Avapro 150 mg / Irovel 150 mg
IRBESARTAN
Composition:
Each uncoated tablet contains 150 mg or 300mg of Irbesartan
Clinical Pharmacology
Mechanism of Action:
Angiotensin II is a potent vasoconstrictor formed from angiotensin I in a reaction catalysed by angiotensin-converting enzyme (ACE, kininase II). Angiotensin II is the principle pressor agent of the rennin-angiotensin system (RAS) and also stimulates aldosterone synthesis and secretion by adrenal cortex, cardiac contraction, renal resorption of sodium, activity of sympathetic nervous system, and smooth muscle-cell growth.
Irbesartan is a specific antagonist of AT 1 receptors with a much greater affinity (more than 8500-fold) for the AT 1 receptor than for the AT 2 receptor and no agonist activity. AT 2 receptors are not involved in cardiovascular homeostasis.
Blockade of the AT1 receptor removes the negative feedback of angiotensin II on rennin secretion, but the resulting increases plasma rennin activity and circulating angiotensin II do not overcome the effects of Irbesartan on blood pressure.
Irbesartan does not inhibit ACE or rennin or affect other hormone receptors or ion channels known to be involved in the cardiovascular regulation of blood pressure and sodium homeostasis. Because Irbesartan does not inhibit ACE, it does not affect the response to bradykinin; whether this has clinical relevance is not known.
Pharmacokinetics:
Irbesartan is an orally action agent that does not require biotransformation into an active from. It is rapidly absorbed from the gastro-intestinal tract with an oral bioavailability of 60 to 80%. It undergoes some metabolism in the
liver to inactive metabolites. Peak plasma concentrations of Irbesartan occur 1.5 to 2 hours after an oral dose. Irbesartan is about 90% bound to plasma proteins. It is excreted as unchanged drug and metabolites in the bite and urine. Following oral administration of Irbesartan approximately 20% of the dose is excreted in urine, with less than 2% as unchanged drug. The terminal elimination half-life is about 11 to 15 hours.
In vitro studies of Irbesartan oxidation by cytochrome P450 enzymes indicated that Irbesartan was oxidized primarily by CYP 2C9; metabolism by CYP 3A4 was negligible. Irbesartan was not metabolized by, nor did it substantially induce or inhibit isoenzymes commonly associated with drug metabolism. There was no induction or inhibition of 3A4.
No gender related differences in pharmacokinetics were observed in healthy elderly or in healthy young subjects. In elderly subjects, Irbesartan elimination half-life was not significantly altered, but AUC and Cmax were about 20-50% greater than those of young subjects. However, no dosage adjustment is necessary.
The pharmacokinetics of Irbesartan is not altered in patients with renal impairment or in patient with haemodialysis. Irbesartan is not removed by haemodialysis. No dosage adjustment is necessary in patients with mild to severe renal impairment unless a patient with renal impairment is also volume depleted. The pharmacokinetic of Irbesartan following oral administration was not significantly affected in patients with mild to moderate cirrhosis of the liver. No dosage adjustment is necessary in patients with hepatic insufficiency.
Indications:
Treatment of hypertension. The drug may be sued alone or in combination with other antihypertensive agents.
Contra-indications:
Patients who are hypersensitive to Irbesartan or nay component of the formulation.
Warnings and Precautions:
Keep out of reach of children.
Hypotension in Volume-or Salt – Depleted patients
Excessive reduction of blood pressure is rarely seen in patient with uncomplicated hypertension. Initiation of antihypertensive therapy may cause symptomatic hypotension in patients with intravascular volume-or sodium-depletion (for example in patients treated vigorously with diuretics or in patients on dialysis.) Such volume depletion should be corrected prior to administration of Irbesartan or a low starting dose (75mg) should be used.
If hypotension occurs, the patient should be placed in a supine position and, if necessary, given an intravenous infusion of normal saline. A transient hypertensive response is not a contraindication to further treatment, which usually can be continued without difficulty once the blood pressure has been stabilized.
Pregnancy & Lactation:
Drugs that act directly on rennin-angiotensin system can cause fetol and neonatal and death when administered to pregnant women. Therefore, when pregnancy is detected, Irbesartan should be discontinued as soon as possible.
The sue of drugs that act directly on the rennin-angiotensin system during the second and third trimesters of pregnancy has been associated with foetal and neonatal injury, inclosing hy0potenion, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death. Oligohydramnios has also been reported, presumably resulting from decreased foetal renal function; oligohydramnios has been associated with foetal limb contractures, craniofacial deformation and hypoplastic lung development. Prematurity, intra uterine growth retardation, and patent ductus arterious have also been reported, although it is not clear whether these occurrences were due tot exposure to the drug. It is not known whether Irbesartan is excreted in human milk, nut Irbesartan or some metabolite of Irbesartan is excreted at low concentration in the milk of lactating rats. Because of the potential for adverse effects on the nursing infant, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of drug to the mother.
Drug Interactions:
No significant drug –drug pharmacokinetic or pharmacodynamic interactions have been found in interaction studies with hydrochlorothiazide, digoxin, warfarin, and nifedipine. In vitro studies show significant inhibition of the formation of exidised
Irbesartan metabolites with known cytochrome CVP2C9 substrates/inhibitors sulphenazole, tolbutamide and nifedipine.
Side effects:
Irbesartan has been generally well tolerated in human studies. Adverse events reported are headache, sinus, abnormality, cough, pharyngitis, diarrhea, rhinitis, urinary tract infection, rash, anxiety/ nervousness, and muscle cramp. However, most side effects have been mild and transient in nature and have not required
discontinuation of therapy. Rare case of hypersensitivity reaction occasionally severe (e.g. anaphylaxis) have been reported.
Overdosage:
There is no data available with regard to overdosage in humans. However, daily doses of 900 mg for 8 weeks were well tolerated. The most likely manifestations of overdosage are expected to be hypotension and tachycardia; bradycardia might also occur from overdose. In managing overdose consider the possibilities of multiple drug interactions, drug-drug interactions, and unusual drug kinetics in the patient. Irbesatan is not removed by haemodialysis.
Dosage and Administration:
The recommended initial dose of Irbesartan is 150 mg once daily with or without food. Patients requiring further reduction in blood pressure should be titrated to 300 mg once daily.
A low dose of diuretic may be added, if blood pressure is not controlled by Irbesatan alone. Patients not adequately treated by the maximum dose of 30 mg once daily are unlikely to derive additional benefit from higher dose or twice-daily dosing.
No dosage adjustment is necessary in elderly patients or in patients with hepatic impairment or mild to severe renal impairment.
The dug may be administered with other antihypertensive agent.
Volume and salt depleted patients:
A lower initial doe or Xarb 75 mg is recommended in patients with depletion of intravascular volume or salt ( for example, patients treated vigorously with diuretics or on haemodialysis).
