Avapro (Irbesartan)

AVAPRO™

Bristol-Myers Squibb/Sanofi Canada

Irbesartan

Angiotensin II AT1 Receptor Blocker

Action And Clinical Pharmacology: Irbesartan antagonizes angiotensin II by blocking AT1 receptors.

Angiotensin II is the primary vasoactive hormone in the renin-angiotensin system. Its effects include vasoconstriction and the stimulation of aldosterone secretion by the adrenal cortex.

Irbesartan blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II by selectively blocking in a noncompetitive manner the binding of angiotensin II to the AT1 receptor found in many tissues. Irbesartan has no agonist activity at the AT1 receptor. AT2 receptors have been found in many tissues, but to date they have not been associated with cardiovascular homeostasis. Irbesartan has essentially no affinity for the AT2 receptors.

Irbesartan does not inhibit angiotensin converting enzyme, also known as kininase II, the enzyme that converts angiotensin I to angiotensin II and degrades bradykinin, nor does it affect renin or other hormone receptors or ion channels involved in cadiovascular regulation of blood pressure and sodium homeostasis.

Pharmacokinetics: Irbesartan is an orally active agent . The oral absorption of irbesartan is rapid and complete with an average absolute bioavailability of 60 to 80%. Irbesartan exhibits linear pharmacokinetics over the therapeutic dose range with an average terminal elimination half-life of 11 to 15 hours. Following oral administration, peak plasma concentrations are attained at 1.5 to 2 hours after dosing. Steady-state concentrations are achieved within 3 days.

Irbesartan is 90% protein-bound in the plasma, primarily to albumin and a1-acid glycoprotein.

The average volume of distribution of irbesartan is 53 to 93 L. Total plasma and renal clearances are in the range of 157 to 176 and 3 to 3.5 mL/minute, respectively.

Irbesartan is metabolized via glucuronide conjugation, and oxidation by the cytochrome P-450 system. Following either oral or i.v. administration of 4-labeled irbesartan, more than 80% of the circulating plasma radioactivity is attributable to unchanged irbesartan. The primary circulating metabolite is the inactive irbesartan glucuronide (approximately 6%). The remaining oxidative metabolites do not add appreciably to the pharmacologic activity.

Irbesartan and its metabolites are excreted by both biliary and renal routes. Following either oral or i.v. administration of 4-labeled irbesartan, about 20% of radioactivity is recovered in the urine and the remainder in the feces. Less than 2% of the dose is excreted in urine as unchanged irbesartan.

In vitro studies of irbesartan indicate that the oxidation of irbesartan is primarily by cytochrome P-450 isoenzyme CYP 2C9. Metabolism of irbesartan by CYP 3A4 is negligible. Irbesartan is neither metabolized, nor does it substantially induce or inhibit the following isoenzymes: CYP 1A1, 1A2, 2A6, 2B6, 2D6, 2E1. There was no induction or inhibition of CYP 3A4.

In subjects over the age of 65 years, irbesartan elimination half-life was not significantly altered, but AUC and CMAX values were about 20 to 50% greater than those of young subjects.

The mean AUC and Cmax were not altered in patients with any degree of renal impairment, including patients on hemodialysis. However, a wide variance was seen in patients with severe renal impairment.

The pharmacokinetics of irbesartan following repeated oral administration were not significantly affected in patients with mild to moderate cirrhosis of the liver. No data are available in patients with severe liver disease.

Pharmacodynamics: In healthy subjects, single oral doses of irbesartan up to 300 mg produced dose-dependent inhibition of the pressor effect of angiotensin II infusions. The pressor effect of angiotensin II was completely blocked (³90%) at the time of peak irbesartan concentrations; 60% and 40% inhibition persisted for 24 hours following doses of 300 mg and 150 mg, respectively.

In hypertensive patients, angiotensin II receptor inhibition following chronic administration of irbesartan causes a 1.5 to 2 fold rise in angiotensin II plasma concentration and a 2 to 3 fold increase in plasma renin levels. Aldosterone plasma concentrations generally decline following irbesartan administration; however, serum potassium levels are not significantly affected at recommended doses.

During clinical trials, minimal incremental blood pressure response was observed at doses greater than 300 mg.

The blood pressure lowering effect of irbesartan is apparent after the first dose and substantially present within 1 to 2 weeks, with the maximal effect occurring by 4 to 6 weeks. In long-term studies, the effect of irbesartan appeared to be maintained for more than 1 year. There was essentially no change in average heart rate in patients treated with irbesartan in controlled trials.

There is no rebound effect after withdrawal of irbesartan.

Black hypertensive patients had a smaller blood pressure response to irbesartan monotherapy than caucasians.

Indications And Clinical Uses: For the treatment of essential hypertension.

Irbesartan may be used alone or concomitantly with thiazide diuretics.

Irbesartan should normally be used in those patients in whom treatment with diuretic or beta-blocker was found ineffective or has been associated with unacceptable adverse effects. Irbesartan can also be tried as an initial agent in those patients in whom the use of diuretics and/or beta-blockers is contraindicated or in patients with medical conditions in which these drugs frequently cause serious adverse effects.

The safety and efficacy of concurrent use with angiotensin converting enzyme inhibitors have not been established.

Contra-Indications: In patients who are hypersensitive to any component of this product.

Manufacturers’ Warnings In Clinical States: Pregnancy: Drugs that act directly on the renin-angiotensin system can cause fetal and neonatal morbidity and death when administered to pregnant women. When pregnancy is detected, irbesartan should be discontinued as soon as possible.

The use of drugs that act directly on the renin-angiotensin system during the second and third trimesters of pregnancy has been associated with fetal and neonatal injury, including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and death. Oligohydramnios has also been reported, presumably resulting from decreased fetal renal function; oligohydramnios in this setting has been associated with fetal limb contractures, craniofacial deformation, and hypoplastic lung development. Prematurity, intrauterine growth retardation, and patent ductus arteriosus have also been reported, although it is not clear whether these occurrences were due to exposure to the drug. These adverse effects do not appear to have resulted from intrauterine drug exposure that has been limited to the first trimester.

Mothers whose embryos and fetuses are exposed to an angiotensin Il receptor antagonist only during the first trimester should be so informed. Nonetheless, when patients become pregnant, physicians should have the patient discontinue the use of irbesartan as soon as possible.

Rarely (probably less often than once in every thousand pregnancies), no alternative to an angiotensin II receptor antagonist will be found. In these rare cases, the mothers should be apprised of the potential hazards to their fetuses, and serial ultrasound examinations should be performed to assess the intra-amniotic environment.

If oligohydramnios is observed, irbesartan should be discontinued unless it is considered life-saving for the mother. Contraction stress testing (CST), a nonstress test (NST), or biophysical profiling (BPP) may be appropriate, depending upon the week of pregnancy. Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury.

Infants with histories of in utero exposure to an angiotensin II receptor antagonist should be closely observed for hypotension, oliguria, and hyperkalemia. If oliguria occurs, attention should be directed toward support of blood pressure and renal perfusion. Exchange transfusion may be required as means of reversing hypotension and/or substituting for disordered renal function. Irbesartan is not removed by hemodialysis.

Hypotension: Occasionally, symptomatic hypotension has occurred after administration of irbesartan, in some cases after the first dose. It is more likely to occur in patients who are volume depleted by diuretic therapy, dietary salt restriction, dialysis, diarrhea or vomiting. In these patients, because of the potential fall in blood pressure, therapy should be started under close medical supervision (see Dosage). Similar considerations apply to patients with ischemic heart or cerebrovascular disease, in whom an excessive fall in blood pressure could result in myocardial infarction or cerebrovascular accident.

Precautions: Renal Impairment: As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function have been seen in susceptible individuals. In patients whose renal function may depend on the activity of the renin-angiotensin-aldosterone system, such as patients with bilateral renal artery stenosis, unilateral renal artery stenosis to a solitary kidney, or severe congestive heart failure, treatment with agents that inhibit this system has been associated with oliguria, progressive azotemia, and rarely, acute renal failure and/or death. In susceptible patients, concomitant diuretic use may further increase risk.

Use of irbesartan should include appropriate assessment of renal function.

Valvular Stenosis: There is concern on theoretical grounds that patients with aortic stenosis might be at particular risk of decreased coronary perfusion when treated with vasodilators because they do not develop as much afterload reduction.

Lactation: It is not known whether irbesartan is excreted in human milk, but measurable levels of radioactivity was shown to be present in milk of lactating rats. Because many drugs are excreted in human milk, and because of their potential for affecting the nursing infant adversely, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Children: Safety and effectiveness have not been established.

Geriatrics: Of the 4 140 hypertensive patients receiving irbesartan in clinical studies, 793 patients were 65 years of age and over. No overall age-related differences were seen in the adverse effect profile but greater sensitivity in some older individuals cannot be ruled out.

Drug Interactions: Diuretics: Patients on diuretics, and especially those in whom diuretic therapy was recently instituted, may occasionally experience an excessive reduction of blood pressure after initiation of therapy with irbesartan. The possibility of symptomatic hypotension with the use of irbesartan can be minimized by discontinuing the diuretic prior to initiation of treatment and/or lowering the initial dose of irbesartan (see Warnings, Hypotension and Dosage). No drug interaction of clinical significance has been identified with thiazide diuretics.

Agents Increasing Serum Potassium: Since irbesartan decreases the production of aldosterone, potassium-sparing diuretics or potassium supplements should be given only for documented hypokalemia and with frequent monitoring of serum potassium. Potassium-containing salt substitutes should also be used with caution.

Lithium Salts: As with other drugs which eliminate sodium, lithium clearance may be reduced. Therefore, serum lithium levels should be monitored carefully if lithium salts are to be administered.

Warfarin: When irbesartan was administered as 300 mg once daily under steady-state conditions, no pharmacodynamic effect on PT was demonstrated in subjects stabilized on warfarin.

Digoxin: When irbesartan was administered as 150 mg once daily under steady-state conditions, no effect was seen on the pharmacokinetics of digoxin at steady-state.

Adverse Reactions: Irbesartan has been evaluated for safety in more than 4 100 patients with essential hypertension including approximately 1 300 patients for over 6 months and 400 patients for 1 year or more.

In placebo-controlled clinical trials, therapy was discontinued due to a clinical adverse event in 3.3% of patients treated with irbesartan, versus 4.5% of patients given placebo.

The following potentially serious adverse reactions have been reported rarely with irbesartan in controlled clinical trials: syncope, hypotension.

Adverse events occurring in 1% or more of the 2 606 hypertensive patients in placebo-controlled clinical trials include those shown in Table I.

The incidence of hypotension or orthostatic hypotension occurred in 0.4% of irbesartan treated patients, unrelated to dosage, and in 0.2% of patients receiving placebo.

In addition, the following potentially important events occurred in less than 1% of patients receiving irbesartan, regardless of drug relationship: Body as a Whole: fever.

Cardiovascular: flushing, hypertension, myocardial infarction, angina pectoris, arrhythmic/conduction disorder, cardiorespiratory arrest, heart failure, hypertensive crisis.

Dermatologic: pruritus, dermatitis, ecchymosis, erythema, urticaria, photosensitivity.

Endocrine: sexual dysfunction, libido change, gout.

Gastrointestinal: constipation, gastroenteritis, flatulence, distention abdomen, hepatitis.

Musculoskeletal: muscle cramp, arthritis, myalgia, muscle weakness.

Nervous System: sleep disturbance, numbness, somnolence, vertigo, depression, paresthesia, tremor, transient ischemic attack, cerebrovascular accident.

Renal/Genitourinary: abnormal urination.

Respiratory: epistaxis, tracheobronchitis, pulmonary congestion, dyspnea, wheezing.

Special Senses: visual disturbance, hearing abnormality, conjunctivitis, taste disturbance.

Angioedema (involving swelling of the face, lips, and/or tongue) has been reported rarely in postmarketing use.

Laboratory Test Findings: In controlled clinical trials, clinically important differences in laboratory tests were rarely associated with irbesartan.

Liver Function Tests: In placebo-controlled trials, elevations of AST and ALT ³3 times upper limit of normal occurred in 0.1% and 0.2%, respectively, of irbesartan treated patients compared to 0.3% and 0.3%, respectively, of patients receiving placebo. The cumulative incidence of AST and/or ALT elevations ³3 times upper limit of normal was 0.4% in patients treated with irbesartan for a mean duration of over 1 year.

Hyperkalemia: In placebo-controlled trials, greater than a 10% increase in serum potassium was observed in 0.4% of irbesartan treated patients compared to 0.5% of patients receiving placebo.

Creatinine, Blood Urea Nitrogen: Minor increases in blood urea nitrogen (BUN) or serum creatinine were observed in less than 0.7% of patients with essential hypertension treated with irbesartan alone versus 0.9% on placebo.

Hemoglobin: Mean decreases in hemoglobin of 0.16g/dL were observed in patients receiving irbesartan. No patients were discontinued due to anemia.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: No data are available in regard to overdosage in humans. The most likely manifestations of overdosage would be hypotension and/or tachycardia; bradycardia might also occur in this setting.

Irbesartan is not removed by hemodialysis.

Dosage And Administration: Initiation of therapy requires consideration of recent antihypertensive drug treatment, the extent of blood pressure elevation, salt restriction and other pertinent clinical factors. The dosage of other antihypertensive agents used with irbesartan may need to be adjusted.

Irbesartan may be administered with or without food.

The recommended dose is 150 mg once daily. In patients whose blood pressure is not adequately controlled, the daily dose may be increased to 300 mg.

No initial dosage adjustment is required in the elderly or in patients with renal impairment (see Pharmacology, Pharmacokinetics and Precautions, Geriatrics). However, due to the apparent greater sensitivity of hemodialysis patients, an initial dose of 75 mg is recommended in this group of patients.

No initial dosage adjustment is required in patients with mild-to-moderate hepatic impairment (see Pharmacology, Pharmacokinetics).

Concomitant Diuretic Therapy: In patients receiving diuretics, irbesartan therapy should be initiated with caution, since these patients may be volume-depleted and thus more likely to experience hypotension following initiation of additional antihypertensive therapy. Whenever possible, all diuretics should be discontinued 2 to 3 days prior to the administration of irbesartan to reduce the likelihood of hypotension (see Warnings, Hypotension and Precautions, Drug Interactions). If this is not possible because of the patient’s condition, irbesartan should be administered with caution and the blood pressure monitered closely. The recommended starting dose of irbesartan is 75 mg once daily in hypovolemic patients (see Warning, Hypotension). Thereafter, the dosage should be adjusted according to the individual response of the patient.

Availability And Storage: 75 mg: Each white to off-white biconvex, oval tablet, with a heart shape debossed on one side and the digits 2771 on the other, contains: irbesartan 75 mg. Nonmedicinal ingredients: croscarmellose sodium, lactose, magnesium stearate, microcrystalline cellulose, poloxamer 188, pregelatinized starch and silicon dioxide. Bottles of 90.

150 mg: Each white to off-white biconvex, oval tablet, with a heart shape debossed on one side and the digits 2772 on the other, contains: irbesartan 150 mg. Nonmedicinal ingredients: croscarmellose sodium, lactose, magnesium stearate, microcrystalline cellulose, poloxamer 188, pregelatinized starch and silicon dioxide. Bottles of 90.

300 mg: Each white to off-white biconvex, oval tablet, with a heart shape debossed on one side and the digits 2773 on the other, contains: irbesartan 300 mg. Nonmedicinal ingredients: croscarmellose sodium, lactose, magnesium stearate, microcrystalline cellulose, poloxamer 188, pregelatinized starch and silicon dioxide. Bottles of 90.

Store at room temperature (15 to 30°C).

AVAPRO™ Bristol-Myers Squibb/Sanofi Canada Irbesartan Angiotensin II AT1 Receptor Blocker

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