Aprovel 150 mg tablets: Each tablet contains 150 mg irbesartan.
Aprovel 300 mg tablets: Each tablet contains 300 mg irbesartan.
Pharmacology: Pharmacodynamics: Mechanism of Action: Irbesartan is a specific insurmountable antagonist of angiotensin II receptors (AT1 subtype). Angiotensin II is an important component of the renin-angiotensin system and is involved in the pathophysiology of hypertension and in sodium homeostasis. Irbesartan does not require metabolic activation for its activity.
Irbesartan blocks the potent vasoconstrictor and aldosterone-secreting effects of angiotensin II by selective antagonism of the angiotensin II (AT1 subtype) receptors localized on vascular smooth muscle cells and in the adrenal cortex. It has no agonist activity at the AT1 receptor and a much greater affinity (more than 8500-fold) for the AT1 receptor than for the AT2 receptor (a receptor that has not been shown to be associated with cardiovascular homeostasis).
Irbesartan does not inhibit enzymes involved in the renin-angiotensin system [ie, renin, angiotensin converting enzyme (ACE)] or affect other hormone receptors or ion channels involved in the cardiovascular regulation of blood pressure and sodium homeostasis. Irbesartan blockade of AT1 receptors interrupts the feedback loop within the renin-angiotensin system, resulting in increases in plasma renin levels and angiotensin II levels. Aldosterone plasma concentrations decline following irbesartan administration, however, serum potassium levels are not significantly affected (mean increase of <0.1 mEq/L) at the recommended doses. Irbesartan has no notable effects on serum triglycerides, cholesterol or glucose concentrations. There is no effect on serum uric acid or urinary uric acid excretion.
Clinical Efficacy/Clinical Studies: The blood pressure-lowering effect of irbesartan is apparent after the first dose and substantially present within 1-2 weeks, with the maximal effect occurring by 4-6 weeks. In long-term follow-up studies, the effect of irbesartan was maintained for over one year.
Once-daily doses of up to 900 mg provided dose-related decreases in blood pressure. Doses of 150-300 mg once daily lower supine or seated blood pressures at trough (ie, 24 hours after dosing) by an average of 8-13/5-8 mmHg (systolic/diastolic) greater than those associated with placebo. The trough effects are 60-70% of the corresponding peak diastolic and peak systolic responses. Optimal effects on 24-hour blood pressure are achieved with once daily dosing.
Blood pressure is lowered to about the same extent in both standing and supine positions. Orthostatic effects are infrequent, but as with ACE inhibitors, may be expected to occur in patients who are sodium-depleted and/or volume-depleted.
The blood pressure-lowering effects of irbesartan and thiazide-type diuretics are additive. In patients not adequately controlled by irbesartan alone, the addition of a low dose of hydrochlorothiazide (12.5 mg) to irbesartan once daily results in a further placebo-adjusted blood pressure reduction at trough of 7-10/3-6 mmHg (systolic/diastolic).
The effectiveness of irbesartan is not influenced by age or gender. As is the case with other drugs that affect the renin-angiotensin system, black patients have notably less response to irbesartan monotherapy. When irbesartan is administered concomitantly with low-dose hydrochlorothiazide (eg, 12.5 mg daily), the antihypertensive response in black patients approaches that of white patients.
After withdrawal of irbesartan, blood pressure gradually returns toward baseline. Rebound hypertension has not been observed.
Hypertension and type 2 diabetic renal disease: The Irbesartan Diabetic Nephropathy Trial (IDNT) was a multicenter, randomized, controlled, double-blind, morbidity and mortality trial comparing Aprovel, amlodipine and placebo. In 1715 hypertensive patients with type 2 diabetes (proteinuria ≥900 mg/day and serum creatinine 1.0 - 3.0 mg/dL) the long-term effects (mean 2.6 years) of Aprovel on the progression of renal disease and all-cause mortality were examined. In addition, a secondary endpoint, the effect of Aprovel on the risk of fatal or non-fatal cardiovascular events was assessed. Patients were randomized to receive AVAPRO 75 mg, amlodipine 2.5 mg, or matching placebo once-daily. Patients were then titrated to a maintenance dose of 300 mg AVAPRO, 10 mg amlodipine, or placebo as tolerated. Aprovel demonstrated a 20% relative risk reduction in the composite primary endpoint (first occurrence of any of the following: doubling of serum creatinine, end-stage renal disease or all-cause mortality) compared to placebo (p=0.024) and a 23% relative risk reduction compared to amlodipine (p=0.006). Similar blood pressure was achieved in the Aprovel and amlodipine groups. There was no significant difference in the assessment of fatal or non-fatal cardiovascular events (cardiovascular death, non-fatal myocardial infarction, hospitalization for heart failure, permanent neurologic deficit attributed to stroke, or above-the-ankle amputation) among the three treatment groups.
The effects of irbesartan on renal events were not uniform across all subgroups: they appeared less favorable in women and non-whites. Subgroup analyses are difficult to interpret and it is not known whether these observations represent true differences or chance effects.
The study of the Effects of Irbesartan on MicroAlbuminuria in Hypertensive Patients with Type 2 Diabetes Mellitus (IRMA 2) was a multicenter, randomized, placebo-controlled, double-blind morbidity study conducted in 590 hypertensive patients with type 2 diabetes, microalbuminuria (20-200 mcg/min; 30-300 mg/day) and normal renal function (serum creatinine ≤ 1.5 mg/dL in males and ≤ 1.1 mg/dL in females). The study examined as a primary endpoint the long-term effects (2 years) of Aprovel on the progression to clinical (overt) proteinuria (urinary albumin excretion rate [AER] >200 mcg/min [>300mg/day] and an increase in AER of at least 30% from baseline). In addition, after one and two years of treatment, the effect of Aprovel on the change in overnight AER and the change in 24-hour creatinine clearance was assessed. Aprovel 300 mg demonstrated a 70% relative risk reduction in the development of clinical (overt) proteinuria compared to placebo (p=0.0004). Aprovel 150 mg demonstrated a 39% relative risk reduction in the development of proteinuria compared to placebo (p=0.085). The slowing of progression to clinical (overt) proteinuria was evident as early as three months and continued over the 2-year period. The decline in 24-hour creatinine clearance did not differ significantly among the 3 groups. Regression to normoalbuminuria (<20 mcg/min; <30 mg/day) was more frequent in the Aprovel 300 mg group (34%) than in the placebo group (21%).
Pharmacokinetics: Absorption: Irbesartan is an orally active agent and does not require biotransformation for its activity. Peak plasma concentration occurs at 1.5-2 hours after oral administration. Following oral administration, irbesartan is rapidly and completely absorbed. The absolute oral bioavailability of irbesartan is 60-80%. Food does not affect the bioavailability.
Distribution: Irbesartan is approximately 96% protein-bound in plasma, and has negligible binding to cellular components of blood.
The volume of distribution is 53-93 Liters.
Metabolism: In plasma, unchanged irbesartan accounts for 80-85% of the circulating radioactivity following oral or intravenous administration of 14C irbesartan. Irbesartan is metabolized by the liver via glucuronide conjugation and oxidation. The major circulating metabolite is irbesartan glucuronide (~6%). Irbesartan does not induce nor inhibit isoenzyme CYP3A4. Irbesartan undergoes oxidation primarily by the cytochrome P450 isoenzyme CYP2C9; isoenzyme CYP3A4 has negligible effect. It is not metabolized by, nor does it substantially induce or inhibit, most isoenzymes commonly associated with drug metabolism (ie, CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2D6, or CYP2E1).
Elimination: Irbesartan and its metabolites are excreted by both biliary and renal routes. About 20% of the administered radioactivity after an oral or intravenous dose of 14C irbesartan is recovered in urine with the remainder in the feces. Less than 2% of the dose is excreted in urine as unchanged irbesartan. The terminal elimination half-life (t½) of irbesartan is 11-15 hours. The total body clearance of intravenously administered irbesartan is 157-176 mL/min, of which 3.0-3.5 mL/min is renal clearance. Irbesartan exhibits linear pharmacokinetics over the therapeutic dose range.
Steady-state plasma concentrations are attained within 3 days after initiation of a once-daily dosing regimen. Limited accumulation (<20%) is observed in plasma upon repeated once-daily dosing.
Special Populations: Gender: In male and female hypertensive subjects, higher (11-44%) plasma concentrations of irbesartan were observed in females than in males, although, following multiple dosing, males and females did not show differences in either accumulation or elimination half-life. No gender-specific differences in clinical effect have been observed.
Elderly patients: In elderly (male and female) normotensive subjects (65-80 years) with clinically normal renal and hepatic function, the plasma AUC and peak plasma concentrations (Cmax) of irbesartan are approximately 20%-50% greater than those observed in younger subjects (18-40 years). Regardless of age, the elimination half-life is comparable. No significant age-related differences in clinical effect have been observed.
Hepatic impairment: In patients with hepatic insufficiency due to mild to moderate cirrhosis, the pharmacokinetics of irbesartan are not significantly altered.
Renal impairment: In patients with renal impairment (regardless of degree) and in hemodialysis patients, the pharmacokinetics of irbesartan are not significantly altered. Irbesartan is not removed by hemodialysis.
Race: In black and white normotensive subjects, the plasma AUC and t½ of irbesartan are approximately 20-25% greater in blacks than in whites; the peak plasma concentrations (Cmax) of irbesartan are essentially equivalent.
Aprovel is indicated for the treatment of hypertension. It may be used either alone or in combination with other antihypertensive agents (eg, thiazide diuretics, beta-adrenergic blocking agents, long-acting calcium-channel blocking agents).
Aprovel (irbesartan) is indicated for the treatment of renal disease in patients with hypertension and type 2 diabetes.
General: The usual initial dose of Aprovel is 150 mg once daily. Patients requiring further reduction in blood pressure should have the dose increased to 300 mg once daily.
If blood pressure is not adequately controlled with Aprovel alone, a diuretic (eg, hydrochlorothiazide 12.5 mg daily) or another antihypertensive drug (eg, beta-adrenergic blocking agent, long-acting calcium channel blocking agent) may be added.
In patients with hypertension and type 2 diabetic renal disease, 300 mg of Aprovel once daily is the preferred maintenance dose.
Aprovel may be administered with or without food.
Special Population: Pediatric Patients: Safety and effectiveness in pediatric patients have not been established.
Elderly patients: No dosage reduction is generally necessary in the elderly.
Among patients who received irbesartan in clinical studies, no overall differences in efficacy or safety were observed between older patients (65 years or older) and younger patients.
Hepatic impairment: No dosage reduction is generally necessary in patients with impaired hepatic function (mild to moderate degree).
Renal impairment: No dosage reduction is generally necessary in patients with impaired renal function (regardless of degree).
Patients with intravascular volume depletion: In severely volume-depleted and/or sodium-depleted patients, such as those treated vigorously with diuretics or hemodialysis, the condition should be corrected prior to administration of Aprovel, or a lower initial dose should be considered. If the blood pressure is not adequately controlled, the dose can be increased.
Signs and Symptoms: Experience in adults exposed to doses of up to 900 mg/day for 8 weeks revealed no toxicity. No specific information is available on the treatment of overdosage with Aprovel.
Management: The patient should be closely monitored, and the treatment should be symptomatic and supportive. Suggested measures include induction of emesis and/or gastric lavage. Irbesartan is not removed from the body by hemodialysis.
Aprovel is contraindicated in patients who are hypersensitive to irbesartan or to any other component of the Aprovel formulation.
Do not co-administer Aprovel with aliskiren-containing medicines in patients with diabetes or with moderate to severe renal impairment (glomerular filtration rate [GFR] <60 mL/min/1.73 m2).
Do not co-administer Aprovel with Angiotensin-Converting Enzyme Inhibitors (ACEIs) in patients with diabetic nephropathy.
Intravascular volume depletion: symptomatic hypotension, especially after the first dose, may occur in patients who are volume and/or sodium depleted by vigorous diuretic therapy, dietary salt restriction, diarrhoea or vomiting. Such conditions should be corrected before the administration of Aprovel.
Renovascular hypertension: there is an increased risk of severe hypotension and renal insufficiency when patients with bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney are treated with medicinal products that affect the renin-angiotensin-aldosterone system. While this is not documented with Aprovel, a similar effect should be anticipated with angiotensin-II receptor antagonists.
Renal impairment and kidney transplantation: when Aprovel is used in patients with impaired renal function, a periodic monitoring of potassium and creatinine serum levels is recommended. There is no experience regarding the administration of Aprovel in patients with a recent kidney transplantation.
Hypertensive patients with type 2 diabetes and renal disease: the effects of irbesartan both on renal and cardiovascular events were not uniform across all subgroups, in an analysis carried out in the study with patients with advanced renal disease. In particular, they appeared less favourable in women and non-white subjects (see section Pharmacology under Actions).
Dual blockade of the renin-angiotensin-aldosterone system (RAAS): there is evidence that the concomitant use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren increases the risk of hypotension, hyperkalaemia and decreased renal function (including acute renal failure). Dual blockade of RAAS through the combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is therefore not recommended (see Interactions and Pharmacology under Actions). If dual blockade therapy is considered absolutely necessary, this should only occur under specialist supervision and subject to frequent close monitoring of renal function, electrolytes and blood pressure. ACE-inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy.
Hyperkalaemia: as with other medicinal products that affect the renin-angiotensin-aldosterone system, hyperkalaemia may occur during the treatment with Aprovel, especially in the presence of renal impairment, overt proteinuria due to diabetic renal disease, and/or heart failure. Close monitoring of serum potassium in patients at risk is recommended (see Interactions).
Lithium: the combination of lithium and Aprovel is not recommended (see Interactions).
Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy: as with other vasodilators, special caution is indicated in patients suffering from aortic or mitral stenosis, or obstructive hypertrophic cardiomyopathy.
Primary aldosteronism: patients with primary aldosteronism generally will not respond to antihypertensive medicinal products acting through inhibition of the renin-angiotensin system. Therefore, the use of Aprovel is not recommended.
General: in patients whose vascular tone and renal function depend predominantly on the activity of the renin-angiotensin-aldosterone system (e.g. patients with severe congestive heart failure or underlying renal disease, including renal artery stenosis), treatment with angiotensin converting enzyme inhibitors or angiotensin-II receptor antagonists that affect this system has been associated with acute hypotension, azotaemia, oliguria, or rarely acute renal failure. As with any antihypertensive agent, excessive blood pressure decrease in patients with ischaemic cardiopathy or ischaemic cardiovascular disease could result in a myocardial infarction or stroke.
As observed for angiotensin converting enzyme inhibitors, irbesartan and the other angiotensin antagonists are apparently less effective in lowering blood pressure in black people than in non-blacks, possibly because of higher prevalence of low-renin states in the black hypertensive population (see Pharmacology under Actions).
Lactose: Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Driving A Vehicle Or Performing Other Hazardous Tasks: The effect of irbesartan on ability to drive and use machines has not been studied, but based on its pharmacodynamic properties; irbesartan is unlikely to affect this ability. When driving vehicles or operating machines, it should be taken into account that occasionally dizziness or weariness may occur during treatment of hypertension.
Use in Children: irbesartan has been studied in paediatric populations aged 6 to 16 years old but the current data are insufficient to support an extension of the use in children until further data become available (see Adverse Reactions and Pharmacology: Pharmacokinetics under Actions).
Use in Pregnancy: angiotensin II Receptor Antagonists (AIIRAs) should not be initiated during pregnancy. Unless continued AIIRA therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with AIIRAs should be stopped immediately, and, if appropriate, alternative therapy should be started (see Use in Pregnancy & Lactation).
Pregnancy: When pregnancy is detected, Aprovel should be discontinued as soon as possible (see Precautions).
Lactation: Irbesartan is excreted in the milk of lactating rats. It is not known whether irbesartan or its metabolites are excreted in human milk. A decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of Aprovel to the therapy of the mother and the potential risk to the infant.
In placebo-controlled trials in patients with hypertension, the overall incidence of adverse events did not differ between the irbesartan (56.2%) and the placebo groups (56.5%). Discontinuation due to any clinical or laboratory adverse event was less frequent for irbesartan-treated patients (3.3%) than for placebo-treated patients (4.5%). The incidence of adverse events was not related to dose (in the recommended dose range), gender, age, race, or duration of treatment.
In diabetic hypertensive patients with microalbuminuria and normal renal function, orthostatic dizziness and orthostatic hypotension were reported in 0.5% of the patients (i.e., uncommon) but in excess of placebo.
The following table presents the adverse drug reactions that were reported in placebo-controlled trials in which 1,965 hypertensive patients received irbesartan. Terms marked with a star (*) refer to the adverse reactions that were additionally reported in > 2% of diabetic hypertensive patients with chronic renal insufficiency and overt proteinuria and in excess of placebo.
The frequency of adverse reactions listed as follows is defined using the following convention: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Adverse reactions additionally reported from post-marketing experience are also listed. These adverse reactions are derived from spontaneous reports. (See table.)
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In a randomised trial of 318 hypertensive children and adolescents aged 6 to 16 years, the following adverse reactions occurred in the 3-week double-blind phase: headache (7.9%), hypotension (2.2%), dizziness (1.9%), cough (0.9%). In the 26-week open-label period of this trial the most frequent laboratory abnormalities observed were creatinine increases (6.5%) and elevated CK values in 2% of child recipients.
Reporting of suspected adverse reactions:
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system: www.fda.gov.ph.
Based on in vitro data, no interactions would be expected to occur with drugs whose metabolism is dependent upon cytochrome P450 isoenzymes CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2D6, CYP2E1 or CYP3A4. Irbesartan is primarily metabolized by CYP2C9, however, during clinical interaction studies, no significant pharmacodynamic interactions were observed when irbesartan was coadministered with warfarin (a drug metabolized by CYP2C9). Irbesartan does not affect the pharmacokinetics of digoxin or simvastatin. The pharmacokinetic parameters of irbesartan are not affected by coadministration with nifedipine or hydrochlorothiazide.
The combination of Aprovel with aliskiren-containing medicinal products is contraindicated in patients with diabetes mellitus or moderate to severe renal impairment (GFR <60 mL/min/1.73 m2) and is not recommended in other patients (see Contraindications and Precautions).
Angiotensin-converting enzyme inhibitors (ACEIs): The use of Aprovel in combination with an ACEI is contraindicated in patients with diabetic nephropathy and is not recommended in other patients (see Contraindications and Precautions).
Based on experience with the use of other drugs that affect the renin-angiotensin system, concomitant use of potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium or other medicinal products that may increase kalaemia with irbesartan may lead to increases in serum potassium, sometimes severe, and requires close monitoring of serum potassium.
In patients who are elderly, volume-depleted (including those on diuretic therapy), or with compromised renal function, coadministration of NSAIDs, including selective COX-2 inhibitors, with angiotensin II receptor antagonists, including irbesartan, may result in deterioration of renal function, including possible acute renal failure. These effects are usually reversible. Monitor renal function periodically in patients receiving irbesartan and NSAID therapy. The antihypertensive effect of angiotensin II receptor antagonists, including irbesartan, may be attenuated by NSAIDs including selective COX-2 inhibitors.
Lithium: Increases in serum lithium concentrations and lithium toxicity have been reported with concomitant use of irbesartan. Monitor lithium levels in patients receiving irbesartan and lithium.
Store at temperatures not exceeding 30°C.
C09CA04 - irbesartan ; Belongs to the class of angiotensin II receptor blockers (ARBs). Used in the treatment of cardiovascular disease.
Tab 150 mg (white to off-white, biconvex and oval-shaped with a heart debossed on one side and the number 2872 engraved on the other side) x 28's. 300 mg (white to off-white, biconvex and oval-shaped with a heart debossed on one side and the number 2873 engraved on the other side) x 28's.