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VECTORYL® PLUS, TABLET

SCHEDULING STATUS:
S3

PROPRIETARY NAME
(and dosage form):

VECTORYL® PLUS, TABLET

COMPOSITION:
Each tablet contains 4 mg of perindopril tert-butylamine salt and 1,25 mg of indapamide.

PHARMACOLOGICAL CLASSIFICATION:
A 7.1.3 Other hypotensives.

PHARMACOLOGICAL ACTION:
Vectoryl® Plus is a combination of perindopril tert-butylamine salt, an angiotensin-converting enzyme inhibitor (ACE-inhibitor), and indapamide, a chlorosulphamoyl diuretic. Perindopril acts through its active metabolite, perindoprilat. The other metabolites are inactive.
Following oral administration the absorption of perindopril is rapid (peak concentration within 1 hour), and relatively complete (plasma-availability above 75%). The peak concentration of perindoprilat, the active metabolite, is reached within 3 to 4 hours and peak pharmacological activity is obtained within 4 to 6 hours.
In terms of trough versus peak blood pressure effect, the trough effect ranges between 75 –100% of peak effects.
Perindopril and perindoprilat both have a low volume of distribution and plasma protein binding is weak. Perindoprilat binds to angiotensin converting enzyme at both plasma and tissue levels. Apart from active perindoprilat, perindopril gives rise to 5 metabolites, all of which are inactive. Perindopril is eliminated in the urine and the half-life of its free fraction is approximately one hour. Breakdown of the bond between perindoprilat and the angiotensin converting enzyme leads to a pharmacodynamic half-life of about 25 hours.
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.

INDICATIONS:
Vectoryl® Plus is indicated for the treatment of essential hypertension, in patients where blood pressure is not adequately controlled and where fixed combination is considered more appropriate than monotherapy.

CONTRA-INDICATIONS:
This medicine is contra-indicated in the following circumstances:

•	Hypersensitivity to perindopril, indapamide or sulphonamides,
•	History of angioneurotic oedema linked to previous ACE-inhibitor therapy,
•	Severe renal failure, serious liver disorder,
•	Hypokalaemia,
•	Pregnancy and lactation (see PREGNANCY AND LACTATION),
•	This medicine should not be used in combination with lithium, potassium salts, potassium-sparing diuretics and certain medicines which can cause heart rhythm disorders (see INTERACTIONS),
•	Bilateral renal artery stenosis or single functioning kidney,
•	Uncompensated cardiac failure.

WARNINGS:

Should a woman become pregnant while receiving an ACE-inhibitor, the treatment must be stopped promptly and switched to a different medicine. Should a woman contemplate pregnancy, the doctor should consider alternative medication.

Linked to perindopril:
Risk of neutropenia/agranulocytosis in immuno-suppressed patients:
The risk of neutropenia appears to be dose related and is dependent on the patient’s clinical status. It is rarely seen in uncomplicated patients but may occur in patients with some degree of renal impairment especially when it is associated with collagen vascular disease, e.g. systemic lupus erythematosus, scleroderma and therapy with immunosuppressive agents. It is reversible after discontinuation of perindopril. However, if Vectoryl® Plus is to be administered to this type of patient, the risk/benefit ratio should be carefully evaluated.
Angioneurotic oedema:
Angioneurotic oedema of the face, extremities, lips, tongue, glottis and/or larynx has been reported rarely in patients receiving treatment with ACE-inhibitors, including perindopril. In such cases, treatment with Vectoryl® Plus should be stopped immediately and the patient should be monitored until the oedema has disappeared.
Angioneurotic oedema combined with laryngeal oedema may be fatal. Involvement of tongue, glottis or larynx may lead to an obstruction of the airways. A subcutaneous injection of adrenaline (epinephrine) at 1:1 000 (0,3 mL to 0,5 mL) should be administered quickly and other appropriate measures taken.
The prescription of Vectoryl® Plus or any other ACE-inhibitor should subsequently not be considered in these patients (see CONTRA-INDICATIONS).
Patients with a previous history of angioneurotic oedema, which was not linked to taking an ACE-inhibitor, have an increased risk of angioneurotic oedema with Vectoryl® Plus.
Linked to indapamide:
When liver function is impaired, thiazide diuretics and thiazide-related diuretics may cause hepatic encephalopathy. Administration of Vectoryl® Plus should be stopped immediately if this occurs.

INTERACTIONS:
Linked to Vectoryl® Plus:
Lithium:
An increase in lithium levels may occur. If the combination of an ACE-inhibitor and a potassium-sparing diuretic is unavoidable, strict monitoring of lithium levels and adjustment of the dose are necessary.
Antidiabetic agents (insulin, hypoglycaemic sulphonamides):
The use of Vectoryl® Plus may increase the hypoglycaemic effect in diabetics receiving treatment with insulin or with hypoglycaemic sulphonamides.
Baclofen:
Potentiation of antihypertensive effect.
N.S.A.I.D. (systemic route), high-dose salicylates:
Acute renal insufficiency in dehydrated patients (reduction in glomerular filtration). The patient should be well hydrated; renal function should be monitored at the start of treatment.
Tricyclic antidepressants, neuroleptics:
Increased antihypertensive effect and increased risk of orthostatic hypotension (additive effect).
Corticosteroids, tetracosactide:
Reduction in antihypertensive effect (salt and water retention due to corticosteroids).

Linked to perindopril:
Potassium-sparing diuretics (spironolactone, triamterene, alone or in combination), potassium salts):
Increased levels of potassium (potentially lethal), particularly in cases of renal insufficiency (addition of potassium-sparing effects). Potassium-raising agents should not be combined with Vectoryl® Plus, except when potassium levels are low. (See CONTRA-INDICATIONS.)
Anaesthetic agents:
Vectoryl® Plus may enhance the hypotensive effects of certain anaesthetic drugs.
Allopurinol, cytostatic or immunosuppressive agents, systemic corticosteroids or procainamide:
Concomitant administration with Vectoryl® Plus may lead to an increased risk for leucopenia.
Antihypertensive agents:
Increase of the hypotensive effect of Vectoryl® Plus.

Linked to indapamide:
Non anti-arrhythmic drugs which prolong the QT interval or cause torsades de pointes (erythromycin, halofantrine, pentamidine, terfenadine):
Torsades de pointes (low potassium levels are a risk, as are bradycardia and pre-existing long QT interval).
N.S.A.I.D., high-dose salicylates:
Possible reduction in the antihypertensive effect of indapamide.
Acute renal insufficiency in dehydrated patients (reduction in glomerular filtration).
Hydrate the patient, monitor renal function at the start of the treatment.
Potassium-lowering medicines: amphotericin B (IV route), glucocorticoids and mineralocorticoids, tetracosactide, stimulant laxatives:
Increased risk of low potassium levels (additive effect).
Monitoring of potassium levels, and correction if necessary.
Cardiac glycosides:
Low potassium levels favour the toxic effects of cardiac glycosides.
Potassium levels and ECG should be monitored and treatment reconsidered if necessary.
Potassium-sparing diuretics (amiloride, spironolactone, triamterene):
Potassium levels and ECG should be monitored and treatment reconsidered if necessary.
Anti-arrhythmic drugs, which produce torsades de pointes: Class IA anti-arrhythmic agents (quinidine, hydroquinidine, disopyramide), amiodarone, sotalol:
Torsades de pointes (low potassium levels are a risk factor, as are bradycardia and a pre-existing long QT interval). Prevention of low potassium levels and correction if necessary: monitoring of the QT interval.
Metformin:
Lactic acidosis due to metformin caused by possible functional renal insufficiency linked to diuretics and in particular to loop diuretics. Do not use metformin when plasma creatinine levels exceed 15 mg/L (135 micromol/L) in men and 12 mg/L (110 micromol/L) in women.
Iodinated contrast media:
In cases of dehydration caused by indapamide, there is an increased risk of acute renal insufficiency, particularly when high doses of iodinated contrast media are used.
Rehydration should be carried out before the iodinated compound is administered.
Calcium (salts):
Risk of increased levels of calcium due to reduced elimination of calcium in the urine.
Ciclosporin:
Risk of increased creatinine levels with no change in circulating levels of ciclosporin, even when there is no salt and water depletion.
Corticosteroids, tetracosactide (systemic route):
Reduction in antihypertensive effect (salt and water retention due to corticosteroids).

PREGNANCY AND LACTATION:
Vectoryl® Plus passes through the placenta and can be presumed to 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 skull ossification have been observed. Prematurity and low birth mass can occur.

DOSAGE AND DIRECTIONS FOR USE:
The dosage regimen depends upon the individual requirements of the patient and is at the discretion of the medical doctor.
One Vectoryl® Plus tablet per day as a single dose, preferably to be taken in the morning before a meal.
Elderly:
It is recommended to start the treatment with only one of the constituents.
Patients with renal failure:
In cases of severe renal failure (creatinine clearance below 30 mL/min), treatment is contra-indicated.
In patients with a creatinine clearance greater than or equal to 30 mL/min and less than 60 mL/min, it is recommended to start the treatment with only one of the constituents. It is not necessary to change the dose when the creatinine clearance is greater than 60 mL/min.

SIDE-EFFECTS AND SPECIAL PRECAUTIONS:
Side-effects:
Gastro-intestinal tract:

•	Common (> 1/100, < 1/10):
	Constipation, dry mouth, nausea, epigastric pain, anorexia, abdominal pains, taste disturbance.
•	Very rare (< 1/10 000): pancreatitis.
	In case of hepatic insufficiency, there is a possibility of onset of hepatic encephalopathy.

Respiratory system:

•	Common (> 1/100, < 1/10):
	A dry cough has been reported with the use of angiotensin converting enzyme 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.

Cardio-vascular system:

•	Uncommon (> 1/1 000, < 1/100):
	Hypotension whether orthostatic or not.

Skin appendages:

•	Uncommon (> 1/1 000, < 1/100):
	Hypersensitivity reactions, mainly dermatological, in subjects with a predisposition to allergic and asthmatic reactions. Maculopapular eruptions, purpura, possible aggravation of pre-existing acute disseminated lupus erythematosus. Skin rash.
•	Very rare (< 1/10 000):
	Angioneurotic oedema (Quincke’s oedema).

Nervous system:

•	Uncommon (> 1/1 000, < 1/100):
	Headache, asthenia, feelings of dizziness, mood disturbances and/or sleep disturbances.

Muscular system:

•	Uncommon (> 1/1 000, < 1/100):
	Cramps, paraesthesia.

Haemolytic system:

•	Very rare (< 1/10 000):
	Thrombocytopenia, leucopenia, agranulocytosis, aplastic anaemia, hemolytic anaemia. Anaemia has been reported with angiotensin converting enzyme inhibitors in specific circumstances (patients who have had kidney transplants, patients undergoing haemodialysis).

Laboratory parameters:

•	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. Indapamide may precipitate secondary gout.
•	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 transient.
•	Rare (> 1/10 000, < 1/1 000):
	Raised plasma calcium levels.

Special precautions:
This medicine should be used with caution in the following circumstances:

•	Disorders of electrolyte balance, diabetes, gout, hypotension or strict sodium-free diets.
•	Heart or kidney failure, atherosclerosis, renal artery stenosis.
•	Elderly.
•	Surgery.

The treatment may be monitored by blood tests. The normal medical practice includes periodic testing for creatinine and potassium.
A dry cough may occur. In such cases, medical advice is necessary for assessing whether the treatment should be continued.
Angioneurotic oedema of the face, extremities, lips, tongue and glottis or larynx has been reported with ACE-inhibitors. In such cases, Vectoryl® Plus should be discontinued and appropriate medical measures taken immediately.

Linked to Vectoryl® Plus:
Renal insufficiency:
In cases of severe renal insufficiency (creatinine clearance < 30 mL/min), treatment is contra-indicated.
In patients without pre-existing apparent renal lesions and for whom renal blood tests show functional renal insufficiency, treatment should be stopped and possibly restarted with one constituent only.
In these patients usual medical follow-up will include frequent monitoring of potassium and creatinine, after two weeks of treatment and then every two months during the therapeutic stability period.
Renal failure has been reported mainly in patients with severe heart failure or underlying renal failure including renal artery stenosis.
Hypotension and water and electrolyte depletion:
There is a risk of sudden hypotension in the presence of pre-existing sodium depletion (in particular in individuals with renal artery stenosis). Therefore, systematic testing should be carried out for 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 intravenous infusion of isotonic saline. Transient hypotension is not a contra-indication to continuation of treatment. After re-establishment of a satisfactory blood volume and blood pressure, treatment can be started again with only one 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. Regular monitoring of plasma potassium levels should be carried out.

Linked to 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.
Children:
The efficacy and safety of perindopril in children, alone or in combination has not been established.
Risk of arterial hypotension and/or renal insufficiency (in cases of cardiac insufficiency, water and electrolyte depletion, etc.):
Blocking the renin-angiotensin-aldosterone system with an ACE-inhibitor may cause, particularly at the time of the first administration and during the first two weeks of treatment, a sudden drop in blood pressure 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 with only one of the constituents and increased progressively.
Elderly:
Renal function and potassium levels should be 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.
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 with only one of the constituents.
Renovascular hypertension:
The treatment of 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 should be started in a hospital setting with only one of the constituents 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 only one of the constituents. Treatment with beta-blockers in hypertensive patients with coronary insufficiency should not be stopped: the ACE-inhibitor should be added to the beta-blocker.
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 if initial values were high. This reduction is slight, occurs within 1 to 6 months, and then remains stable. It is reversible when treatment is stopped. Treatment can be continued with regular haematological testing.
Surgery:
Perindopril may precipitate hypotension during general anaesthesia. It is therefore recommended that treatment with perindopril should be discontinued where possible two days before surgery.
Aortic stenosis/hypertrophic cardiomyopathy:
ACE-inhibitors should be used with caution in patients with an obstruction in the outflow tract of the left ventricle.

Linked to indapamide:
Water and electrolyte balance:
Indapamide may cause electrolyte imbalances.
Sodium levels:
Indapamide treatment can cause a reduction in sodium levels, which may have serious consequences.
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 such as 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 torsades de pointes, which may be fatal.
In all cases more frequent testing of potassium levels is necessary. The first measurement of plasma potassium levels should be carried out during the first 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 the urinary excretion of calcium and cause a mild and transient increase in plasma calcium levels. Marked raised levels of calcium may be related to undiagnosed hyperparathyroidism. In such cases 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.
Renal function and diuretics:
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:
clcr = (140 –age) x body weight/0,814 x plasma creatinine level

with:	age expressed in years
	body weight in kg
	plasma creatinine level in micromol/L

This formula is suitable for an elderly male 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 pre-existing renal insufficiency.
Drivers and people operating machinery:
Individual reactions related to a reduction in blood pressure may occur in some patients. As a result, the ability to drive or operate machinery may be impaired.
Athletes:
Athletes should be aware that this product contains indapamide, which may give a positive reaction in drug tests.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT:
The most likely adverse event in case of overdose 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 levels, low potassium levels) may occur.
The first measures to be taken consist of rapidly eliminating 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.

IDENTIFICATION:
White, 8 mm x 4 mm rod-shaped tablets.

PRESENTATION:
Blister packs of clear PVC and aluminium with 30 tablets overwrapped with a laminated foil sachet with desiccant in a carton box.

STORAGE INSTRUCTIONS:
Store below 30ºC in a dry place.
Keep out of reach of children.

REGISTRATION NUMBER:
38/7.1.3/0027

NAME AND BUSINESS ADDRESS OF THE HOLDER OF THE CERTIFICATE OF REGISTRATION:
Biogaran South Africa (Pty) Ltd
Devcon Park
7 Autumn Street
RIVONIA
2191

DATE OF PUBLICATION OF THIS PACKAGE INSERT:
3 June 2005

640/3/2008
BRITEPAK

New addition to this site: June 2008
Source: Pharmaceutical Industry
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