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VECTORYL® 4mg tablet. ; VECTORYL® 8mg tablet.
VECTORYL® 4mg tablet.
VECTORYL® 8mg tablet.
SCHEDULING STATUS:
S3
PROPRIETARY NAME
(and dosage form):
VECTORYL® 4mg tablet.
VECTORYL® 8mg tablet.
COMPOSITION:
Each Vectoryl® 4mg tablet contains 4mg perindopril, tert-butylamine salt.
Each Vectoryl® 8mg tablet contains 8mg perindopril, tert-butylamine salt.
PHARMACOLOGICAL CLASSIFICATION:
A 7.1.3 Other hypotensives.
PHARMACOLOGICAL ACTION:
Vectoryl® (perindopril) is a specific non-sulphydryl competitive angiotensin-1 converting enzyme (ACE) inhibitor. Perindopril acts through its active metabolite, perindoprilat. The other metabolites are pharmacologically inactive.
Following oral administration, the absorption of perindopril is rapid (peak concentration is reached 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.
Elimination of perindoprilat is slower in the elderly, as well as in patients with cardiac failure or renal failure. In such patients, dosage adjustment should be applied in relation to the degree of reduction in creatinine clearance.
Reduction in blood pressure in patients treated with perindopril was accompanied by a reduction in peripheral resistance, with no significant changes in heart rate or glomerular filtration rate. An increase in the compliance of large arteries was also observed, suggesting a direct effect on arterial smooth muscle, consistent with the results of animal studies.
INDICATIONS:
Vectoryl® 4mg is indicated in mild to moderate hypertension and in congestive heart failure not adequately controlled by conventional therapy with diuretics and digitalis in whom vasodilatation is indicated.
Vectoryl® 8mg is indicated in mild to moderate hypertension.
CONTRA-INDICATIONS:
Pregnancy:
(see Warnings and Pregnancy and Lactation).
Children:
The safety in children has not been established.
Lactation:
The safety of Vectoryl® during lactation has not been established.
Hypersensitivity to the product or any of its components.
WARNINGS:
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Should a woman become pregnant while receiving an ACE-inhibitor including Vectoryl®, the treatment must be stopped promptly and switched to a different medicine. Should a woman contemplate pregnancy, the doctor should consider alternative medication. |
INTERACTIONS:
The combination of Vectoryl® with other antihypertensive agents may increase the antihypertensive effect, especially when combined with a diuretic: the effects of ACE-inhibitors may be potentiated in a situation where hypovolaemia may occur. If this is the case, vascular filling by perfusion of isotonic saline solution should be carried out.
Potassium sparing diuretics or potassium supplements: ACE-inhibitors attenuate diuretic induced potassium loss. Potassium sparing diuretics e.g. spironolactone, triamterene, amiloride potassium supplements, or potassium containing salt substitutes may lead to significant increases in serum potassium. If concomitant use is indicated because of demonstrated hypokalaemia, they should be used with caution and with frequent monitoring of serum potassium.
Lithium: The concomitant administration of ACE-inhibitors with lithium may reduce the excretion of lithium. Serum lithium levels should be monitored frequently.
Antidiabetic agents: The use of ACE-inhibitors can increase the hypoglycaemic effect in diabetics receiving insulin or sulphonylureas. Hypoglycaemic malaise appears to be very rare (improved glucose tolerance leading to reduction in insulin or sulphonylurea requirements).
Narcotic drugs/Antipsychotics: Postural hypotension may occur.
Antihypertensive agents: Increase of the hypotensive effect of ACE-inhibitors.
Sympathomimetics: may reduce the antihypertensive effect of ACE-inhibitors; patients should be carefully monitored to confirm that the desired effect is being obtained.
Special populations:
Dosage should be adjusted in the elderly and in patients with renal insufficiency. (see DOSAGE AND DIRECTIONS FOR USE).
PREGNANCY AND LACTATION:
ACE-inhibitors pass through the placenta and can be presumed to cause disturbance in foetal blood pressure regularity 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.
DOSAGE AND DIRECTIONS FOR USE:
Mild to moderate hypertension:
The recommended dosage is a 4mg Vectoryl® tablet, taken orally in the morning before breakfast. This can be increased to a single daily dose of 8mg of Vectoryl® if necessary, after one month of treatment. The tablets should be taken before meals.
In elderly patients and in cardiac failure a substantially lower dosage should be used because of impaired clearance. Insulin and non-insulin dependent diabetics can be treated with the usual doses.
Congestive heart failure:
Treatment should be initiated under close medical supervision. Initial dose of 2mg of Vectoryl® orally as a single dose in the morning, which may, in most instances, be increased to 4mg of Vectoryl® (once blood pressure acceptability has been demonstrated).
Concomitant diuretic therapy in hypertension:
Caution is recommended in patients who are currently being treated with diuretics. As the effects of ACE-inhibitors may be potentiated in a situation where hypovolaemia may occur, the diuretic therapy should be discontinued prior to initiation of therapy with Vectoryl®. In the case of combination with a diuretic, it is not advisable to prescribe a potassium salt or a potassium sparing agent before an assay of blood potassium, and attention should be paid to possible over dosage of the diuretic.
Renal insufficiency:
In patients with renal insufficiency, the dosage of perindopril must be adjusted in relation to the severity of the insufficiency. The following dosages may be recommended:
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Creatinine clearance |
Recommended dosage |
|
Between 30 and 60mL/min |
2mg Vectoryl® per day |
|
Between 15 and 30mL/min |
2mg Vectoryl® every other day |
|
<15mL/min |
2mg Vectoryl® on day of dialysis |
Perindopril is dialysable (70mL/min).
SIDE-EFFECTS AND SPECIAL PRECAUTIONS:
Side effects:
The following side-effects have been observed during treatment with Vectoryl® and ranked under the following frequency:
|
Very common |
>10% (more than 1per 10) |
|
Common |
> 1% and < 10% (less than 1 per 10 but more than 1 per 100) |
|
Uncommon |
0,1% to 1% (less than 1 per 100 but more than 1 per 1000) |
|
Rare |
0,01% to 0,1% (less than 1 per 1000 but more than 1 per 10000) |
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Very rare |
Up to 0,01% (less than 1 per 10000 including isolated reports) |
Psychiatric disorders:
Uncommon: mood or sleep disturbances.
Nervous system disorders:
Common: headache, dizziness, vertigo and paraesthesia.
Very rare: confusion.
Eye disorders:
Common: visual disturbances.
Ear and labyrinth disorders:
Common: tinnitus.
Cardio-vascular disorders:
Common: hypotension and effects related to hypotension.
Very rare: arrhythmia, angina pectoris, myocardial infarction and stroke, possibly secondary to excessive hypotension in high-risk patients.
Respiratory, thoracic and mediastinal disorders:
Common: cough and dyspnoea.
Uncommon: bronchospasm.
Very rare: eosinophilic pneumonia and rhinitis.
Gastro-intestinal disorders:
Common: nausea, vomiting, abdominal pain, taste disturbance, dyspepsia, diarrhoea and constipation.
Uncommon: dry mouth.
Very rare: pancreatitis.
Hepato-biliary disorders:
Very rare: hepatitis either cytolytic or cholestatic.
Skin and subcutaneous tissue disorders:
Common: rash and pruritus.
Uncommon: angioedema of face, lips, mucous membranes, tongue, glottis and/or larynx, extremities and urticaria.
Very rare: erythema multiforme.
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:
Common: asthenia
Uncommon: sweating
Blood and the lymphatic system disorders:
Decreases in haemoglobin, haematocrit, thrombocytopenia, leucopenia/neutropenia and cases of agranulocytosis or pancytopenia, have been reported very rarely. Also very rare, are cases in patients with a congenital deficiency of G-6PDH, of haemolytic anaemia reported.
Laboratory investigations:
In the presence of renal insufficiency, severe heart failure and renovascular hypertension there may be an increase in blood urea, plasma creatinine and hyperkalaemia, but it is reversible on discontinuation of the medication. Elevation of liver enzymes and serum bilirubin has rarely been reported.
Special precautions:
Angioneurotic oedema of the face, extremities, lips, tongue and glottis or larynx has been reported with angiotensin converting enzyme-inhibitors. In such cases Vectoryl® should be discontinued and appropriate medical measures taken immediately.
Hypotensionhas been reported in patients commencing treatment with ACE-inhibitors. This usually occurs in patients on multiple or high-dose diuretics with hypovolaemia; hyponatraemia; pre-existing hypotension; patients with unstable cardiac failure; renal impairment; those on high-dose vasodilator therapy, patients aged 70years and over, dietary salt restriction, dialysis, diarrhoea and vomiting. If hypotension occurs, the patient should be placed in the supine position and if necessary, given an intravenous infusion of normal saline.
Patients with renovascular hypertension:
There is an increased risk of severe hypotension and renal insufficiency when patients with renovascular hypertension and pre-existing bilateral renal artery stenosis or stenosis of the artery to a solitary kidney, are treated with ACE-inhibitors. Treatment with diuretics may be a contributory factor. Loss of renal function may occur with only mild changes in serum creatinine, even in patients with unilateral renal artery stenosis. In these patients, treatment should be started in hospital under close medical supervision with low doses and careful dose titration. Diuretic treatment should be discontinued and renal function should be monitored during the first weeks of therapy.
Patients with renal insufficiency:
Changes in renal function may be anticipated in susceptible individuals, due to the inhibition of the renin-angiotensin-aldosterone system. Therefore ACE-inhibitors should be used with caution in patients with renal insufficiency, as they may require reduced or less frequent doses. Close monitoring of renal function during therapy, should be performed as deemed appropriate in patients with renal insufficiency. Renal failure has been reported in association with ACE-inhibitors, mainly in patients with severe heart failure or underlying renal disease, including renal artery stenosis. Some patients have developed increases in blood urea and creatinine concentrations when a diuretic is given concomitantly. Dosage reduction of the ACE-inhibitor and/or discontinuation of the diuretic may be required. It is recommended that renal function be monitored during the first weeks of therapy.
Anaphylactic reactions during Membrane Exposure:
There have been reports of patients experiencing sustained, life-threatening anaphylactic reactions while receiving ACE-inhibitors during dialysis with high-flux membranes or low-density lipoprotein (LDL) apheresis with dextran sulphate adsorption. ACE-inhibitors should be avoided in patients undergoing dialysis with high-flux membranes or LDL apheresis with dextran sulphate adsorption. However, these reactions could be prevented by temporary withdrawal of the ACE-inhibitor for at least 24 hours before treatment in patients who require both ACE-inhibitors and LDL apheresis.
Anaphylactic reactions during desensitisation:
There have been isolated reports of patients experiencing sustained, life-threatening anaphylactic reactions while receiving ACE-inhibitors during desensitisation treatment with hymenoptera (bee, wasp) venom. ACE-inhibitors should be used with caution in allergic patients receiving desensitisation treatment, and avoided in those undergoing venom immunotherapy. However, these reactions could be prevented by temporary withdrawal of the ACE-inhibitor for at least 24hours before treatment in patients who require both ACE inhibitors and desensitisation.
Hyperkalaemia may occur during treatment with an ACE-inhibitor, especially in the presence of renal insufficiency and/or heart failure. Potassium supplements or potassium-sparing diuretics are generally not recommended, since they may lead to significant increases in plasma potassium. If concomitant use of the above mentioned agents is deemed appropriate, they should be used with frequent monitoring of serum potassium.
Patients with severe impaired liver functionmay develop elevated plasma levels of ACE-inhibitors.
Patients with aortic stenosis/hypertrophic cardiomyopathy:
ACE-inhibitors should be used with caution in patients with an obstruction in the outflow tract of the left ventricle (increased risk of decreased coronary perfusion).
Surgery/Anaesthesia:
In patients undergoing major surgery, or during anaesthesia with agents that produce hypotension, perindopril blocks angiotensinII formation secondary to compensatory renin release. If hypotension occurs, and is considered to be due to this mechanism, it can be corrected by volume expansion.
Clinical Laboratory Test Findings:
Decreases in haemoglobin and hematocrit have been reported at the start of treatment. A rise in plasma potassium has been reported, especially in the presence of renal insufficiency and/or heart failure.
Increases in blood urea and plasma creatinine may occur in the presence of renal insufficiency, severe heart failure and renovascular hypertension, but are reversible on discontinuation of treatment.
Neutropenia/Agranulocytosis: have been caused by ACE-inhibitors. Periodic monitoring of white blood cells should be considered, especially in patients with collagen vascular disease, and therapy with immune suppressive agents. Neutropenia is reversible after discontinuation of the ACE-inhibitor.
Proteinuria: This may occur particularly in patients with existing renal function impairment, or on relatively high doses of ACE-inhibitors.
KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT:
Expected symptoms and signs would be linked to hypotension. Apart from gastric washout, administering of an intravenous infusion of isotonic saline solution is recommended. Perindopril is dialysable (70mL/min). Further treatment is symptomatic and supportive.
IDENTIFICATION:
Vectoryl® 4mg: White rod-shaped tablets, scored on both sides.
Vectoryl® 8mg: Green, round, biconvex, uncoated tablets engraved with a heart on one face and a logo on the other face.
PRESENTATION:
In blister packs of 30tablets overwrapped with laminated foil sachet with desiccant.
STORAGE INSTRUCTIONS:
Store below 25ºC in a dry place.
Keep out of reach of children.
REGISTRATION NUMBER:
Vectoryl® 4mg: 34/7.1.3/0480
Vectoryl® 8mg: 38/7.1.3/0116
NAME AND BUSINESS ADDRESS OF THE APPLICANT
Biogaran South Africa (Pty) Ltd
Devcon Park
7 Autumn Street
Rivonia
2191
DATE OF PUBLICATION OF THIS PACKAGE INSERT:
7 April 2006
Updated on this site: December 2008
Source: Pharmaceutical Industry |
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