Cilzec-A Mechanism of Action

Pharmacotherapeutic group: Agents acting on the renin-angiotensin system, angiotensin II receptor blockers (ARBs) and calcium channel blockers. ATC code: C09DB04.
Pharmacology: Pharmacodynamics: Telmisartan + Amlodipine (Cilzec-A) combines two antihypertensive compounds with complementary mechanisms to control blood pressure in patients with essential hypertension: an angiotensin II receptor antagonist, telmisartan, and a dihydropyridine calcium channel blocker, amlodipine.
The combination of these substances has an additive antihypertensive effect, reducing blood pressure to a greater degree than either component alone.
Telmisartan/Amlodipine combination once daily produces effective and consistent reductions in blood pressure across the 24-hour therapeutic dose range.
Telmisartan: Telmisartan is an orally active and specific angiotensin II receptor (type AT1) antagonist. Telmisartan displaces angiotensin II with very high affinity from its binding site at the AT1 receptor subtype, which is responsible for the known actions of angiotensin II. Telmisartan does not exhibit any partial agonist activity at the AT1 receptor. Telmisartan selectively binds the AT1 receptor. The binding is long-lasting.
Telmisartan does not show affinity for other receptors, including AT2 and other less characterised AT receptors. The functional role of these receptors is not known, nor is the effect of their possible overstimulation by angiotensin II, whose levels are increased by telmisartan. Plasma aldosterone levels are decreased by telmisartan. Telmisartan does not inhibit human plasma renin or block ion channels.
Telmisartan does not inhibit angiotensin-converting enzyme (kininase II), the enzyme which also degrades bradykinin. Therefore it is not expected to potentiate bradykinin-mediated adverse reactions.
In humans, an 80 mg dose of telmisartan almost completely inhibits the angiotensin II evoked blood pressure increase. The inhibitory effect is maintained over 24 hours and still measurable up to 48 hours.
After the first dose of telmisartan, the antihypertensive activity gradually becomes evident within 3 hours. The maximum reduction in blood pressure is generally attained 4 to 8 weeks after the start of treatment and is sustained during long-term therapy.
The antihypertensive effect persists constantly over 24 hours after dosing and includes the last 4 hours before the next dose as shown by ambulatory blood pressure measurements. This is confirmed by trough to peak ratios consistently above 80% seen after doses of 40 and 80 mg of telmisartan in placebo-controlled clinical studies. There is an apparent trend to a dose relationship to a time to recovery of baseline systolic blood pressure. In this respect data concerning diastolic blood pressure are inconsistent.
In patients with hypertension, telmisartan reduces both systolic and diastolic blood pressure without affecting pulse rate. The contribution of the medicinal product's diuretic and natriuretic effect to its hypotensive activity has still to be defined. The antihypertensive efficacy of telmisartan is comparable to that of substances representative of other classes of antihypertensive medicinal products (demonstrated in clinical trials comparing telmisartan to amlodipine, atenolol, enalapril, hydrochlorothiazide, and lisinopril).
Upon abrupt cessation of treatment with telmisartan, blood pressure gradually returns to pre-treatment values over a period of several days without evidence of rebound hypertension. The incidence of dry cough was significantly lower in patients treated with telmisartan than in those given angiotensin-converting enzyme inhibitors in clinical trials directly comparing the two antihypertensive treatments.
Amlodipine: Amlodipine is a calcium ion influx inhibitor of the dihydropyridine group (slow channel blocker or calcium ion antagonist) and 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, leading to reductions in peripheral vascular resistance and in blood pressure. Experimental data indicate that amlodipine binds to both dihydropyridine and non-dihydropyridine binding sites. Amlodipine is relatively vessel-selective, with a greater effect on vascular smooth muscle cells than on cardiac muscle cells.
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 hypertensive patients with normal renal function, therapeutic doses of amlodipine resulted in a decrease in renal vascular resistance and an increase in glomerular filtration rate and effective renal plasma flow, without change in filtration fraction or proteinuria.
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.
Use in patients with heart failure: Haemodynamic studies and exercise based controlled clinical trials in NYHA Class II-IV heart failure patients have shown that amlodipine did not lead to clinical deterioration as measured by exercise tolerance, left ventricular ejection fraction and clinical symptomatology.
A placebo-controlled study (PRAISE) designed to evaluate patients in NYHA Class III-IV heart failure receiving digoxin, diuretics and ACE inhibitors has shown that amlodipine did not lead to an increase in risk of mortality or combined mortality and morbidity with heart failure.
In a follow-up, long term, placebo-controlled study (PRAISE-2) of amlodipine in patients with NYHA III and IV heart failure without clinical symptoms or objective findings suggestive of underlying ischaemic disease, on stable doses of ACE inhibitors, digitalis, and diuretics, amlodipine had no effect on total cardiovascular mortality. In this same population amlodipine was associated with increased reports of pulmonary oedema.
Telmisartan/Amlodipine: In an 8-week multicenter, randomised, double-blind, placebo-controlled, parallel group factorial study in 1,461 patients with mild to severe hypertension (mean seated diastolic blood pressure ≥95 and ≤119 mmHg), treatment with each combination dose of Telmisartan/Amlodipine combination resulted in significantly greater diastolic and systolic blood pressure reductions and higher control rates compared to the respective monotherapy components.
Telmisartan/Amlodipine combination showed dose-related reductions in systolic/diastolic blood pressure across the therapeutic dose range of -21.8/-16.5 mmHg (40 mg/5 mg), -22.1/-18.2 mmHg (80 mg/5 mg), -24.7/-20.2 mmHg (40 mg/10 mg) and -26.4/-20.1 mmHg (80 mg/10 mg). The reduction in diastolic blood pressure <90 mmHg was achieved in 71.6%, 74.8%, 82.1%, 85.3% of patients respectively. Values are adjusted for baseline and country.
The majority of the antihypertensive effect was attained within 2 weeks after initiation of therapy.
In a subset of 1,050 patients with moderate to severe hypertension (DBP ≥100 mmHg) 32.7-51.8% responded sufficiently to monotherapy of either telmisartan or amlodipine. The observed mean changes in systolic/diastolic blood pressure with a combination therapy containing amlodipine 5 mg (-22.2/-17.2 mmHg with 40 mg/5 mg; -22.5/-19.1 mmHg with 80 mg/5 mg) were comparable to or greater than those seen with amlodipine 10 mg (-21.0/-17.6 mmHg) and associated with significantly lower oedema rates (1.4% with 40 mg/5 mg; 0.5% with 80 mg/5 mg; 17.6% with amlodipine 10 mg).
Automated ambulatory blood pressure monitoring (ABPM) performed in a subset of 562 patients confirmed the results seen with in-clinic systolic and diastolic blood pressure reductions consistently over the entire 24-hour dosing period.
The overall incidence of adverse reactions with Telmisartan/Amlodipine combination in the clinical trial programme was low with only 12.7% of patients on treatment experiencing adverse reactions. The most common adverse reactions were peripheral oedema and dizziness. The adverse reactions reported were in agreement with those anticipated from the safety profiles of the components telmisartan and amlodipine.
No new or more severe adverse reactions were observed. The oedema related events (peripheral oedema, generalised oedema, and oedema) were consistently lower in patients who received Telmisartan/Amlodipine combination as compared to patients who received amlodipine 10 mg. In the factorial design trial the oedema rates were 1.3% with Telmisartan/Amlodipine combination 40 mg/5 mg and 80 mg/5 mg, 8.8% with Telmisartan/Amlodipine combination 40 mg/10 mg and 80 mg/10 mg and 18.4% with Amlodipine 10 mg. In patients not controlled on amlodipine 5 mg the oedema rates were 4.4% for 40 mg/5 mg and 80 mg/5 mg and 24.9% for amlodipine 10 mg.
The antihypertensive effect of Telmisartan/Amlodipine combination was similar irrespective of age and gender, and was similar in patients with and without diabetes. Telmisartan/Amlodipine combination has not been studied in any patient population other than hypertension.
Telmisartan has been studied in a large outcome study in 25,620 patients with high cardiovascular risk (ONTARGET).
Amlodipine has been studied in patients with chronic stable angina, vasospastic angina and angiographically documented coronary artery disease.
Paediatric population: The European Medicines Agency has waived the obligation to submit the results of studies with Telmisartan/Amlodipine combination in all subsets of the paediatric population in hypertension.
Pharmacokinetics: Pharmacokinetics of the fixed dose combination: The rate and extent of absorption of Telmisartan/Amlodipine combination are equivalent to the bioavailability of telmisartan and amlodipine when administered as individual tablets.
Absorption: Absorption of telmisartan is rapid although the amount absorbed varies. The mean absolute bioavailability for telmisartan is about 50%. When telmisartan is taken with food, the reduction in the area under the plasma concentration-time curve (AUC0_-∞) of telmisartan varies from approximately 6% (40 mg dose) to approximately 19% (160 mg dose). By 3 hours after administration, plasma concentrations are similar whether telmisartan is taken fasting or with food.
After oral administration of therapeutic doses, amlodipine is well absorbed with peak blood levels between 6-12 hours post dose. Absolute bioavailability has been estimated to be between 64 and 80%.
Amlodipine bioavailability is not affected by food ingestion.
Distribution: Telmisartan is largely bound to plasma protein (>99.5%), mainly albumin and alpha-1 acid glycoprotein.
The mean steady-state apparent volume of distribution (Vd_ss) is approximately 500 L.
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 in hypertensive patients.
Biotransformation: Telmisartan is metabolised by conjugation to the glucuronide of the parent compound. No pharmacological activity has been shown for the conjugate.
Amlodipine is extensively (approximately 90%) metabolised by the liver to inactive metabolites.
Elimination: Telmisartan is characterised by biexponential decay pharmacokinetics with a terminal elimination half-life of >20 hours. The maximum plasma concentration (C_max) and, to a smaller extent, the area under the plasma concentration-time curve (AUC), increase disproportionately with dose. There is no evidence of clinically relevant accumulation of telmisartan taken at the recommended dose. Plasma concentrations were higher in females than in males, without relevant influence on efficacy.
After oral (and intravenous) administration, telmisartan is nearly exclusively excreted with the faeces, mainly as unchanged compound. Cumulative urinary excretion is <1% of dose. Total plasma clearance (Cl_tot) is high (approximately 1,000 ml/min) compared with hepatic blood flow (about 1,500 ml/min).
Amlodipine elimination from plasma is biphasic, with a terminal elimination half-life of approximately 30 to 50 hours consistent with once-daily dosing. Steady-state plasma levels are reached after continuous administration for 7-8 days. Ten percent of original amlodipine and 60% of amlodipine metabolites are excreted in urine.
Linearity/non-linearity: The small reduction in AUC for telmisartan is not expected to cause a reduction in the therapeutic efficacy. There is no linear relationship between doses and plasma levels. C_max and to a lesser extent AUC increase disproportionately at doses above 40 mg. Amlodipine exhibits linear pharmacokinetics.
Paediatric population (age below 18 years): No pharmacokinetic data are available in the paediatric population.
Gender: Differences in plasma concentrations of telmisartan were observed, with C_max and AUC being approximately 3- and 2-fold higher, respectively, in females compared to males.
Elderly: The pharmacokinetics of telmisartan do not differ in young and elderly patients. The time to reach peak plasma concentrations of amlodipine is similar in elderly and younger subjects. In elderly patients, amlodipine clearance tends to decline with resulting increases in AUC and elimination half-life.
Renal impairment: In patients with mild to moderate and severe renal impairment, doubling of plasma concentrations of telmisartan was observed. However, lower plasma concentrations were observed in patients with renal insufficiency undergoing dialysis. Telmisartan is highly bound to plasma protein in renal-insufficient subjects and cannot be removed by dialysis. The elimination half-life is not changed in patients with renal impairment. The pharmacokinetics of amlodipine are not significantly influenced by renal impairment.
Hepatic impairment: Pharmacokinetic studies in patients with hepatic impairment showed an increase in absolute bioavailability of telmisartan up to nearly 100%. The elimination half-life of telmisartan is not changed in patients with hepatic impairment. Patients with hepatic insufficiency have decreased clearance of amlodipine with resulting increase of approximately 40-60% in AUC.