a different class of antihypertensive medicine
• Perindopril
  The use of perindopril/ indapamide/ amlodipine is contraindicated during pregnancy. Pregnant women should be informed of the potential hazards to the foetus and must not take perindopril/ indapamide/ amlodipine 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/ indapamide/ amlodipine should be stopped immediately 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/ indapamide/ amlodipine passes through the placenta and causes 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, such as perindopril/ indapamide/ amlodipine, during the second and third trimester. Cases of defective skull ossification have been observed. Prematurity and low birth mass can occur
• Indapamide
  There are no or limited amount of data (less than 300 pregnancy outcomes) from the use of indapamide in pregnant women. Prolonged exposure to thiazide during the third trimester of pregnancy can reduce maternal plasma volume as well as uteroplacental blood flow, which may cause a feto-placental ischemia and growth retardation. Moreover, cases of hypoglycemia and thrombocytopenia in neonates have been reported following exposure near term
  Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity
• Amlodipine
  The safety of amlodipine in human pregnancy has not been established
  In animal studies, reproductive toxicity was observed at high doses

Breastfeeding

South African recommendations

• Contraindicated
• Perindopril
  Because no information is available regarding the use of perindopril during breastfeeding, perindopril is not recommended and alternative treatments with better established safety profiles during breastfeeding are preferable, especially while breastfeeding a newborn or preterm infant
• Indapamide
  There is insufficient information on the excretion of indapamide/ metabolites in human milk. Hypersensitivity to sulphonamide-derived medicines and hypokalaemia might occur. A risk to newborns/ infants cannot be excluded
  Indapamide is closely related to thiazide diuretics which have been associated, during breastfeeding, with a decrease or even suppression of milk lactation
• Amlodipine
  Amlodipine is excreted in human milk. The proportion of the maternal dose received by the infant has been estimated with an interquartile range of 3–7%, with a maximum of 15%. The effect of amlodipine on infants is unknown

Fertility

South African recommendations

• Perindopril, Indapamide 
  Reproductive toxicity studies showed no effect on fertility in female and male rats. No effects on human fertility are anticipated
• Amlodipine 
  Reversible biochemical changes in the head of spermatozoa have been reported in some patients treated by calcium channel blockers
  Clinical data are insufficient regarding the potential effect of amlodipine on fertility. In one rat study, adverse effects were found on male fertility

South African recommendations

• Mild (CrCl>60ml/min): Caution; no dose adjustment recommended
• Moderate (CrCl 30-60ml/min): Caution; no dose adjustment recommended (5/1.25/5 (mg) 5/1.25/10 (mg))
• Moderate (CrCl 30-60ml/min): Contraindicated (10/2.5/5 (mg) and 10/2.5/10 (mg))
  It is recommended to start treatment with appropriate doses of the individual components
• Concomitant use of perindopril/ indapamide/ amlodipine with aliskiren in patients with renal impairment (GFR <60ml/min/1.73 m²): Contraindicated
• Severe (CrCl<30ml/min): Contraindicated

South African recommendations

• Mild (Child-Pugh Class A): Caution; no dose adjustment recommended
• Moderate to severe (Child-Pugh Classes B&C): Contraindicated

South African recommendations

• Caution; no dose adjustment recommended
  Elimination of perindoprilat is decreased in the elderly
  Elderly can be treated with perindopril/ indapamide/ amlodipine according to renal function
  Monitor renal function and potassium levels
  Initial dose should be adjusted according to blood pressure response, especially in cases of water and electrolyte depletion, in order to avoid sudden onset of hypotension
  In the elderly increase of the dosage of amlodipine should take place with care

Central Nervous System Disorders

• Insomnia
• Mood altered (including anxiety)
• Depression
• Sleep disorder
• Confusional state
• Dizziness
• Headache
• Paraesthesia
• Somnolence
• Hypoaesthesia
• Dysgeusia
• Tremor
• Syncope
• Hypertonia
• Peripheral neuropathy
• Extrapyramidal disorder (extrapyramidal syndrome)
• Stroke possibly secondary to excessive hypotension in high-risk patients
• Fatigue

Cardiovascular Disorders

• Palpitations
• Tachycardia
• Angina pectoris
• Dysrthymia
  - Bradycardia
  - Ventricular tachycardia
  - Atrial fibrillation
• Myocardial infarction, possibly secondary to excessive hypotension in high risk patients
• Torsade de Pointes (potentially fatal)
• Flushing
• Hypotension (and effects related to hypotension)
• Vasculitis
• Raynaud’s phenomenon
• Oedema
• Prolonged QT electrocardiogram
• Chest pain

Respiratory Disorders

• Cough
• Dyspnoea
• Bronchospasm
• Eosinophilic pneumonia
• Rhinitis

Gastrointestinal Disorders

• Abdominal pain
• Constipation
• Diarrhoea
• Dyspepsia
• Nausea and vomiting
• Dry mouth
• Change of bowel habit
• Gingival hyperplasia
• Pancreatitis
• Gastritis
• Intestinal angioedema

Hepatobiliary Disorders

• Possibility of onset of hepatic encephalopathy in case of hepatic insufficiency
• Hepatitis
• Jaundice
• Abnormal hepatic function
• Increased hepatic enzyme
• Increased blood bilirubin

Genitourinary Disorders

• Micturition disorder
• Nocturia
• Pollakiuria
• Acute renal failure
• Renal failure
• Erectile dysfunction
• Gynaecomastia
• Increased blood urea
• Increased blood creatinine
• Increased blood creatinine

Endocrine and Metabolic Disorders

• Increased weight
• Decreased weight
• Increased blood glucose
• Hypoglycaemia
• Hyperglycaemia
• Hyperkalaemia (reversible on discontinuation)
• Hyponatraemia
• Hypercalcaemia
• Potassium depletion with hypokalemia, particularly serious in certain high-risk populations

Musculoskeletal Disorders

• Muscle spasms
• Ankle swelling
• Arthralgia
• Myalgia
• Back pain
• Possible worsening of pre-existing systemic lupus erythematosus

Skin and Subcutaneous Tissue Disorders

• Pruritus
• Rash
• Maculo-papular rash
• Urticaria
• Angioedema
• Alopecia
• Purpura
• Skin discolouration
• Hyperhidrosis
• Exanthema
• Photosensitivity reaction
• Psoriasis aggravation
• Pemphigoid
• Erythema multiforme
• Stevens-Johnson Syndrome
• Exfoliative dermatitis
• Toxic epidermal necrolysis
• Quincke’s oedema (angioedema)

Immune, Blood and Lymphatic System Disorders

• Peripheral oedema
• Pyrexia
• Decreased haemoglobin
• Decreased haematocrit
• Eosinophilia
• Agranulocytosis
• Aplastic anaemia
• Pancytopenia
• Leukopenia
• Neutropenia
• Haemolytic anaemia
• Thrombocytopenia
• Hypersensitivity

Sensory Disorders

• Visual impairment
• Diplopia
• Myopia
• Blurred vision
• Tinnitus
• Vertigo

Others

• Pain
• Fall

• Fluoroquinolones
• Hyperkalaemic agents
• Aliskiren-containing products
• Potassium salts
• Potassium-sparing diuretics
• Spironolactone
• Eplerenone
• Triamterene
• Amiloride
• Lithium
• Sacubitril/ valsartan
• ACE-inhibitors
• Angiotensin-II receptors antagonists
• Non-steroidal anti-inflammatory drugs
• Heparins
• Immunosuppressant agents
• Ciclosporin
• Tacrolimus
• Trimethoprim

Other interactions

• Extracorporeal treatments
  - Dialysis or haemofiltration with certain high-flux membranes (e.g. polyacrylonitrile membranes)
  - Low-density lipoprotein apheresis with dextran sulphate

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Interactions known for Perindopril

• ACE-inhibitors
• Angiotensin-II receptor blocker
• Estramustine
• Potassium-sparing agents
• Triamterene
• Amiloride
• Potassium salts
• Co-trimoxazole (trimethoprim/ sulfamethoxazole)

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Interactions known for Perindopril/ Indapamide

• Baclofen
• Non-steroidal anti-inflammatory drugs
• Acetylsalicylic acid (at high doses)
• COX-2 inhibitors

- Perindopril

• Antidiabetics
• Insulin
• Oral hypoglycaemic agents
• Non-potassium-sparing diuretics
• Potassium-sparing diuretics
• Eplerenone
• Spironolactone
• NEP inhibitors
• Racecadotril
• mTOR inhibitors
• Sirolimus
• Everolimus
• Temsirolimus

- Indapamide

• Torsades de Pointes-inducing agents
• Class IA anti-dysrhythmic agents
• Quinidine
• Hydroquinidine
• Disopyramide
• Class III anti-dysrhythmic agents
• Amiodarone
• Dofetilide
• Ibutilide
• Bretylium
• Sotalol
• Certain neuroleptics
• Chlorpromazine
• Cyamemazine
• Levomepromazine
• Thioridazine
• Trifluoperazine
• Benzamides
• Amisulpride
• Sulpiride
• Sultopride
• Tiapride
• Butyrophenones
• Droperidol
• Haloperidol
• Pimozide
• Bepridil
• Cisapride
• Diphemanil
• IV erythromycin
• Halofantrine
• Mizolastine
• Moxifloxacin
• Pentamidine
• Sparfloxacin
• IV vincamine
• Methadone
• Astemizole
• Terfenadine
• Amphotericin B (IV route)
• Glucocorticoids and mineralocorticoids (systemic  route)
• Tetracosactide
• Stimulant laxatives
• Digoxin
• Allopurinol

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Interactions known for Amlodipine

• Dantrolene (infusion)
  - Patients susceptible to malignant hyperthermia and in the management of malignant hyperthermia
• CYP3A4 inducers (particularly for strong inducers)
• Rifampicin
• CYP3A4 inhibitors (strong or moderate)
• Protease inhibitors
• Azole antifungals
• Macrolides
• Erythromycin
• Clarithromycin
• Verapamil
• Diltiazem

Other interactions known for Amlodipine

• Grapefruit or grapefruit juice
• Hypericum perforatum (St John's wort)

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Interactions known for Perindopril/ Indapamide/ Amlodipine

• Imipramine-like antidepressants (tricyclics)
• Neuroleptics
• Other antihypertensive medicines
• Corticosteroids
• Tetracosactide

- Perindopril

• Antihypertensive medicines
• Vasodilators
• Nitroglycerin
• Other nitrates
• Allopurinol
• Cytostatic agents
• Immunosuppressive agents
• Systemic corticosteroids
• Procainamide
• Anaesthetic agents
• Diuretics
• Thiazide diuretics
• Loop diuretics
• Gliptins
• Linagliptin
• Saxagliptin
• Sitagliptin
• Vildagliptin
• Sympathomimetics

Other interactions known for perindopril

• Gold

- Indapamide

• Metformin
• Calcium (salts)
• Ciclosporin

Other interactions known for indapamide

• Iodinated contrast media

- Amlodipine

• Mechanistic target of rapamycin (mTOR) inhibitors
• Tacrolimus
• CYP3A substrates
• Sirolimus
• Temsirolimus
• Everolimus
• Ciclosporin (renal transplant patients)
• Simvastatin

• Blood pressure
• Creatinine
• Renal function
• Electrolytes (including potassium)

Specific cases may require

• Full blood count
• Plasma urea
• Hydration status
• Blood glucose
• QT interval
• Respiratory function
• Cardiac function

 

Anaphylactoid reactions during desensitisation

• There have been reports of patients experiencing sustained, life-threatening anaphylactoid reactions while receiving ACE-inhibitors such as contained in perindopril/ indapamide/ amlodipine, 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 the temporary withdrawal of the ACE-inhibitor for at least 24 hours before treatment in patients who require both ACE-inhibitors and desensitisation

Anaphylactoid reactions during LDL apheresis

• Patients receiving ACE-inhibitors such as contained in perindopril/ indapamide/ amlodipine, during low-density lipoprotein(LDL)-apheresis with dextran sulphate have experienced life-threatening anaphylactoid reactions
• These reactions were avoided by temporarily withholding ACE-inhibitor therapy prior to each apheresis

Haemodialysis patients

• Anaphylactoid reactions have been reported in patients dialysed with high-flux membranes (e.g. AN 69®) and treated concomitantly with an ACE-inhibitor such as contained in perindopril/ indapamide/ amlodipine
• In these patients, consideration should be given to using a different type of dialysis membrane or a different class of antihypertensive medicine

Surgery/ anaesthesia

• Angiotensin converting enzyme inhibitors (such as perindopril) can cause hypotension during anaesthesia, especially if hypotension is also a known adverse reaction of the anaesthetic administered. It is recommended that perindopril/ indapamide/ amlodipine should be discontinued where possible one day before surgery

Coadministration with sacubitril/ valsartan

• The concomitant use of perindopril with sacubitril/ valsartan is contraindicated as the concomitant inhibition of neprilysin and ACE may increase the risk of angioedema
• Sacubitril/ valsartan must not be started until 36 hours after taking the last dose of perindopril/ indapamide/ amlodipine, similarly perindopril/ indapamide/ amlodipine must not be started until 36 hours after the last dose of sacubitril/ valsartan

Prohibited medicines for athletes

• Perindopril/ indapamide/ amlodipine contains the diuretic indapamide, which is a prohibited medicine for athletes
• Athletes will test positive for a prohibited medicine if they are on treatment with perindopril/ indapamide/ amlodipine

Perindopril
Perindopril is an angiotensin-converting enzyme inhibitor. Inhibition of this enzyme results in a reduction of angiotensin II levels, which leads to increased plasma renin activity and reduced secretion of aldosterone. It also causes an increase in the activity of circulating and local kallikrein-kinin systems.

Indapamide
Indapamide is a sulphonamide derivative with an indole ring, pharmacologically related to thiazide diuretics, which acts by inhibiting the reabsorption of sodium in the distal convoluted tubule. 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. 

Amlodipine
Amlodipine is a calcium ion influx inhibitor and inhibits the transmembrane influx of calcium ions into cardiac and vascular smooth muscle. Amlodipine dilates peripheral arterioles and thus reduces afterload, it also dilates coronary arteries and arterioles which increases myocardial oxygen delivery.

COMBINATION PREPARATIONS

Perindopril/ Indapamide/ Amlodipine

Film-coated tablet 5mg/1.25mg/5mg

• Triplixam (Servier Laboratories SA)

Film-coated tablet 5mg/1.25mg/10mg

• Triplixam (Servier Laboratories SA)

Film-coated tablet 10mg/2.5mg/5mg

• Triplixam (Servier Laboratories SA)

Film-coated tablet 10mg/2.5mg/10mg

• Triplixam (Servier Laboratories SA)