Ibetan

For 150 mg strength: White to off white, film coated oval shaped biconvex tablet debossed with '14' on one side and plain on the other.
Each tablet contains 150 mg Irbesartan.
For 300 mg strength: White to off white, film coated oval shaped biconvex tablet debossed with '15' on one side and plain on the other.
Each tablet contains 300 mg Irbesartan.
Each tablets contains irbesartan, an angiotensin II receptor (type AT₁) antagonist. Irbesartan is a non-peptide compound, chemically described as a 2-butyl-3-[p-(o-1H-tetrazol-5-ylphenyl)benzyl]-1,3-diazaspiro[4.4]non-1-en-4-one.

Pharmacology: Pharmacodynamics: Mechanism of Action: Irbesartan is a potent, orally active, selective angiotensin II receptor (type AT₁) antagonist. It is expected to block 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 (AT₁) 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 ACE (kininase II), an enzyme which generates angiotensin II and also degrades bradykinin into inactive metabolites. Irbesartan does not require metabolic activation for its activity.
Pharmacokinetics: After oral administration, irbesartan is well absorbed. Studies of absolute bioavailability gave values of approximately 60-80%. Concomitant food intake does not significantly influence the bioavailability of irbesartan. Plasma protein binding is approximately 96%, with negligible binding to cellular blood components. The volume of distribution is 53-93 liters. Following oral or intravenous administration of ₁₄C irbesartan, 80-85% of the circulating plasma radioactivity is attributable to unchanged irbesartan.
Irbesartan is metabolized by the liver via glucuronide conjugation and oxidation. The major circulating metabolite is irbesartan glucuronide (approximately 6%). In vitro studies indicate that irbesartan is primarily oxidized by the cytochrome P450 enzyme CYP2C9; isoenzyme CYP3A4 has negligible effect. 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 greater than 600 mg (twice the maximal recommended dose) was observed; the mechanism for this is unknown. Peak plasma concentrations are attained at 1.5-2 hours after oral administration. The total body and renal clearance are 157-176 and 3-3.5 mL/min, respectively. The terminal elimination half-life t½ of irbesartan is 11-15 hours. Steady-state plasma concentrations are attained within 3 days after initiation of a once daily dosing regimen. Limited accumulation of irbesartan (<20%) is observed in plasma upon repeated once-daily dosing.
In a study, somewhat higher plasma concentrations of irbesartan were observed in female hypertensive patients. However, there was no difference in the half-life and accumulation of irbesartan. No dosage adjustment is necessary in female patients. Irbesartan AUC and C_max values were also somewhat greater in older subjects (≥65 years) than those of young subjects (18-40 years). However, the terminal half-life was not significantly altered. No dosage adjustment is necessary in older people.
Irbesartan and its metabolites are eliminated by both biliary and renal pathways. After either oral or IV administration of ₁₄C irbesartan, about 20% of the radioactivity is recovered in the urine and the remainder in the feces. Less than 2% of the dose is excreted in the urine as unchanged irbesartan.
Pharmacokinetics in Special Populations: Renal Impairment: In patients with renal impairment or those undergoing hemodialysis, the pharmacokinetic parameters of irbesartan are not significantly altered. Irbesartan is not removed by hemodialysis.
Hepatic Impairment: In patients with mild to moderate cirrhosis, the pharmacokinetic parameters of irbesartan are not significantly altered. Studies have not been performed in patients with severe hepatic impairment.
Pediatric Population: The pharmacokinetics of irbesartan were evaluated in 23 hypertensive children after the administration of single and multiple daily doses of irbesartan (2 mg/kg) up to a maximum daily dose of 150 mg for four weeks. Of those 23 children, 21 were evaluable for comparison of pharmacokinetics with adults (twelve children over 12 years, nine children between 6 and 12 years). Results showed that C_max, AUC and clearance rates were comparable to those observed in adult patients receiving 150 mg irbesartan daily. A limited accumulation of irbesartan (18%) in plasma was observed upon repeated once daily dosing.

Treatment of essential hypertension.
Treatment of diabetic nephropathy with an elevated serum creatinine and proteinuria (>300 mg/day) in patients with type 2 diabetes and hypertension. In this population, irbesartan reduces the rate of progression of nephropathy as measured by the occurrence of doubling of serum creatinine or end stage renal disease (need for dialysis or renal transplantation).

The usual recommended initial and maintenance dose is 150 mg once daily, with or without food. Irbesartan at a dose of 150 mg once daily generally provides a better 24 hour blood pressure control than 75 mg. However, initiation of therapy with 75 mg could be considered, particularly in hemodialysed patients and in the elderly over 75 years.
In patients insufficiently controlled with 150 mg once daily, the dose of irbesartan can be increased to 300 mg, or other antihypertensive agents can be added. In particular, the addition of a diuretic such as hydrochlorothiazide has been shown to have an additive effect with irbesartan.
In hypertensive type 2 diabetic patients, therapy should be initiated at 150 mg irbesartan once daily and titrated up to 300 mg once daily as the preferred maintenance dose for treatment of renal disease.
The demonstration of renal benefit of irbesartan in hypertensive type 2 diabetic patients is based on studies where irbesartan was used in addition to other antihypertensive agents, as needed, to reach target blood pressure.
Special Populations: Renal Impairment: No dosage adjustment is necessary in patients with impaired renal function. A lower starting dose (75 mg) should be considered for patients undergoing hemodialysis.
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.
Elderly Patients: Although consideration should be given to initiating therapy with 75 mg in patients over 75 years of age, dosage adjustment is not usually necessary for the elderly.

Symptoms: Experience in adults exposed to doses of up to 900 mg/day for 8 weeks revealed no toxicity. The most likely manifestations of overdose are expected to be hypotension and tachycardia; bradycardia might also occur from overdose.
Treatment: No specific information is available on the treatment of overdose with irbesartan. The patient should be closely monitored, and the treatment should be symptomatic and supportive. Suggested measures include induction of emesis and/or gastric lavage.
Activated charcoal may be useful in the treatment of overdose. Irbesartan is not removed by hemodialysis.

Hypersensitivity to the active substance, or to any of the excipients.
Second and third trimester of pregnancy.
Lactation.
The concomitant use of irbesartan with aliskiren-containing products is contraindicated in patients with diabetes mellitus or renal impairment (glomerular filtration rate (GFR) <60 mL/min/1.73 m²).

Use in Pregnancy: The use of Angiotensin II Receptor Antagonists (AIIRAs) is not recommended during the first trimester of pregnancy (see Precautions). The use of AIIRAs is contraindicated during the second and third trimesters of pregnancy (see Contraindications and Precautions).

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, diarrhea or vomiting. Such conditions should be corrected before the administration of irbesartan.
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 drugs that affect the renin-angiotensin-aldosterone system. While this is not documented with irbesartan, a similar effect should be anticipated with angiotensin II receptor antagonists.
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 favorable in women and non-white subjects.
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, hyperkalemia 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). 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.
Hyperkalemia: As with other drugs that affect the renin-angiotensin-aldosterone system, hyperkalemia may occur during the treatment with irbesartan, 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 irbesartan 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 drugs acting through inhibition of the renin-angiotensin system. Therefore, the use of irbesartan 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, azotemia, oliguria, or rarely acute renal failure. As with any antihypertensive agent, excessive blood pressure decrease in patients with ischemic cardiopathy or ischemic 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.
Effects on the Ability to Drive and Use Machines: No studies on the effects on the ability to drive and use machines have been performed. 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 dizziness or weariness may occur during treatment.
Renal Impairment and Kidney Transplantation: When irbesartan 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 irbesartan in patients with recent kidney transplantation. In patients whose renal function may depend on the activity of the renin-angiotensin-aldosterone system (e. g. patients with severe congestive heart failure), treatment with angiotensin-converting enzyme inhibitors has been associated with oliguria and/or progressive azotemia and (rarely) with acute renal failure and/or death. Irbesartan would be expected to behave similarly.
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 Contraindications and Use in Pregnancy & Lactation).
Use in Children: Irbesartan has been studied in pediatric 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).
This drug contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
Safety and efficacy of irbesartan have not been established in children.
Use in the Elderly: No overall difference in effectiveness or safety has been reported between elderly subjects and younger subjects, but greater sensitivity of some older individuals cannot be ruled out.

Pregnancy: Epidemiological evidence regarding the risk of teratogenicity following exposure to ACE inhibitors during the first trimester of pregnancy has not been conclusive; however, a small increase in risk cannot be excluded. While there is no controlled epidemiological data on the risk with Angiotensin II Receptor Antagonists (AIIRAs), similar risks may exist for this class of drugs. 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.
Exposure to AIIRA therapy during the second and third trimesters is known to induce human fetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalemia).
Should exposure to AIIRAs occur from the second trimester of pregnancy, ultrasound check of renal function and skull is recommended.
Infants whose mothers have taken AIIRAS should be closely observed for hypotension (see Contraindications and Precautions).
Lactation: Because no information is available regarding the use of irbesartan during breastfeeding, irbesartan is not recommended and alternative treatments with better established safety profiles during breastfeeding are preferable, especially while nursing a newborn or preterm infant.
It is unknown whether irbesartan or its metabolites are excreted in human milk.
Available pharmacodynamic/toxicological data in rats have shown excretion of irbesartan or its metabolites in milk.
Fertility: Irbesartan had no effect upon fertility of treated rats and their offspring up to the dose levels inducing the first signs of parental toxicity.

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.
Immune system disorders: Not known: hypersensitivity reactions such as angioedema, rash, urticaria.
Metabolism and nutrition disorders: Not known: hyperkalemia.
Nervous system disorders: Common: dizziness, orthostatic dizziness*.
Not known: vertigo, headache.
Ear and labyrinth disorder: Not known: tinnitus.
Cardiac disorders: Uncommon: tachycardia.
Vascular disorders: Common: orthostatic hypotension*.
Uncommon: flushing.
Respiratory, thoracic and mediastinal disorders: Uncommon: cough.
Gastrointestinal disorders: Common: nausea/vomiting.
Uncommon: diarrhea, dyspepsia/heartburn.
Not known: dysgeusia.
Hepatobiliary disorders: Uncommon: jaundice. Not known: hepatitis, abnormal liver function.
Skin and subcutaneous tissue disorders: Not known: leukocytoclastic vasculitis.
Musculoskeletal and connective tissue disorders: Common: musculoskeletal pain.
Not known: arthralgia, myalgia (in some cases associated with increased plasma creatine kinase levels), muscle cramps.
Renal and urinary disorders: Not known: impaired renal function including cases of renal failure in patients at risk (see Precautions).
Reproductive system and breast disorders: Uncommon: sexual dysfunction.
General disorders and administration site conditions: Common: fatigue.
Uncommon: chest pain.
Investigations: Very common: Hyperkalemia* occurred more often in diabetic patients treated with irbesartan than with placebo. In diabetic hypertensive patients with microalbuminuria and normal renal function, hyperkalemia (≥5.5 mEq/L) occurred in 29.4% of the patients in the irbesartan 300 mg group and 22% of the patients in the placebo group. In diabetic hypertensive patients with chronic renal insufficiency and overt proteinuria, hyperkalemia (≥5.5 mEq/L) occurred in 46.3% of the patients in the irbesartan group and 26.3% of the patients in the placebo group.
Common: Significant increases in plasma creatine kinase were commonly observed (1.7%) in irbesartan treated subjects. None of these increases were associated with identifiable clinical musculoskeletal events.
In 1.7% of hypertensive patients with advanced diabetic renal disease treated with irbesartan, a decrease in hemoglobin*, which was not clinically significant, has been observed.
Pediatric Population: In a randomized 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.

Diuretics and Other Antihypertensive Agents: Other antihypertensive agents may increase the hypotensive effects of irbesartan; however irbesartan has been safely administered 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 therapy with irbesartan (see Precautions).
Aliskiren-containing Products or ACE-inhibitors: Clinical trial data has shown that dual blockade of the renin-angiotensin-aldosterone system (RAAS) through the combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is associated with a higher frequency of adverse events such as hypotension, hyperkalemia and decreased renal function (including acute renal failure) compared to the use of a single RAAS-acting agent (see Contraindications and Precautions).
Potassium Supplements and Potassium-Sparing Diuretics: 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 drugs that may increase serum potassium levels (e.g. heparin) may lead to increases in serum potassium and is, therefore, not recommended (see Precautions).
Lithium: Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with angiotensin converting enzyme inhibitors. Similar effects have been very rarely reported with irbesartan so far. Therefore, this combination is not recommended (see Precautions). If the combination proves necessary, careful monitoring of serum lithium levels is recommended.
Non-Steroidal Anti-inflammatory Drugs: When angiotensin II antagonists are administered simultaneously with non-steroidal anti-inflammatory drugs (i.e. selective COX-2 inhibitors, acetylsalicylic acid (>3 g/day) and non-selective NSAIDS), attenuation of the antihypertensive effect may occur.
As with ACE inhibitors, concomitant use of angiotensin II antagonists and NSAIDs may lead to an increased risk of worsening of renal function, including possible acute renal failure, and an increase in serum potassium, especially in patients with poor pre-existing renal function. The combination should be administered with caution, especially in the elderly. Patients should be adequately hydrated and consideration should be given to monitoring renal function after initiation of concomitant therapy, and periodically thereafter.
Additional Information on Irbesartan Interactions: In clinical studies, the pharmacokinetic of irbesartan is not affected by hydrochlorothiazide. Irbesartan is mainly metabolized by CYP2C9 and to a lesser extent by glucuronidation. No significant pharmacokinetic or pharmacodynamic interactions were observed when irbesartan was co-administered with warfarin, a drug metabolized by CYP2C9. The effects of CYP2C9 inducers such as rifampicin on the pharmacokinetics of irbesartan have not been evaluated. The pharmacokinetics of digoxin was not altered by co-administration of irbesartan.

Store at temperatures not exceeding 30°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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