APROVASC Irbesartan / Amlodipine 300mg / 10mg Film-Coated Tablet 28's

General: The recommended dosage of Irbesartan/Amlodipine (Aprovasc) is one tablet per day.
Irbesartan/Amlodipine (Aprovasc) should be administered in patients whose blood pressure is not adequately controlled on monotherapy with irbesartan or amlodipine or for continuation of therapy for patients receiving irbesartan and amlodipine as separate tablets. Dose should be individualized based on response to therapy with individual components and antihypertensive response required. The maximum recommended dose with Irbesartan/Amlodipine (Aprovasc) is 300 mg/10 mg per day.
Special Populations: Children: The safety and efficacy of Irbesartan/Amlodipine (Aprovasc) has not been established in this population.
Elderly: No dosage adjustment for Irbesartan/Amlodipine (Aprovasc) is necessary in the elderly. (See Pharmacology: Pharmacokinetics under Actions.)
Hepatic impairment: Due to the presence of amlodipine, Irbesartan/Amlodipine (Aprovasc) should be administered with caution in patients with hepatic insufficiency. (See Warnings and Pharmacology: Pharmacokinetics under Actions.)
Renal impairment: No dosage adjustment for Irbesartan/Amlodipine (Aprovasc) is necessary in patients with impaired renal function.
Administration: Irbesartan/Amlodipine (Aprovasc) can be used with or without food.

Signs and Symptoms: Experience in adults exposed to doses of up to 900 mg/day irbesartan for 8 weeks revealed no toxicity.
No specific information is available on the treatment of overdosage with irbesartan.
Available data for amlodipine suggest that gross overdosage could result in excessive peripheral vasodilatation and possibly reflex tachycardia. Marked and probably prolonged systemic hypotension up to and including shock with fatal outcome have been reported.
Management: The patient should be closely monitored, and the treatment should be symptomatic and supportive.
Suggested measures include gastric lavage. Administration of activated charcoal to healthy volunteers immediately or up to two hours after ingestion of amlodipine 10 mg has been shown to significantly decrease amlodipine absorption.
As amlodipine is highly protein bound and irbesartan is not removed from the body by hemodialysis, hemodialysis is not likely to be of benefit.
If massive overdose should occur, initiate active cardiac and respiratory monitoring. Frequent blood pressure measurements are essential. Clinically significant hypotension due to amlodipine overdosage calls for active cardiovascular support including elevation of extremities and attention to circulating fluid volume and urine output. A vasoconstrictor may be helpful in restoring vascular tone and blood pressure, provided that there is no contraindication to its use. Intravenous calcium gluconate may be beneficial in reversing the effects of calcium channel blockade.

May be taken with or without food.

Due to the presence of both irbesartan and amlodipine in the medicinal product, Irbesartan/Amlodipine (Aprovasc) is contraindicated in hypersensitivity to either or both of the active substances or to any of the excipients; hypersensitivity to dihydropyridines; cardiogenic shock, clinically significant aortic stenosis, unstable angina (excluding Prinzmetal's angina); pregnancy and lactation. (See Warnings and Use in Pregnancy & Lactation.)
Do not co-administer Irbesartan/Amlodipine (Aprovasc) 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). (See Precautions and Interactions.)
Do not co-administer Irbesartan/Amlodipine (Aprovasc) with Angiotensin-Converting Enzyme Inhibitors (ACEIs) in patients with diabetic nephropathy.

Hypotension-Volume-Depleted Patients: Irbesartan has been rarely associated with hypotension in hypertensive patients without other comorbid conditions. Symptomatic hypotension, as with ACE inhibitors, may be expected to occur in sodium/volume-depleted patients such as those treated vigorously with diuretics and/or salt restriction, or on hernodialysis. Volume and sodium-depletion should be corrected before initiating therapy with Irbesartan/Amlodipine (Aprovasc) or on lower starting dose should be considered.
Fetal/Neonatal Morbidity and Mortality: Although there is no experience with irbesartan in pregnant women, in utero exposure to ACE inhibitors given to pregnant women during the second and third trimesters has been reported to cause injury and death to the developing fetus. Thus, as for any drug that also acts directly on the renin-angiotensin-aldosterone system, Irbesartan/Amlodipine (Aprovasc) should not be used during pregnancy. If pregnancy is detected during therapy, Irbesartan/Amlodipine (Aprovasc) should be discontinued as soon as possible.
Patients with Heart Failure: In a long-term, placebo controlled study (PRAISE-2) of amlodipine in patients with NYHA III and IV heart failure of non-ischemic etiology, amlodipine was associated with increased reports of pulmonary edema despite no significant difference in the incidence of worsening heart failure as compared to placebo (See Pharmacology: Pharmacodynamics under Actions).
Hepatic impairment: As with all calcium antagonists, the half-life of amlodipine is prolonged in patients with impaired liver function and dosage recommendations have not been established. Irbesartan/Amlodipine (Aprovasc) should therefore be administered with caution in these patients.
Hypertensive crisis: The safety and efficacy of Irbesartan/Amlodipine (Aprovasc) in hypertensive crisis has not been established.

Dual Blockade of the Renin Angiotensin-Aldosterone System (RAAS): Dual blockade of the RMS by combining Irbesartan/Amlodipine (Aprovasc) with an angiotensin-converting enzyme inhibitor (ACEI) a with aliskiren is not recommended since there are increased risks of hypotension, hyperkalemia, and changes in renal function.
The use of Irbesartan/Amlodipine (Aprovasc) in combination with aliskiren is contraindicated in patients with diabetes mellitus or with renal impairment (GFR <60 mL/min/1.73 m²).
The use of Irbesartan/Amlodipine (Aprovasc) in combination with an ACEI is contraindicated in patients with diabetic nephropathy (See Contraindications and Interactions).
General: As a consequence of inhibiting the renin-angiotensin aldosterone system, changes in renal function may be anticipated in susceptible individuals. In patients whose renal function depends on the activity of the renin-angiotensin-aldosterone system (e.g., hypertensive patients with renal artery stenosis in one or both kidneys, or patients with severe congestive heart failure), treatment with drugs that affect this system has been associated with oliguria and/or progressive azotemia and (rarely) with acute renal failure and/or death. The possibility of a similar effect occurring with the use of an angiotensin II receptor antagonist, including irbesartan, cannot be excluded.
Driving a Vehicle or Performing Other Hazardous Tasks: The effect of Irbesartan/Amlodipine (Aprovasc) on the ability to drive and use machines has not been studied. but based on its pharmacodynamic properties, irbesartan and amlodipine are 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.

Pregnancy: There are no adequate and well-controlled studies in pregnant women. Irbesartan/Amlodipine (Aprovasc) is contraindicated during pregnancy. Irbesartan/Amlodipine(Aprovasc) must not be administered to women of childbearing potential unless effective contraception is used. When pregnancy is detected, Irbesartan/Amlodipine (Aprovasc) shall be discontinued as soon as possible. (See Contraindications and Warnings).
Lactation: Irbesartan/Amlodipine (Aprovasc) is contraindicated during lactation (See Contraindications).

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
For irbesartan: Irbesartan has been evaluated for safety in about 5000 subjects in clinical studies. This experience includes 1300 hypertensive patients treated for over 6 months and over 400 patients for 1 year or more. Adverse events generally were mild and transient with no relationship to the dose. The incidence of adverse events was not related to age, gender or race.
In placebo-controlled clinical studies, including 1965 irbesartan-treated patients (usual duration of treatment 1 to 3 months), discontinuations due to any clinical or laboratory adverse events were 3.3% for irbesartan-treated patients and 4.5% for placebo-treated patients (p=0.029). Adverse events that have been reported in irbesartan trials or postmarketing are categorized below according to system organ class and frequency (see Table 3).
The following CIOMS frequency raring is used, when applicable: Very common ≥10%; Common ≥1 and <10%; Uncommon ≥0.1 and <1%; Rare ≥0.01 and <0.1%; Very rare <0.01%, Unknown (cannot be estimated from available data).
Frequencies of adverse reactions from postmarketing experience are unknown, as these reactions are reported voluntarily from a population of uncertain size. (See Table 3.)




Laboratory Test Abnormalities: No clinically significant changes in laboratory test parameters occurred in controlled clinical studies of hypertension. No special monitoring of laboratory parameters is necessary for patients with essential hypertension receiving therapy with irbesartan.
For amlodipine: Adverse events that have been reported in amlodipine trials are categorized below according to system organ class and frequency (see Table 4).
The following CIOMS frequency rating is used, when applicable: Very common ≥10%; Common ≥1 and <10%; Uncommon ≥0.1 and <1%; Rare ≥0.01 and <0.1%; Very rare <0.01%, Unknown (cannot be estimated from available data). (See Table 4.)




In the clinical trials comparing the fixed-dose combination irbesartan/amlodipine to either irbesartan or amlodipine monotherapy, the types and incidences of treatment-emergent adverse events (TEAEs) possibly related to study treatment were similar to those observed in the earlier monotherapy clinical trials and postmarketing reports. The most frequently reported adverse event was peripheral edema, mainly associated with amlodipine.
The following CIOMS frequency rating is used, when applicable: Very common ≥10%; Common ≥1 and <10%; Uncommon ≥0.1 and <1%; Rare ≥0.01 and <0.1%; Very rare <0.01%, Unknown (cannot be estimated from available data). (See Table 5.)

For Irbesartan and Amlodipine: Based on a pharmacokinetic study where irbesartan and amlodipine were given alone or in combination, there is no pharmacokinetic interaction between irbesartan and amlodipine.
No drug interaction studies have been performed with Irbesartan/Amlodipine (Aprovasc) and other medicinal products.
For Irbesartan: Based on in vitro data, no interactions would be expected to occur when irbesartan is co-administered with drugs primarily metabolized by 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 co-administered with warfarin (metabolized by CYP2C9).
Irbesartan does not affect the pharmacokinetics of simvastatin (metabolized by CYP3A4) or digoxin (substrate of P-glycoprotein efflux transporter).
The pharmacokinetic parameters of irbesartan are not affected by the co-administration with nifedipine or hydrochlorothiazide.
The combination of Irbesartan/Amlodipine (Aprovasc) 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.
Angiotensin-converting enzyme inhibitors (ACEIs): The use of Irbesartan/Amlodipine (Aprovasc) 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, or salt substitutes containing potassium may lead to increases in 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.
For Amlodipine: Amlodipine has been safely administered with thiazide diuretics, alpha blockers, beta blockers, angiotensin-converting enzyme inhibitors, long-acting nitrates, sublingual glyceryl trinitrate, non-steroidal anti-inflammatory drugs, antibiotics, and oral hypoglycemic drugs.
In vitro data indicate that amlodipine has no effect on the human plasma protein binding of digoxin, phenytoin, warfarin, and indomethacin.
Cimetidine: Co-administration of amlodipine with cimetidine did not alter the pharmacokinetics of amlodipine.
Grapefruit juice: Co-administration of 240 mL of grapefruit juice with a single oral dose of amlodipine 10 mg in 20 healthy volunteers had no significant effect on the pharmacokinetics of amlodipine.
Sildenafil: When amlodipine and sildenafil were used in combination, each agent independently exerted its own blood pressure lowering effect.
Atorvastatin: Co-administration of multiple 10-mg doses of amlodipine with 80 mg of atorvastatin resulted in no significant change in the steady-state pharmacokinetic parameters of atorvastatin.
Digoxin: Co-administration of amlodipine with digoxin did not change serum digoxin levels or digoxin renal clearance in normal volunteers.
Warfarin: Co-administration of amlodipine with warfarin did not change the warfarin prothrombin response time.
Cyclosporine: Pharmacokinetic studies with cyclosporine have demonstrated that amlodipine does not significantly alter the pharmacokinetics of cyclosporine.
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.
Drug/Laboratory Test Interactions: None known.

Store at temperatures not exceeding 30°C.

Pharmacology: Pharmacodynamics: Mechanism of action: For Irbesartan and Amlodipine: Pharmacodynamic properties of each drug, irbesartan and amlodipine, are in favor of an addition of antihypertensive effects when considered in combination versus alone: both AT₁ receptor antagonists and calcium channel blockers lower blood pressure by reducing peripheral resistance, but calcium influx blockade and reduction of angiotensin II vasoconstriction are complementary mechanisms.
For Irbesartan: 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 (i.e., renin, angiotensin converting enzyme [ACED]) 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.
Pharmacodynamic Properties: 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 (i.e., 24 hours after dosing) by an average of 8-13/5-8 mm Hg (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 mm Hg (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 (e.g., 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.
For Amlodipine: Mechanism of action: Amlodipine is a dihydropyridine calcium antagonist (calcium ion antagonist or slow-channel blocker) that inhibits the transmembrane influx of calcium ions into cardiac and vascular smooth muscle. The mechanism of the antihypertensive action of amlodipine is due to a direct relaxant effect on vascular smooth muscle. The precise mechanism by which amlodipine relieves angina has not been fully determined but amlodipine reduces total ischemic burden by the following two actions: Amlodipine dilates peripheral arterioles and thus, reduces the total peripheral resistance (afterload) against which the heart works. Since the heart rate remains stable, this unloading of the heart reduces myocardial energy consumption and oxygen requirements.
The mechanism of action of amlodipine also probably involves dilatation of the main coronary arteries and coronary arterioles, both in normal and ischemic regions. This dilatation increases myocardial oxygen delivery in patients with coronary artery spasm (Prinzmetal's or variant angina).
In patients with hypertension, once daily dosing provides clinically significant reductions of blood pressure in both the supine and standing positions throughout the 24 hour interval. Due to the slow onset of action, acute hypotension is not a feature of amlodipine administration.
In patients with angina, once daily administration of amlodipine increases total exercise time, time to angina onset, and time to 1 mm ST segment depression, and decreases both angina attack frequency and glyceryl trinitrate tablet consumption.
Amlodipine has not been associated with any adverse metabolic effects or changes in plasma lipids and is suitable for use in patients with asthma, diabetes, and gout.
Clinical Efficacy/Clinical Studies: The clinical evidence for the efficacy of the fixed-dose combination of irbesartan and amlodipine is derived from two studies; the I-ADD and I-COMBINE studies. Both studies were multi-center, prospective, randomized, open-label, parallel-group studies with blinded endpoint evaluation design. The studies were conducted in patients with established essential hypertension, having uncontrolled blood pressure [mean systolic blood pressure (SBP) ≥145 mmHg] after at least four weeks of treatment with irbesartan 150 mg (I-ADD) or amlodipine 5 mg (I-COMBINE).
Both studies consisted of three treatment periods, A, B, and C. During Period A, all patients received amlodipine 5 mg or irbesartan 150 mg, once daily, for seven to ten days. At the end of Period A, if a patient's mean SBP was <135 mmHg, he or she was withdrawn from the respective study.
In I-ADD, patients (n=325) were randomized following Period A to receive either irbesartan 150 mg or fixed-dose combination irbesartan/amlodipine 150 mg/5 mg once daily for five weeks (Period B).
At Week 5 the doses were increased (forced titration) to irbesartan 300 mg or fixed-dose combination irbesartan/amlodipine 300 mg/5 mg once daily and continued for five weeks.
In I-COMBINE, patients (n=290) were randomized following Period A to receive either amlodipine 5 mg or fixed-dose combination irbesartan/amlodipine 150 mg/5 mg once daily for five weeks (Period B). At Week 5 the doses were increased (forced titration) to amlodipine 10 mg or fixed-dose combination irbesartan/amlodipine 150 mg/10 mg once daily and continued for five weeks (Period C).
In I-ADD the primary endpoint was the change in home SBP at Week 10. In I-COMBINE the primary endpoint was the change in home SBP at Week 5. Secondary endpoints were home diastolic blood pressure (DBP) and office blood pressure measurement (OBPM) as well as the percentage of controlled patients (mean home SBP <135 mmHg) and responder patients (mean home SBP <135 mmHg and mean home DBP <85 mmHg) at Week 10 for both studies.
Results of both studies demonstrated significantly greater efficacy of the fixed-dose combination over amlodipine alone or irbesartan alone (see Tables 1 and 2).








Pharmacokinetics: Absorption: For Irbesartan and Amlodipine: Concurrent administration of irbesartan and amlodipine, whether in a fixed dose combination tablet or the free combination, has no influence on the bioavailability of the individual components.
The three fixed dose combinations of irbesartan and amlodipine (150 mg/10 mg, 300 mg/5 mg, and 300 mg/10 mg) are bioequivalent to the free dose combinations (150 mg/10 mg, 300 mg/5 mg, and 300 mg/10 mg) both in terms of rate and extent of absorption.
When given separately or concomitantly at 300 mg and 10 mg dose levels, time to median peak plasma concentrations of irbesartan and amlodipine remain unchanged i.e. 0.75-1 hour and 5 hours respectively after administration. Similarly C_max and AUCs are in the same range resulting in a relative bioavailability of 95% for irbesartan and 98% for amlodipine when they are co-administered.
For Irbesartan: Irbesartan is an orally active agent and does not require biotransformation for its activity. Following oral administration, irbesartan is rapidly and completely absorbed. Peak plasma concentration occurs at 1.5-2 hours after oral administration. The absolute oral bioavailability of irbesartan is 60-80%. Food does not affect the bioavailability.
For Amlodipine: After oral administration of therapeutic doses, amlodipine is well absorbed with peak blood levels between 6 and 12 hours post dose. Absolute bioavailability is estimated to be between 64 and 90%.
Distribution: For Irbesartan: Irbesartan is approximately 96% protein-bound in plasma, and has negligible binding to cellular components of blood. The volume of distribution is 53-93 L/kg.
For Amlodipine: The volume of distribution of amlodipine is approximately 21 L/kg. In vitro studies have shown that approximately 97.5% of circulating amlodipine is bound to plasma proteins.
Metabolism: For Irbesartan: 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 (approximately 6%).
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 (i.e., CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2D6, or CYP2E1). Irbesartan does not induce nor inhibit isoenzyme CYP3A4.
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.
For Amlodipine: Amlodipine is extensively converted to inactive metabolites via hepatic metabolism with 10% of the parent compound and 60% of the metabolites excreted in the urine.
Elimination: For Irbesartan and Amlodipine: The mean half-life values for irbesartan and amlodipine, given alone or in combination, are similar: 17.6 hours versus 17.7 for irbesartan, and 58.5 hours versus 52.1 hours for amlodipine. Elimination of irbesartan and amlodipine is unchanged when the drugs are administered alone or concomitantly.
The pharmacokinetics of both drugs appears to be linear over the co-administered dose range (i.e. between 150 mg and 300 mg for irbesartan, and between 5 mg and 10 mg for amlodipine).
For Irbesartan: The terminal elimination half-life (t_1/2) 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.
For Amlodipine: The terminal plasma elimination half-life is about 35-50 hours and is consistent with once daily dosing.
Special Populations: For Irbesartan and Amlodipine: Pediatric patients: No information is available for the fixed dose combination.
For Irbesartan: Race: In black and white normotensive subjects, the plasma AUC and t_1/2 of irbesartan are approximately 20-25% greater in blacks than in whites; the peak plasma concentrations (C_max) of irbesartan are essentially equivalent.
Gender: In male and female hypertensive subjects, higher (11-44%) plasma concentrations of irbesartan are observed in females than in males, although, following multiple dosing, males and females do not show differences in either accumulation or elimination half-life. No gender-specific differences in clinical effect have been observed.
Elderly: In elderly (male and female) normotensive subjects (65-80 years) with clinically normal renal and hepatic function, the plasma AUC and peak plasma concentrations (C_max) 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.
Pediatric patients: Safety and effectiveness in pediatric patients have not been established.
Hepatic impairment: In patients with hepatic insufficiency due to mild to moderate cirrhosis, the pharmacokinetics of irbesartan is not significantly altered.
Renal impairment: In patients with hepatic insufficiency due to mild to moderate cirrhosis, the pharmacokinetics of irbesartan is not significantly altered. Irbesartan is not removed by hemodialysis.
For Amlodipine: Elderly: The time to reach peak plasma concentrations of amlodipine is similar in elderly and younger subjects. Amlodipine clearance tends to be decreased with resulting increases in AUC and elimination half-life in elderly patients.
Pediatric patients: A population PK study has been conducted in 74 hypertensive children aged from 12 months to 17 years (with 34 patients aged 6 to 12 years and 28 patients aged 13 to 17 years) receiving amlodipine between 1.25 and 20 mg given either once or twice daily. In children 6 to 12 years and in adolescents 13-17 years of age the typical oral clearance (CL/F) was 22.5 and 27.4 L/hr respectively in males and 16.4 and 21.3 L/hr respectively in females. Large variability in exposure between individuals was observed. Data reported in children below 6 years are limited.
Hepatic impairment: See Warnings.
Other: Increases in AUC and elimination half-life in patients with congestive heart failure were as expected for the patient age group studied.
Toxicology: Non-Clinical Safety Data: Carcinogenicity: For the single components, there was no evidence of clastogenicity or carcinogenicity.
Mutagenicity: For the single components, there was no evidence of mutagenicity.
Teratogenicity: For Irbesartan: At doses of 50 mg/kg/day and higher of irbesartan, transient effects (increased renal pelvic cavitation, hydroureter or subcutaneous edema) were noted in rat fetuses, which were resolved after birth. In rabbits at doses of 30 mg/kg/day, maternal mortality, abortion and early fetal resorption were noted. No teratogenic effects were observed in the rat or rabbit.
For amlodipine: There was no evidence of teratogenicity in rats and rabbits.
Impairment of Fertility: For Irbesartan: Fertility and reproductive performance were not affected in studies of male and female rats even at oral doses of irbesartan causing some parental toxicity (up to 650 mg/kg/day). No significant effects on the number of corpora lutea, implants or live fetuses were observed. Irbesartan did not affect survival, development or reproduction of offspring.
For amlodipine: In animal studies with respect to the reproduction in rats at high doses delayed parturition, difficult labor and impaired fetal and pup survival were seen.

Angiotensin II Antagonists / Calcium Antagonists