|
Provinace
COMPOSITION
Each tablet contains Perindopril erbumine 4 mg.
PHARMACODYNAMICS
Perindopril is an inhibitor of the enzyme that converts
angiotensin I into angiotensin II (Angiotensin Converting Enzyme ACE). The
converting enzyme, or kinase, is an exopeptidase that allows conversion of
angiotensin I into the vasoconstrictor angiotensin II as well as causing the
degradation of the vasodilator bradykinin into an inactive heptapeptide.
Inhibition of ACE results in a reduction of angiotensin II in the plasma,
which leads to increased plasma renin activity (by inhibition of the
negative feedback of renin release) and reduced secretion of aldosterone.
Since ACE inactivates bradykinin, inhibition of ACE also results in an
increased activity of circulating and local kallikrein-kinin systems (and
thus also activation of the prostaglandin system). It is possible that this
mechanism contributes to the blood pressure-lowering action of ACE
inhibitors and is partially responsible for certain of their side effects
(e.g. cough). Perindopril acts through its active metabolite, perindoprilat.
The other metabolites show no inhibition of ACE activity in vitro.
Hypertension – Perindopril is active in all grades of hypertension: mild,
moderate, severe; a reduction in systolic and diastolic blood pressures in
both supine and standing positions is observed. Perindopril reduces
peripheral vascular resistance, leading to blood pressure reduction. As a
consequence, peripheral blood flow increases, with no effect on heart rate.
Renal blood flow increases as a rule, while the glomerular filtration rate (GFR)
is usually unchanged. The antihypertensive activity is maximal between 4 and
6 hours after a single dose and is sustained for at least 24 hours: trough
effects are about 87-100 % of peak effects. The decrease in blood pressure
occurs rapidly. In responding patients, normalisation is achieved within a
month and persists without the occurrence of tachyphylaxis. Discontinuation
of treatment does not lead to a rebound effect. Perindopril reduces left
ventricular hypertrophy. In man, perindopril has been confirmed to
demonstrate vasodilatory properties. It improves large artery elasticity and
decreases the media: lumen ratio of small arteries. An adjunctive therapy
with a thiazide diuretic produces an additive-type of synergy. The
combination of an ACE inhibitor and a thiazide also decreases the risk of
hypokalaemia induced by the diuretic treatment.
Heart failure – Perindopril reduces cardiac work by a decrease in preload
and afterload.
Studies in patients with heart
failure have demonstrated :
- decreased left and right ventricular filling pressures.
- reduced total peripheral vascular resistance.
- increased cardiac output and improved cardiac index.
In comparative studies, the first administration of 2 mg of Perindopril to
patients with mild to moderate heart failure was not associated with any
significant reduction of blood pressure as compared to placebo.
PHARMACOKINETICS
After oral administration, the absorption of perindopril is
rapid and the peak concentration complete within 1 hour. Bioavailability is
65 to 70 %. About 20 % of the total quantity of perindopril absorbed is
converted into perindoprilat, the active metabolite. In addition to active
perindoprilat, perindopril yields five metabolites, all inactive. The plasma
half-life of perindopril is equal to 1 hour. The peak plasma concentration
of perindeprilat is achieved within 3 to 4 hours. As ingestion of food
decreases conversion to perindoprilat, hence bioavailability, PROVINACE
should be administered orally in a single daily dose in the morning before a
meal. The volume of distribution is approximately 0.2 L/kg for unbound
perindoprilat. Protein binding is slight (binding of perindoprilat to
angiotensin converting enzyme is less than 30 %), but is
concentration-dependent. Perindoprilat is eliminated in the urine and the
half-life of the unbound traction is approximately 3 to 5 hours.
Dissociation of perindoprilat bound to angiotensin converting enzyme leads
to an "effective" elimination half-life of 25 hours, resulting in
steady-state within 4 days. After repeated administration, no accumulation
of perindopril is observed. Elimination of perindoprilat is decreased in the
elderly, and also in patients with heart or renal failure. Dosage adjustment
in renal insufficiency is desirable depending on the degree of impairment (creatinine
clearance). Dialysis clearance of perindoprilat is equal to 70ml/min.
Perindopril kinetics are modified in patients with cirrhosis: hepatic
clearance of the parent molecule is reduced by halt. However, the quantity
of perindoprilat formed is not reduced and therefore no dosage adjustment is
required (see also "Dosage and Administration" and "Warnings and
Precautions").
INDICATIONS
Hypertension: Treatment of hypertension
Heart Failure: Treatment of symptomatic heart failure
RECOMMENDED DOSE
It is recommended that PROVINACE is taken once daily in
the morning before a meal. The dose should be individualised according to
the patient profile (see "Warnings and Precautions") and blood pressure
response.
Hypertension – PROVINACE may be used in monotherapy or in combination with
other classes of antihypertensive therapy. The recommended starting dose is
4 mg given once daily in the morning. Patients with a strongly activated
renin-angiotensin-aldosterone system ( in particular, renovascular
hypertension, salt and/ or volume depletion, cardiac decompensation or
severe hypertension) may experience an excessive drop in blood pressure
following the initial dose. A starting dose of 2 mg is recommended in such
patients and the initiation of treatment should take place under medical
supervision. The dose may be increased to 8 mg once daily after one month of
treatment. Symptomatic hypotension may occur following initiation of therapy
with PROVINACE; this is more likely in patients who are being treated
concurrently with diuretics. Caution is therefore recommended since these
patients may be volume and/or salt depleted. It possible, the diuretic
should be discontinued 2 to 3 days before beginning therapy with PROVINACE
(see "Warnings and Precautions"). In hypertensive patients in whom the
diuretic cannot be discontinued, therapy with PROVINACE should be initiated
with a 2 mg dose. Renal function and serum potassium should be monitored.
The subsequent dosage of PROVINACE should be adjusted according to blood
pressure response. If required, diuretic therapy may be resumed. In elderly
patients treatment should be initiated at a dose of 2 mg which may be
progressively increased to 4 mg after one month then to 8 mg if necessary
depending on renal function (see table below).
Symptomatic heart failure – It is recommended that PROVINACE, generally
associated with a non-potassium-sparing diuretic and/or digoxin and/or a
beta blocker, be introduced under close medical supervision with a
recommended starting dose of 2 mg taken in the morning. This dose may be
increased by increments of 2 mg at intervals of no less than 2 weeks to 4 mg
once daily it tolerated. The dose adjustment should be based on the clinical
response of the individual patient. In severe heart failure and in other
patients considered to be at high risk (patients with impaired renal
function and a tendency to have electrolyte disturbances, patients receiving
simultaneous treatment with diuretics and/or treatment with vasodilating
agents), treatment should be initiated under careful supervision
(see"Warnings and Precautions") . Patients at high risk of symptomatic hypotension e.g. patients with
salt depletion with or without hyponatraemia, patients with hypovolaemia or
patients who have been receiving vigorous diuretic therapy should have these
conditions corrected, if possible, prior to therapy with PROVINACE. Blood
pressure, renal function and serum potassium should be monitored closely,
both before and during treatment with PROVINACE (see"Warnings and
Precautions").
1
2
3
4
|
