Idezar

Pharmacology: Irbesartan is a potent, orally active, selective angiotensin II (type AT₁) receptor antagonist. It blocks all actions of angiotensin II mediated by the AT₁ receptor regardless of the source or route of synthesis of angiotensin II. The selective angiotensin II receptors results in increases in plasma rennin levels and angiotensin II levels, and a decrease in plasma aldosterone concentration. Serum potassium levels are not significantly affected by irbesartan alone at the recommended doses. Irbesartan does not inhibit ACE (kininase II), an enzyme that generates angiotensin II and also degrades bradykinin into inactive metabolites.
Irbesartan decreases blood pressure with minimal change in heart rate. The reduction in blood pressure is dose-related for once daily dose with a tendency towards plateau at doses above 300 mg. Doses of 150 to 300 mg once daily lower supine or seated blood pressure at trough (i.e., 24 hours after dosing) by an average of 8 to 13/5 to 8 mmHg (systolic/diastolic) greater than those associated with placebo.
Peak reduction of blood pressure is observed within 3 to 6 hours after administration and the blood pressure lowering effect is maintained for at least 24 hours. At 24 hours, the reduction of blood pressure was 60 to 70% of the corresponding peak diastolic and systolic response at the recommended doses. Once daily dosing with 150 mg produced trough mean and 24-hour response similar to twice daily dosing on the same total dose. Irbesartan's blood pressure lowering effect is evident within 1 to 2 weeks, with maximal effect occurring by 4 to 6 weeks after start of therapy. After withdrawal of therapy, blood pressure gradually returns toward baseline. Rebound hypertension has not been seen.
The blood pressure lowering effects of irbesartan and thiazide-type diuretics are additive. In patients not adequately controlled by irbesartan alone, the addition of low dose hydrochlorothiazide (12.5 mg) to irbesartan once daily results in a further placebo-adjusted blood pressure reduction at trough of 7 to 10/3 to 6 mmHg (systolic/diastolic).
Irbesartan's efficacy is not influenced by age or gender. As with other medicines that affect the rennin-angiotensin-aldosterone system, black hypertensive patients have notably less reponse to irbesartan monotherapy. When irbesartan is coadministered with low dose hydrochlorothiazide, the antihypertensive response in black patients approaches that of white patients.
There is no effect on serum uric acid or urinary uric acid secretion.
Pharmacokinetics: Bioavailability: Irbesartan does not require biotransformation into an active form. Its oral absorption is rapid and complete with an average absolute bioavailability of 60 to 80%. Peak plasma concentrations are attained at 1.5 to 2 hours after oral administration. Food does not affect irbesartan's bioavailability.
Irbesartan exhibits linear and dose proportional pharmacokinetics over the dose range of 10 to 600 mg; however, the antihypertensive dose-response curve is nonlinear, with proportional small decreases in blood pressure attained with increased dosage. A less than proportional increase in oral absorption at doses beyond 600 mg (which is twice the maximum recommended dose) was observed; the mechanism for this is unknown.
Irbesartan is 96% bound to serum proteins (primarily albumin and α₁-acid glycoprotein), with negligible binding to cellular components of blood. The average volume of distribution is 53 to 93 L. Total plasma and renal clearances are 157 to 176 and 3 to 3.5 mL/min, respectively.
Irbesartan's terminal elimination half-life averaged 11 to 15 hours. Steady-state plasma concentrations are achieved within 3 days after initiation of a once-daily dosing regimen. Limited accumulation of irbesartan (>20%) observed in plasma upon repeated once-daily dosing is not clinically relevant.
Irbesartan is metabolized via glucuronide conjugation and oxidation. More than 80% of the circulating plasma radioactivity is attributable to unchanged irbesartan after oral or intravenous administration of 14C-labeled irbesartan. The primary circulating metabolite is the inactive irbesartan glucuronide conjugate (about 6%). The remaining oxidative metabolites do not add appreciably to irbesartan's pharmacologic activity.
Irbesartan and its metabolites are eliminated by both biliary and renal pathways. After either oral or intravenous administration of 14C-labeled irbesartan, about 20% of radioactivity is recovered in the urine and the remainder in the feces, as irbesartan or irbesartan glucuronide. Less than 2% of the dose is excreted in the urine as unchanged irbesartan.
In vitro studies of irbesartan oxidation by cytochrome P450 isoenzymes showed that irbesartan was oxidized primarily by 2C9; metabolism by 3A4 was negligible. Irbesartan was neither metabolized by, nor did it substantially induce or inhibit, isoenzymes commonly associated with drug metabolism (1A1, 1A2, 2A6, 2B6, 2D6, 2E1). There was no induction or inhibition of 3A4.

Hypertension: For the treatment of hypertension; may be used alone or in combination with other antihypertensive agents.
Nephropathy in Type 2 Diabetic Patients: For the treatment of diabetic nephropathy with an increased serum creatinine and proteinuria (>300 mg/day) in patients with type 2 diabetes and hypertension.
Decreases the progression of nehpropathy as measured by the occurrence of doubling serum creatinine or end stage renal disease (need for dialysis or renal transplantation).

General Dosing Recommendations: Dosing must be individualized and adjusted according to blood pressure response.
May be administered with other antihypertensive agents.
May be taken with or without food.
HYPERTENSION: Initial Dose: 150 mg once a day.
Titrate dose to 300 mg once a day in patient requiring further reduction in blood pressure.
If blood pressure is not controlled by irbesartan alone, a low dose diuretics may be added.
Patients inadequately treated by the maximum dose of 300 mg once a day are unlikely to derive additional benefit from a higher dose or twice a day dosing.
NEPHROPATHY IN TYPE 2 DIABETIC PATIENTS: Initial Dose: 150 mg once a day.
Recommended Maintenance Dose: 300 mg once a day.
Or, as prescribed by a physician.
Dosage in elderly (>75 years old): Dosage adjustment is not usually necessary although consider giving an initial dose of 75 mg once a day.
Dosage in patients with hepatic impairment: No dosage adjustment is necessary in patients with mild to moderate hepatic impairment. There is no clinical experience in patients with severe hepatic impairment.
Dosage in patients with mild to severe renal impairment: No dosage adjustment is necessary.
Dosage in volume- and salt-depleted patients (e.g., patients treated vigorously with diuretics or on hemodialysis): Initial Dose: 75 mg once a day.

Hypersensitivity to any component of the product.
Second and third trimesters of pregnancy.

Fetal/Neonatal Morbidity and Mortality: The use of drugs that act directly on the renin-angiotensin-aldosterone system 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 observed, 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 II receptor antagonist only during the first trimester should be so informed. Discontinue irbesartan as soon as possible when pregnancy is detected.
If oligohydramnios is observed, discontinue irbesartan 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. However, physicians and patients should be aware that oligohydramnios may not appear until after the fetus has sustained irreversible injury.
Infants with history 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 or dialysis may be required as a means of reversing hypotension and/or substituting for disordered renal function.
Hypotension in Volume- or Salt-depleted Patients: Excessive reduction in blood pressure was rarely observed in patients with uncomplicated hypertension. Initiation of antihypertensive therapy may cause symptomatic hypotension in patients with intravascular volume- or sodium-depletion (e.g., those treated vigorously with diuretics or in patients on dialysis). These conditions should be corrected before starting irbesartan therapy, or a lower starting dose should be used.
If hypotension occurs, the patient should be placed in the supine position and, if necessary, administered with intravenous infusion of normal saline. A transient hypotensive response is not a contraindication to further treatment, which usually may be continued without difficulty once the blood pressure has stabilized.
Renal Impairment and Kidney Transplantation: In studies, ACE inhibitors may increase blood urea nitrogen (BUN) and serum creatinine in patients with unilateral or bilateral renal artery stenosis. There has been no known use of irbesartan in patients with unilateral or bilateral renal artery stenosis, but a similar effect should be anticipated.
Periodic monitoring of potassium and creatinine serum levels is recommended when irbesartan is used in patients with impaired renal function.
There is no experience regarding the use of irbesartan in patients with recent kidney transplantation.
Hyperkalemia: Hyperkalemia may occur during irbesartan treatment, especially in the presence of renal impairment, overt proteinuria due to diabetic renal disease, and/or heart failure. Monitor closely serum potassium in patients at risk.
Aortic and Mitral Valve Stenosis, Obstructive Hypertrophic Cardiomyopathy: As with other vasodilators, special caution is indicated in patients suffering from aortic or mitral valve stenosis, or obstructive hypertrophic cardiomyopathy.
Primary Aldosteronism: Generally, patients with primary aldosteronism will not respond to antihypertensive agents acting through inhibition of the renin-angiotensin-aldosterone system; thus, irbesartan use is not recommended.
General: Treatment with drugs that affect the renin-angiotensin-aldosterone system has been associated with acute hypotension, azotemia, oliguria or, rarely, acute renal failure in patients whose vascular tone and renal function depend predominantly on the activity of this system (e.g., patients with severe congestive heart failure or underlying renal disease, including renal artery stenosis). As with any antihypertensive agent, excessive hypotension in patients with ischemic cardiopathy or ischemic cardiovascular disease could result in a myocardial infarction or stroke.
Irbesartan and 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.
Use in Children: Irbesartan 4.5 mg/kg/day, once daily, did not appear to decrease blood pressure effectively in children 6 to 16 years old. Irbesartan has not been studied in children less than 6 years old.
Use in Elderly: There were no age-related differences in efficacy or safety profile of irbesartan, but greater sensitivity of some older individuals cannot be ruled out.

Pregnancy: Pregnancy Categories C (first trimester) and D (second and third trimesters) (see Fetal/Neonatal Morbidity and Mortality under Precautions).
Lactation: It is not known whether irbesartan is distributed in human milk. Discontinue breastfeeding or drug due to potential risk to breastfeeding infants, taking into consideration the importance of the drug to the mother.

Body as a whole: Chills, edema, facial edema, fatigue, fever, influenza, upper extremity edema.
Cardiovascular: Angina pectoris, arrhythmic/conduction disorder, cardiac murmur, cardio-respiratory arrest, cerebrovascular accident, chest pain, flushing, heart failure, hypertension, hypertensive crisis, hypotension, myocardial infarction, orthostatic dizziness, orthostatic hypotension, sinus abnormality, tachycardia, transient ischemic attack.
Endocrine-metabolic, and Laboratory Values: Gout; hyperkalemia; libido change; sexual dysfunction; Elevations of the following: liver function tests, blood urea nitrogen (BUN), serum creatinine; decrease in hemoglobin.
Gastrointestinal: Abdominal distention, abdominal pain, constipation, diarrhea, dysgeusia, dyspepsia, flatulence, gastroenteritis, heartburn, hepatitis, jaundice, nausea, oral lesion, vomiting.
Genitourinary: Abnormal urination, impaired renal function including cases of renal failure, prostate disorder, urinary tract infection.
Hematologic: Neutropenia.
Musculoskeletal: Arthralgia, arthritis, bursitis, extremity swelling, joint stiffness, muscle ache, muscle cramp, muscle weakness, musculoskeletal chest pain, musculoskeletal pain, myalgia (in some cases associated with increased plasma creatine kinase levels), rhabdomyolysis (rare).
Nervous: Anxiety, depression, dizziness, emotional disturbance, headache, nervousness, numbness, paresthesia, sleep disturbance, somnolence, syncope, tremor, vertigo.

Potassium-sparing diuretics/potassium supplements/salt substitutes: May increase serum potassium; thus, coadministration is not recommended.
Lithium: Reversible increases in serum lithium concentrations and toxicity; thus, coadministration is not recommended. If coadministration proves necessary, monitor serum lithium levels carefully.
Nonsteroidal anti-inflammatory drugs [NSAIDs, i.e., selective cyclooxygenase-2 (COX-2) inhibitors, aspirin >3 g/day]: Reduced antihypertensive effect of irbesartan. As with ACE inhibitors, concurrent administration of angiotensin II receptor antagonists with NSAIDs may result in an increased risk of worsening of renal function (including possible acute renal failure) and an increase in serum potassium, particularly in patients with poor pre-existing renal function. The combination should be administered with caution, especially in the elderly. Regularly monitor renal function after initiation of concomitant therapy and adequately hydrate patients.
Other antihypertensive agents: Other antihypertensive agents may increase irbesartan's hypotensive effects; however, irbesartan has been safely given with other antihypertensive agents, such as beta-blockers, long-acting calcium channel blockers, and thiazide diuretics. Prior treatment with high dose diuretics may result in volume-depletion and a risk of hypotension when initiating with irbesartan.
Coadministration of irbesartan with other drugs such as hydrochlorothiazide, digoxin, warfarin, and nifedipine showed no significant drug-drug pharmacokinetic or pharmacodynamic interactions.

Angiotensin II Antagonists

C09CA04 - irbesartan ; Belongs to the class of angiotensin II receptor blockers (ARBs). Used in the treatment of cardiovascular disease.

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