Source: Marketing Authorisation Holder Revision Year: 2023 Publisher: Sanofi-aventis de México, S.A. de C.V., Acueducto del Alto Lerma No. 2, Zona Industrial de Ocoyoacac, C. P. 52740 Ocoyoacac, Edo. de México
The pharmacodynamic properties of each drug, irbesartan and amlodipine, provide an additive antihypertensive effect when administered in combination compared to the effect of each drug administered separately. 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.
Irbesartan is a specific angiotensin II receptor antagonist (AT1 subtype). Angiotensin II is an important component of the renin-angiotensin system involved in the pathophysiology of hypertension and sodium homeostasis. Irbesartan does not require metabolic activation to exert its effect.
Irbesartan blocks the potent vasoconstrictor and aldosterone-secreting effects of angiotensin II by selective antagonism of angiotensin II receptors (AT1 subtype) located on vascular smooth muscle cells and the adrenal cortex. Irbesartan has no agonist activity at the AT1 receptor and has a much greater affinity (more than 8500-fold) for the AT1 receptor than for the AT2 receptor (receptor that has not been shown to be associated with cardiovascular homeostasis).
Irbesartan does not inhibit the enzymes in the renin-angiotensin system, i.e., the angiotensin converting enzyme (ACE), nor affects other hormone receptors or ion channels involved in the cardiovascular regulation of blood pressure and sodium homeostasis. The AT1 receptors blockade caused by Irbesartan interrupts the feedback loop within the renin-angiotensin system, resulting in increases in plasma levels of renin and angiotensin II. 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.
The effect on the decrease in blood pressure by irbesartan is apparent after the first dose and becomes substantial within 1-2 weeks, with maximal effect occurs in 4-6 weeks. In long-term follow-up studies, the effect of irbesartan remained for more than one year.
A single daily dose up to 900 mg produced dose related drops in blood pressure. The 150-300 mg once a day dose decreases trough blood pressure in supine or sitting position (i.e., 24 hours after taking the dose), at an average of 8-13/5-8 mm Hg (systolic/diastolic) higher than those observed with placebo. The effects in trough are 60-70% of the corresponding peak diastolic and systolic responses. Optimal effects on blood pressure during the 24 hours are obtained with daily single dose.
Blood pressure decreases approximately to the same degree in both the standing position and the supine position. Orthostatic effects are not frequent, but as with ACE inhibitors, they can be expected in patients who have sodium-depletion and/or volume depletion.
The blood pressure lowering effects of irbesartan and thiazide-type diuretics are additive. In patients who are not adequately controlled by irbesartan alone, the addition of a low dose of hydrochlorothiazide (12.5 mg) to irbesartan once a day results in a greater reduction in blood pressure at trough of 7-10/3-6 mmHg (systolic/diastolic) compared to placebo.
Irbesartan effectiveness is not influenced by age or gender. As with other drugs that affect the renin-angiotensin system, black patients have a markedly lower response to monotherapy with Irbesartan. When irbesartan is administered concomitantly with hydrochlorothiazide at low doses (12.5 mg daily), the antihypertensive response in black patients is similar to that of white patients. After the discontinuation of irbesartan, blood pressure gradually returns to the baseline. Rebound hypertension has not been observed.
Amlodipine is a dihydropyridine calcium antagonist (calcium ion antagonist or slowchannel blocker) that inhibits the entry of calcium ions and the transmembrane influx of these ions into both cardiac smooth muscle and vascular smooth muscle. The mechanism of the antihypertensive action of amlodipine is due to a direct relaxant effect on the vascular smooth muscle. The precise mechanism by which amlodipine alleviates angina symptoms has not been determined, however, amlodipine reduces the total ischemic burden through the following two actions:
1) Amlodipine dilates the peripheral arterioles and thus reduces the total peripheral resistance (after load) against which the heart works. Since the heart rate remains stable, this heart discharge reduces myocardial energy consumption and oxygen requirements;
2) Amlodipine mechanism of action probably involves also dilatation of the main arteries and coronary arterioles, both in ischemia and normal areas. This dilatation increases the oxygen supply to the myocardium in patients with coronary artery spasm (Prinzmetal’s or variant angina).
In patients with hypertension, the administration of a daily dose produces significant reductions in blood pressure, in both standing and supine position for a period of 24 hours. Due to its slow onset of action, acute hypotension is not a characteristic of amlodipine administration.
In patients with angina, the administration of amlodipine once a day increases the total exercise time, the time to angina onset, and the time to 1 mm ST segment depression. In addition, it decreases both the frequency of angina attack and the consumption of nitroglycerin tablets.
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.
The concurrent administration of irbesartan and amlodipine, either in a fixed dose combination tablet or the free dose 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 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 administered separately or concomitantly at 300 mg and 10 mg dose levels, the time to mean peak plasma concentrations of irbesartan and amlodipine remain unchanged, i.e., 0.75-1 hour and 5 hours respectively after administration. Similarly, Cmax and AUC are in the same range resulting in a relative bioavailability of 95% for irbesartan and 98% for amlodipine when administered in combination.
The mean half-life values for irbesartan and amlodipine, administered alone or in combination, are similar: 17.6 hours against 17.7 hours for irbesartan, and 58.5 hours against 52.1 hours for amlodipine. The elimination of irbesartan and amlodipine is unchanged when the drugs are administered alone or concomitantly.
No information available for the fixed dose combination.
The clinical evidence for the efficacy of the irbesartan and amlodipine fixed-dose combination derives from two studies: I-ADD and I-COMBINE. Both were multicenter, prospective, randomized, open-label, parallel groups with blinded endpoint evaluation design. The studies were performed in patients with established, uncontrolled essential hypertension, [mean systolic blood pressure (SBP) ≥145 mmHg] after at least 4 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 5mg of amlodipine or 150 mg of Irbesartan, once daily, for 7 to 10 days. At the end of Period A, if the mean SBP of a patient was <135 mmHg, the patient was withdrawn from the corresponding study.
In the I-ADD study, patients (n=325) were randomized following Period A to receive either 150 mg of Irbesartan or the fixed-dose combination of 150 mg/5 mg of irbesartan/amlodipine once daily for 5 weeks (Period B). In Week 5, doses were increased (forced titration) to 300 mg of Irbesartan or 300 mg/5 mg of the fixed-dose combination of irbesartan/amlodipine once daily and continued for 5 weeks.
In the I-COMBINE study, patients (n=290) were randomized following Period A to receive either 5mg of amlodipine or the fixed-dose combination of 150 mg/5 mg of irbesartan/amlodipine once daily for 5 weeks (Period B). At Week 5, doses were increased (forced titration) to 10mg of amlodipine or the fixed-dose combination of 150 mg/10 mg irbesartan/amlodipine once daily and continued for 5 weeks (Period C).
In the I-ADD study, the primary endpoint was the change in the SBP measured at home at Week 10. In the I-COMBINE study, the primary endpoint was the change in the SBP measured at home at Week 5. Secondary endpoints were home diastolic blood pressure (DBP) and office blood pressure measurements (OBPM), as well as the percentage of controlled patients (mean SBP measured at home <135 mmHg) and patients with a response (mean SBP measured at home <135 mmHg and mean DBP measured at home <85 mmHg) at Week 10 for both studies.
The results of both studies demonstrated a significantly greater efficacy of the fixed-dose combination compared to amlodipine or irbesartan alone (see Tables 1 and 2).
Table 1. I-ADD Adjusted mean changes in blood pressure values from baseline (mmHg):
| Irbesartan/amlodipine Fixed-dose combination (N=155) | Irbesartan Monotherapy (N=165) | |||
|---|---|---|---|---|
| BP in mmHg | Adjusted mean change from baseline assessment (SE) | Adjusted mean change from baseline assessment (SE) | Adjusted mean difference between groups (SE) | p-value |
| Week 5 | ||||
| SBP at home (n=153/163) | -15.4 (0.8) | -5.6 (0.8) | -9.8 (1.1) | p <0.001 |
| DBP at home (n= 153/163) | -7.4 (0.5) | -2.4 (0.5) | -5.0 (0.7) | p <0.001 |
| SBP at doctor’s office (n=154/164) | -14.7 (1.0) | -5.1 (1.0) | -9.6 (1.4) | p <0.001 |
| DBP at doctor’s office (n=154/164) | -7.3 (0.7) | -2.4 (0.6) | -4.9 (0.9) | p <0.001 |
| Week 10 | ||||
| SBP at home* (n=146/153) | -18.7 (0.8) | -9.9 (0.8) | -8.8 (1.1) | p <0.001 |
| DBP at home (n=146/153) | -8.6 (0.5) | -3.9 (0.5) | -4.7 (0.7) | p<0.001 |
| SBP at doctor’s office(n=149/162) | -17.9 (1.2) | -8.4 (1.1) | -9.5 (1.6) | p <0.001 |
| DBP at doctor’s office (n=149/162) | -7.7 (0.7) | -3.5 (0.7) | -4.2 (1.0) | p <0.001 |
* Primary endpoint
n=number of evaluable patients in the fixed-dose combination group/number of evaluable patients in monotherapy group
Table 2. I-Combine – Adjusted mean changes in blood pressure values from the baseline assessment (mmHg) – ITT Population:
| Fixed-dose combination (N=144) | Amlodipine (N=143) | |||
|---|---|---|---|---|
| BP in mmHg | Adjusted mean change from baseline assessment (SE) | Adjusted mean change from baseline assessment (SE) | Adjusted mean difference between groups (SE) | p-value |
| Week 5 | ||||
| SBP at home* (n=141/139) | -12.4 (0.7) | -6.3 (0.7) | -6.2 (1.0) | p <0.001 |
| DBP at home (n=141/139) | -5.6 (0.5) | -3.0 (0.5) | -2.6 (0.7) | p <0.001 |
| SBP at doctor’s office (n=143/143) | -10.8 (1.0) | -3.3 (1.0) | -7.4 (1.4) | p <0.001 |
| DBP at doctor’s office (n=143/143) | -3.8 (0.6) | -1.2 (0.6) | -2.6 (0.9) | P=0.004 |
| Week 10 | ||||
| SBP at home (n=132/131) | -18.1 (0.7) | -13.5 (0.7) | -4.5 (1.0) | p <0.001 |
| DBP at home (n=132/131) | -9.4 (0.5) | -6.2 (0.5) | -3.2 (0.7) | p <0.001 |
| SBP at doctor’s office (n=134/136) | -18.4 (1.1) | -12.4 (1.1) | -6.0 (1.6) | p <0.001 |
| DBP at doctor’s office (n=134/136) | -8.7 (0.6) | -5.6 (0.6) | -3.1 (0.9) | p <0.001 |
* Primary endpoint n=number of evaluable patients in fixed-dose combination group/number of evaluable patients in monotherapy group
Irbesartan is an orally active agent and does not require biotransformation for its activity. After oral administration, irbesartan is rapidly and completely absorbed. Peak plasma concentrations occurs at 1.5-2 hours after oral administration. The absolute bioavailability of irbesartan administered orally is 60-80%. Food does not affect the bioavailability of irbesartan.
Irbesartan is approximately 96% protein-bound in plasma and has negligible binding to cellular components of blood. The distribution volume is 53-93 L/Kg.
In plasma, unchanged irbesartan accounts for 80-85% of the circulating radioactivity after oral or intravenous administration of Irbesartan C14. Irbesartan is metabolized by the liver via glucuronide conjugation and oxidation. The main circulating metabolite is irbesartan glucuronide (approximately 6%). Irbesartan undergoes oxidation primarily by the cytochrome P450 isoenzyme CYP2C9; the CYP3A4 isoenzyme has a negligible effect. Irbesartan is not metabolized by most of the isoenzymes commonly involved in drug metabolism, nor induces or inhibits them substantially (i.e., CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2D6, or CYP2E1). Irbesartan does not induce or inhibit the CYP3A4 isoenzyme.
Irbesartan and its metabolites are excreted by both biliary and renal routes. About 20% of the administered radioactivity after a dose of Irbesartan C14, orally or intravenously, is recovered in the urine and the rest in the feces. Less than 2% of the dose is excreted in the urine as unchanged irbesartan.
The terminal elimination half-life (t½) 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 reached within three days after initiation of a once-daily dosing regimen. Limited accumulation (<20%) is observed in plasma after repeated once-daily dosing.
Irbesartan terminal elimination half-life (t1/2) 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 a linear pharmacokinetics over the therapeutic dose range. Steady-state plasma concentrations are reached within three days after the start of the once a day dosing regimen. Limited accumulation (<20%) is observed in plasma when the daily dose is repeated.
In hypertensive individuals, higher plasma concentrations (11-44%) of Irbesartan were observed in women than in men; However, after multiple doses, no differences were observed in either accumulation or elimination halflife between men and women. No gender-specific differences in clinical effect have been observed.
In elderly normotensive subjects (men and women) (65-80 years old) with clinically normal renal and hepatic function, AUC and peak plasma concentrations (Cmax) of Irbesartan were approximately 20-50% higher than those observed in younger subjects (18-40 years old). Regardless of age, the elimination half-life is comparable.
No significant age-related differences in clinical effect have been observed.
In black and white normotensive subjects, irbesartan AUC in plasma and terminal elimination half-life (t1/2) are approximately 20 to 25% higher in blacks than whites, Irbesartan peak plasma concentrations (Cmax) were essentially equivalent.
In patients with renal impairment (regardless of degree) and in patients on hemodialysis, Irbesartan pharmacokinetics did not change significantly. Irbesartan is not removed by hemodialysis.
In patients with hepatic insufficiency due to mild to moderate cirrhosis, the pharmacokinetics of irbesartan was not significantly affected.
After oral administration of therapeutic doses, amlodipine is well absorbed, with peak blood levels between 6 to 12 hours after dose administration. Absolute bioavailability is estimated to be between 64 to 80%. The volume of distribution is approximately 21 L/kg. In vitro studies have shown approximately 97.5% circulating amlodipine is bound to plasma proteins. Absorption of amlodipine is not affected by food intake.
The plasma terminal elimination half-life is around 35 to 50 hours and is consistent with the dosage once a day. Amlodipine is extensively metabolized by the liver to inactive metabolites, with 10% of the parent compound and 60% of metabolites excreted in the urine.
The time to reach peak plasma concentrations of amlodipine is similar in elderly and young patients. Clearance of amlodipine tends to be reduced with resulting increases in the AUC and the elimination half-life in elderly patients.
The increases in the AUC and elimination half-life in patients with congestive heart failure were as expected in this age group.
Very limited clinical data are available on the administration of amlodipine in patients with liver failure. Patients with liver failure have reduced amlodipine clearance, resulting in a longer half-life.
The pharmacokinetics of both drugs appear to be linear in the range of doses administered together (i.e. between 150 mg and 300 mg for irbesartan, and between 5 mg and 10 mg for amlodipine).
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