RiteMED Irbesartan

RiteMED Irbesartan 150 mg Film-Coated Tablet: White to off-white, oval, film-coated tablet debossed with "J" on one side and "150" on the other side.
RiteMED Irbesartan 300 mg Film-Coated Tablet: White to off-white, oval, film-coated tablet debossed with "J" on one side and "300" on the other side.
Each film-coated tablet contains: Irbesartan 150 mg or 300 mg.

Angiotensin II Antagonist.
Pharmacology: Pharmacodynamics: 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 antagonism of the angiotensin II receptors results in increases in plasma renin 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 angiotensin-converting enzyme (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 doses with a tendency towards plateau at doses above 300 mg. Doses of 150 to 300 mg once daily lower supine or seated blood pressures 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 responses at the recommended doses. Once daily dosing with 150 mg produced trough and mean 24-hour responses 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 renin-angiotensin-aldosterone system, black hypertensive patients have notably less response 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: 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. 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 a day dosing regimen. Limited accumulation of irbesartan (<20%) observed in plasma upon repeated once a day 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.
Special Populations: Geriatric: In elderly subjects 65 to 80 years old, irbesartan elimination half-life was not significantly altered, but AUC and C_max values were about 20 to 50% greater than those of young subjects 18 to 40 years old.
Renal Insufficiency: The pharmacokinetics of irbesartan was not altered in patients with renal impairment or in patients on hemodialysis. No dosage adjustment is necessary in patients with mild to severe renal impairment unless a patient with renal impairment is also volume depleted.
Hepatic Insufficiency: The pharmacokinetics of irbesartan after repeated oral administration was not significantly affected in patients with mild to moderate liver cirrhosis. No dosage adjustment is necessary in patients with hepatic insufficiency.

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 nephropathy 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. (See table.)

Click on icon to see table/diagram/image

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 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.

There is limited data on overdosage with irbesartan in humans; however, daily doses of 900 mg for 8 weeks are well-tolerated. Irbesartan overdose will most likely manifest as hypotension and tachycardia; bradycardia may also occur.
There is no specific information available on the treatment of irbesartan overdose. Closely monitor patient, institute symptomatic and supportive treatment. Suggested measures include induction of emesis and/or gastric lavage. Activated charcoal may be useful in the treatment of overdosage.
Irbesartan is not removed by hemodialysis.

Hypersensitivity to irbesartan, or any component of the product; Pregnancy; Concomitant use with aliskiren in patients with diabetes mellitus or renal impairment [glomerular filtration rate (GFR) <60 mL/min/1.73 m²]; Concomitant use with angiotensin-converting enzyme (ACE) inhibitors in patients with diabetic nephropathy.

Fetal Toxicity: When pregnancy is detected, discontinue irbesartan as soon as possible. Drugs that act directly on the renin-angiotensin-aldosterone system can cause injury and even death to the developing fetus.

Fetal Toxicity: Use of drugs that act on the renin-angiotensin-aldosterone system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue irbesartan as soon as possible. These adverse outcomes are usually associated with the use of these drugs in the second and third trimester of pregnancy. Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin-aldosterone system from other antihypertensive agents. Appropriate management of maternal hypertension during pregnancy is important to optimize outcomes for both mother and fetus.
In the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin-aldosterone system for a particular patient, the mother should be informed of the potential risk to the fetus. Perform serial ultrasound examinations to assess the intra-amniotic environment. If oligohydramnios is observed, discontinue irbesartan, unless it is considered lifesaving for the mother. Fetal testing may be appropriate, based on the week of pregnancy. However, patients and physicians should be aware that oligohydramnios may not appear until after the fetus has sustained irreversible injury.
Infants with history of in utero exposure to irbesartan should be closely observed for hypotension, oliguria and hyperkalemia. If oliguria or hypotension occurs, attention should be directed toward support of blood pressure and renal perfusion. Exchange transfusion or dialysis may be required as means of reversing hypotension and/or substituting for disordered renal function.
Hypotension in Volume- or Salt-depleted Patients: Symptomatic hypotension may be observed in patients who are intravascularly volume- or sodium-depleted (e.g., those treated with high-dose diuretics). These conditions should be corrected before starting irbesartan therapy, or a lower starting dose should be used.
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.
Effect on Ability to Drive and Use Machines: No studies on the effects on the ability to drive and use machines have been performed. However, dizziness or fatigue may occasionally occur when taking antihypertensive therapy. Exercise caution when driving vehicles or operating machinery.
Renal Impairment and Kidney Transplantation: There is an increased risk of severe hypotension and renal insufficiency when patients with unilateral or bilateral renal artery stenosis are treated with drugs that affect the renin-angiotensin-aldosterone system. Increases in blood urea nitrogen (BUN) and serum creatinine may occur in these patients.
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.
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 the 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 Category D (see Fetal Toxicity under Warnings and Fetal Toxicity 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.

The most frequently reported adverse effects with irbesartan in patients with hypertension include diarrhea, dyspepsia/heartburn and fatigue. In patients receiving irbesartan for diabetic nephropathy, the most common adverse effects reported include hyperkalemia, dizziness, orthostatic dizziness, and orthostatic hypotension.
Blood and lymphatic system disorders: Neutropenia, thrombocytopenia.
Immune system disorders: Hypersensitivity reactions such as rash, urticaria, angioedema (involving swelling of the face, lips, pharynx, and/or tongue).
Nervous system disorders: Headache, vertigo.
Ear and labyrinth disorders: Tinnitus.
Cardiac disorders: Tachycardia.
Vascular disorders: Edema.
Respiratory, thoracic and mediastinal disorders: Cough.
Gastrointestinal disorders: Dysgeusia, gastrointestinal disturbances, nausea, vomiting.
Hepatobiliary disorders: Abnormal liver function, hepatitis, jaundice.
Skin and subcutaneous tissue disorders: Leukocytoclastic vasculitis, pruritus.
Musculoskeletal and connective tissue disorders: Arthralgia, back pain, muscle cramps, musculoskeletal pain, myalgia (in some cases associated with increased plasma creatine kinase level), rhabdomyolysis (rare).
Renal and urinary disorders: Impaired renal function including cases of renal failure.
Reproductive system and breast disorders: Sexual dysfunction.
General disorders and administration site conditions: Asthenia, chest pain.
Investigations: Decrease in hemoglobin; increase in liver function tests, BUN, serum creatinine, plasma creatine kinase.

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. 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.
Dual Blockade of the Renin-Angiotensin-Aldosterone System (RAAS): Dual blockade of the RAAS with angiotensin II receptor blockers, ACE inhibitors or aliskiren is associated with increased risk of hypotension, hyperkalemia and changes in renal function (including acute renal failure) compared with monotherapy. Closely monitor blood pressure, renal function and electrolytes in patients on irbesartan and other agents that affect the RAAS.
Do not coadminister irbesartan with aliskiren in patients with diabetes mellitus or renal impairment (GFR <60 mL/min/1.73 m²). Avoid concomitant use of ACE inhibitors and angiotensin II receptor blockers in patients with diabetic nephropathy.
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 treatment with irbesartan.
Coadministration of irbesartan with other drugs such as hydrochlorothiazide, digoxin, warfarin, and nifedipine showed no significant drug pharmacokinetic or pharmacodynamic interactions.

Store at temperatures not exceeding 25°C.

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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