Cilzec-A

Telmisartan + Amlodipine (Cilzec-A) is a fixed dose combination of telmisartan and amlodipine.
Telmisartan + Amlodipine (Cilzec-A) tablets contain telmisartan, a non-peptide angiotensin II receptor (type AT1) angiotensin. Telmisartan is a white to slightly yellowish solid. It is practically insoluble in water and in the pH range of 3 to 9, sparingly soluble in strong acid (except insoluble in hydrochloric acid), and soluble in strong base.
Telmisartan is chemically described as 4'-[(1,4'-dimethyl-2'-propyl[2,6'-bi-1H-benzimidazol]-1'-yl)methyl]-[1,1'-biphenyl]-2-carboxylic acid. Its empirical formula is C₃₃H₃₀N₄O₂.
Telmisartan + Amlodipine (Cilzec-A) tablets contain the Besilate salt of amlodipine, a dihydropyridine calcium-channel blocker (CCB). Amlodipine Besilate is a white to pale yellow crystalline powder, slightly soluble in water and sparingly soluble in ethanol. Amlodipine Besilate's chemical name is 3-Ethyl-5-methyl(4RS)-2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate benzenesulphonate. Its empirical formula is C₂₀H₂₅ClN₂O₅·C₆H₆O₃S.
Telmisartan + Amlodipine (Cilzec-A) tablets are formulated in four strengths for oral administration with a combination of amlodipine Besilate, equivalent to 5 mg or 10 mg of amlodipine free-base, with 40 mg, or 80 mg of telmisartan provided in the following four combinations: 40/5 mg, 40/10 mg, 80/5 mg, and 80/10 mg.
Telmisartan and Amlodipine Tablets 40 mg/5 mg: Blue and white oval shaped two-layer tablet engraved with "139" on blue layer and plain on white layer.
Each uncoated tablet contains: Telmisartan Ph. Eur. 40 mg, Amlodipine Ph. Eur. (as Amlodipine besilate) 5 mg.
Telmisartan and Amlodipine Tablets 40 mg/10 mg: Blue and white oval shaped two-layer tablet engraved with "140" on blue layer and plain on white layer.
Each uncoated tablet contains: Telmisartan Ph. Eur. 40 mg, Amlodipine Ph. Eur. (as Amlodipine besilate) 10 mg.
Telmisartan and Amlodipine Tablets 80 mg/5 mg: Blue and white oval shaped two-layer tablet engraved with "141" on blue layer and plain on white layer.
Each uncoated tablet contains: Telmisartan Ph. Eur. 80 mg, Amlodipine Ph. Eur. (as Amlodipine besilate) 5 mg.
Telmisartan and Amlodipine Tablets 80 mg/10 mg: Blue and white oval shaped two-layer tablet engraved with "142" on blue layer and plain on white layer.
Each uncoated tablet contains: Telmisartan Ph. Eur. 80 mg, Amlodipine Ph. Eur. (as Amlodipine besilate) 10 mg.
Inactive Ingredients: Telmisartan Layer: Sodium Hydroxide (Emprove), Povidone (Plasdone K-25), Meglumine, Mannitol (Pearlitol 200 SD), Purified Water, Magnesium Stearate (Avantor), Sodium Stearyl Fumarate (Alubra PG 100).
Amlodipine Layer: Mannitol (Pearlitol 200 SD), Mannitol (Pearlitol 25 C), Iron Oxide Yellow (Sicovit 10 E172), Black Iron Oxide, Brilliant Blue FCF (Koelow-901), Isopropyl Alcohol, Colloidal SiO2 (Aerosil 200 pharma), Purified Talc, Sodium Stearyl Fumarate (Alubra PG 100).

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.

Treatment of essential hypertension in adults: Add on therapy: Telmisartan + Amlodipine (Cilzec-A) is indicated in adults whose blood pressure is not adequately controlled on amlodipine 5 mg alone.
Replacement therapy: Adult patients receiving telmisartan and amlodipine from separate tablets can instead receive tablets of Telmisartan + Amlodipine (Cilzec-A) containing the same component doses.

The recommended dose of this medicinal product is one tablet per day.
The maximum recommended dose is one tablet 80 mg telmisartan/10 mg amlodipine per day. This medicinal product is indicated for long term treatment.
Administration of amlodipine with grapefruit or grapefruit juice is not recommended as bioavailability may be increased in some patients resulting in increased blood pressure lowering effects.
Add on therapy: Telmisartan + Amlodipine (Cilzec-A) may be administered in patients whose blood pressure is not adequately controlled with amlodipine 5 mg alone.
Individual dose titration with the components (i.e. amlodipine and telmisartan) is recommended before changing to the fixed dose combination. When clinically appropriate, direct change from monotherapy to the fixed combination may be considered.
Patients treated with 10 mg amlodipine who experience any dose limiting adverse reactions such as oedema, may be switched to Telmisartan + Amlodipine (Cilzec-A) once daily, reducing the dose of amlodipine without reducing the overall expected antihypertensive response.
Replacement therapy: Patients receiving telmisartan and amlodipine from separate tablets can instead receive tablets of Telmisartan + Amlodipine (Cilzec-A) containing the same component doses in one tablet once daily.
Elderly (> 65 years): No dose adjustment is necessary for elderly patients. Little information is available in the very elderly patients.
Normal amlodipine dose regimens are recommended in the elderly, but increase of dose should take place with care.
Renal impairment: Limited experience is available in patients with severe renal impairment or haemodialysis. Caution is advised when using telmisartan/amlodipine in such patients as amlodipine and telmisartan are not dialysable.
No posology adjustment is required for patients with mild to moderate renal impairment.
Hepatic impairment: Telmisartan + Amlodipine (Cilzec-A) is contraindicated in patients with severe hepatic impairment.
In patients with mild to moderate hepatic impairment telmisartan/amlodipine should be administered with caution. For telmisartan the posology should not exceed 40 mg once daily.
Paediatric population: The safety and efficacy of telmisartan/amlodipine in children aged below 18 years have not been established. No data are available.
Method of administration: Oral use: Telmisartan + Amlodipine (Cilzec-A) can be taken with or without food.
It is recommended to take Telmisartan + Amlodipine (Cilzec-A) with some liquid.

Symptoms: Signs and symptoms of overdose are expected to be in line with exaggerated pharmacological effects. The most prominent manifestations of telmisartan overdose are expected to be hypotension and tachycardia; bradycardia, dizziness, increase in serum creatinine, and acute renal failure have also been reported.
Overdose with amlodipine may result in excessive peripheral vasodilation and possibly reflex tachycardia. Marked and probably prolonged systemic hypotension up to and including shock with fatal outcome have been reported.
Treatment: The patient should be closely monitored, and the treatment should be symptomatic and supportive. Management depends on the time since ingestion and the severity of the symptoms. Suggested measures include induction of emesis and/or gastric lavage. Activated charcoal may be useful in the treatment of overdose of both telmisartan and amlodipine.
Serum electrolytes and creatinine should be monitored frequently. If hypotension occurs, the patient should be placed in a supine position with elevation of extremities, with salt and volume replacement given quickly. Supportive treatment should be instituted.
Intravenous calcium gluconate may be beneficial in reversing the effects of calcium channel blockade. Gastric lavage may be worthwhile in some cases. In healthy volunteers the use of charcoal up to 2 hours after administration of amlodipine 10 mg has been shown to reduce the absorption rate of amlodipine.
Telmisartan and Amlodipine are not removed by haemodialysis.

Hypersensitivity to the active substances, to dihydropyridine derivatives, or to any of the excipients.
Second and third trimesters of pregnancy.
Biliary obstructive disorders and severe hepatic impairment.
Shock (including cardiogenic shock).
Obstruction of the outflow tract of the left ventricle (e.g., high grade aortic stenosis).
Hemodynamically unstable heart failure after acute myocardial infarction.
The concomitant use of telmisartan/amlodipine with aliskiren-containing medicinal products is contraindicated in patients with diabetes mellitus or renal impairment (GFR <60 ml/min/1.73 m²).

Pregnancy: Angiotensin II receptor antagonists should not be initiated during pregnancy. Unless continued angiotensin II receptor antagonist 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 angiotensin II receptor antagonists should be stopped immediately, and, if appropriate, alternative therapy should be started.
Hepatic impairment: Telmisartan is mostly eliminated in the bile. Patients with biliary obstructive disorders or hepatic insufficiency can be expected to have reduced clearance.
The half-life of amlodipine is prolonged and AUC values are higher in patients with impaired liver function; dose recommendations have not been established. Amlodipine should therefore be initiated at the lower end of the dosing range and caution should be used, both on initial treatment and when increasing the dose.
Telmisartan/amlodipine should therefore be used with caution in these patients.
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 medicinal products that affect the renin-angiotensin-aldosterone system (RAAS).
Renal impairment and kidney transplantation: When telmisartan/amlodipine 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 telmisartan/amlodipine in patients with a recent kidney transplant. Telmisartan and amlodipine are not dialysable.
Intravascular hypovolaemia: Symptomatic hypotension, especially after the first dose, may occur in patients who are volume and/or sodium depleted by e.g. vigorous diuretic therapy, dietary salt restriction, diarrhoea or vomiting. Such conditions should be corrected before the administration of telmisartan. If hypotension occurs with telmisartan/amlodipine, the patient should be placed in the supine position and, if necessary, given an intravenous infusion of normal saline. Treatment can be continued once blood pressure has been stabilised.
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, hyperkalaemia 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. 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.
Other conditions with stimulation of the renin-angiotensin-aldosterone system: 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 medicinal products that affect this system has been associated with acute hypotension, hyperazotaemia, oliguria, or rarely acute renal failure.
Primary aldosteronism: Patients with primary aldosteronism generally will not respond to antihypertensive medicinal products acting through inhibition of the renin-angiotensin system. Therefore, the use of telmisartan is not recommended.
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.
Unstable angina pectoris, acute myocardial infarction: There are no data to support the use of telmisartan/amlodipine in unstable angina pectoris and during or within one month of a myocardial infarction.
Patients with cardiac failure: In an amlodipine long-term, placebo-controlled study in patients with severe heart failure (NYHA class III and IV) the reported incidence of pulmonary oedema was higher in the amlodipine treated group than in the placebo group. Therefore, patients with heart failure should be treated with caution.
Calcium channel blockers, including amlodipine, should be used with caution in patients with congestive heart failure, as they may increase the risk of future cardiovascular events and mortality.
Diabetic patients treated with insulin or antidiabetics: In these patients hypoglycaemia may occur under telmisartan treatment. Therefore, in these patients an appropriate blood glucose monitoring should be considered; a dose adjustment of insulin or antidiabetics may be required when indicated.
Hyperkalaemia: The use of medicinal products that affect the renin-angiotensin-aldosterone system may cause hyperkalaemia. Hyperkalaemia may be fatal in the elderly, in patients with renal insufficiency, in diabetic patients, in patients concomitantly treated with other medicinal products that may increase potassium levels, and/or in patients with intercurrent events.
Before considering the concomitant use of medicinal products that affect the renin-angiotensin-aldosterone system, the benefit risk ratio should be evaluated. The main risk factors for hyperkalaemia to be considered are: Diabetes mellitus, renal impairment, age (>70 years).
Combination with one or more other medicinal products that affect the renin-angiotensin-aldosterone system and/or potassium supplements. Medicinal products or therapeutic classes of medicinal products that may provoke hyperkalaemia are salt substitutes containing potassium, potassium-sparing diuretics, ACE inhibitors, angiotensin II receptor antagonists, nonsteroidal anti-inflammatory medicinal products (NSAIDs, including selective COX-2 inhibitors), heparin, immunosuppressives (cyclosporin or tacrolimus), and trimethoprim.
Intercurrent events, in particular dehydration, acute cardiac decompensation, metabolic acidosis, worsening of renal function, sudden worsening of the renal condition (e.g. infectious diseases), cellular lysis (e.g. acute limb ischemia, rhabdomyolysis, extensive trauma).
Serum potassium should be monitored closely in these patients.
Sorbitol: Each tablet contains 168.64 mg sorbitol (E420).
Sodium: This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially 'sodium-free'.
Other: As with any antihypertensive medicinal product, excessive reduction of blood pressure in patients with ischaemic cardiomyopathy or ischaemic cardiovascular disease could result in a myocardial infarction or stroke.
Effects on ability to drive and use machines: Telmisartan + Amlodipine (Cilzec-A) has moderate influence on the ability to drive and use machines. Patients should be advised that they may experience adverse reactions such as syncope, somnolence, dizziness, or vertigo during treatment. Therefore, caution should be recommended when driving a car or using machines. If patients experience these adverse reactions, they should avoid potentially hazardous tasks such as driving or using machines.
Use in the Elderly: The increase of the amlodipine dose should take place with care in the elderly patients.

Pregnancy: There are limited data from the use of telmisartan/amlodipine in pregnant women. Animal reproductive toxicity studies with telmisartan/amlodipine have not been performed.
Telmisartan: The use of angiotensin II receptor antagonists is not recommended during the first trimester of pregnancy. The use of angiotensin II receptor antagonists is contraindicated during the second and third trimesters of pregnancy.
Studies with telmisartan in animals have shown reproductive toxicity.
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. Whilst there is no controlled epidemiological data on the risk with angiotensin II receptor antagonists, similar risks may exist for this class of medicinal products. Unless continued angiotensin II receptor antagonist 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 angiotensin II receptor antagonists should be stopped immediately, and, if appropriate, alternative therapy should be started.
Exposure to angiotensin II receptor antagonist 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, hyperkalaemia). Should exposure to angiotensin II receptor antagonists have occurred from the second trimester of pregnancy, ultrasound check of renal function and skull is recommended. Infants whose mothers have taken angiotensin II receptor antagonists should be closely observed for hypotension.
Amlodipine: The safety of amlodipine in human pregnancy has not been established.
In animal studies, reproductive toxicity was observed at high doses.
Breast-feeding: Amlodipine is excreted in human milk. The proportion of the maternal dose received by the infant has been estimated with an interquartile range of 3-7%, with a maximum of 15%. The effect of amlodipine on infants is unknown.
Because no information is available regarding the use of telmisartan during breast-feeding, telmisartan/amlodipine is not recommended and alternative treatments with better established safety profiles during breast-feeding are preferable, especially while breast-feeding a newborn or preterm infant.
Fertility: No data from controlled clinical studies with the fixed dose combination or with the individual components are available.
Separate reproductive toxicity studies with the combination of telmisartan and amlodipine have not been conducted.
In preclinical studies, no effects of telmisartan on male and female fertility were observed.
In some patients treated by calcium channel blockers, reversible biochemical changes in the head of spermatozoa have been reported. Clinical data are insufficient regarding the potential effect of amlodipine on fertility. In one rat study, adverse effects were found on male fertility.

Summary of the safety profile: The most common adverse reactions include dizziness and peripheral oedema. Serious syncope may occur rarely (less than 1 case per 1,000 patients).
Adverse reactions previously reported with one of the individual components (telmisartan or amlodipine) may be potential adverse reactions with Telmisartan + Amlodipine (Cilzec-A) as well, even if not observed in clinical trials or during the post-marketing period.
Tabulated list of adverse reactions: The safety and tolerability of Telmisartan + Amlodipine (Cilzec-A) has been evaluated in five controlled clinical studies with over 3,500 patients, over 2,500 of whom received telmisartan in combination with amlodipine.
Adverse reactions have been ranked under headings of frequency 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), not known (cannot be estimated from the available data).
Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. (See tables A and B.)

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Click on icon to see table/diagram/image

Reporting of suspected adverse reactions: Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.

No interactions between the two components of this fixed dose combination have been observed in clinical studies.
Interactions linked to the combination: No drug interaction studies have been performed.
To be taken into account with concomitant use: Other antihypertensive medicinal products: The blood pressure lowering effect of telmisartan/amlodipine can be increased by concomitant use of other antihypertensive medicinal products.
Medicinal products with blood pressure lowering potential: Based on their pharmacological properties it can be expected that the following medicinal products may potentiate the hypotensive effects of all antihypertensives including this medicinal product, e.g. baclofen, amifostine, neuroleptics or antidepressants. Furthermore, orthostatic hypotension may be aggravated by alcohol.
Corticosteroids (systemic route): Reduction of the antihypertensive effect.
Interactions linked to telmisartan: Concomitant use not recommended: Potassium sparing diuretics or potassium supplements: Angiotensin II receptor antagonists such as telmisartan, attenuate diuretic induced potassium loss. Potassium sparing diuretics e.g. spironolactone, eplerenone, triamterene, or amiloride, potassium supplements, or potassium-containing salt substitutes may lead to a significant increase in serum potassium. If concomitant use is indicated because of documented hypokalaemia, they should be used with caution and with frequent monitoring of serum potassium.
Lithium: Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with angiotensin converting enzyme inhibitors, and with angiotensin II receptor antagonists, including telmisartan. If use of the combination proves necessary, careful monitoring of serum lithium levels is recommended.
Other antihypertensive agents acting on the renin-angiotensin-aldosterone system (RAAS): 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, hyperkalaemia and decreased renal function (including acute renal failure) compared to the use of a single RAAS-acting agent.
Concomitant use requiring caution: Non-steroidal anti-inflammatory medicinal products: NSAIDs (i.e. acetylsalicylic acid at anti-inflammatory dose regimens, COX-2 inhibitors and non-selective NSAIDs) may reduce the antihypertensive effect of angiotensin II receptor antagonists.
In some patients with compromised renal function (e.g. dehydrated patients or elderly patients with compromised renal function), the co-administration of angiotensin II receptor antagonists and medicinal products that inhibit cyclo-oxygenase may result in further deterioration of renal function, including possible acute renal failure, which is usually reversible. Therefore, the combination should be administered with caution, especially in the elderly. Patients should be adequately hydrated and consideration should be given to monitoring of renal function after initiation of concomitant therapy and periodically thereafter.
Ramipril: In one study the co-administration of telmisartan and ramipril led to an increase of up to 2.5-fold in the AUC_0-24 and C_max of ramipril and ramiprilat. The clinical relevance of this observation is not known.
Concomitant use to be taken into account: Digoxin: When telmisartan was co-administered with digoxin, median increases in digoxin peak plasma concentration (49%) and in trough concentration (20%) were observed. When initiating, adjusting, and discontinuing telmisartan, monitor digoxin levels in order to maintain levels within the therapeutic range.
Interactions linked to amlodipine: Concomitant use requiring caution: CYP3A4 inhibitors: Concomitant use of amlodipine with strong or moderate CYP3A4 inhibitors (protease inhibitors, azole antifungals, macrolides like erythromycin or clarithromycin, verapamil or diltiazem) may give rise to significant increase in amlodipine exposure resulting in an increased risk of hypotension. The clinical translation of these PK variations may be more pronounced in the elderly. Clinical monitoring and dose adjustment may thus be required.
CYP3A4 inducers: Upon co-administration of known inducers of the CYP3A4, the plasma concentration of amlodipine may vary. Therefore, blood pressure should be monitored and dose regulation considered both during and after concomitant medication particularly with strong CYP3A4 inducers (e.g. rifampicin, Hypericum perforatum).
Dantrolene (infusion): In animals, lethal ventricular fibrillation and cardiovascular collapse are observed in association with hyperkalemia after administration of verapamil and intravenous dantrolene. Due to risk of hyperkalemia, it is recommended that the coadministration of calcium channel blockers such as amlodipine be avoided in patients susceptible to malignant hyperthermia and in the management of malignant hyperthermia.
Grapefruit and grapefruit juice: Administration of Cilzec-A with grapefruit or grapefruit juice is not recommended since bioavailability may be increased in certain patients resulting in increased blood pressure lowering effects.
Concomitant use to be taken into account: Tacrolimus: There is a risk of increased tacrolimus blood levels when co-administered with amlodipine but the pharmacokinetic mechanism of this interaction is not fully understood. In order to avoid toxicity of tacrolimus, administration of amlodipine in a patient treated with tacrolimus requires monitoring of tacrolimus blood levels and dose adjustment of tacrolimus when appropriate.
Cyclosporine: No drug interaction studies have been conducted with cyclosporine and amlodipine in healthy volunteers or other populations with the exception of renal transplant patients, where variable trough concentration increases (average 0%-40%) of cyclosporine were observed. Consideration should be given for monitoring cyclosporine levels in renal transplant patients on amlodipine, and cyclosporine dose reductions should be made as necessary.
Mechanistic Target of Rapamycin (mTOR) Inhibitors: mTOR inhibitors such as sirolimus, temsirolimus, and everolimus are CYP3A substrates. Amlodipine is a weak CYP3A inhibitor. With concomitant use of mTOR inhibitors, amlodipine may increase exposure of mTOR inhibitors.
Simvastatin: Co-administration of multiple doses of 10 mg of amlodipine with simvastatin 80 mg resulted in an increase in exposure to simvastatin up to 77% compared to simvastatin alone. Therefore, the dose of simvastatin in patients on amlodipine should be limited to 20 mg daily.

Store at temperatures not exceeding 30°C.
Protect from light and moisture.

Angiotensin II Antagonists / Calcium Antagonists

C09DB04 - telmisartan and amlodipine ; Belongs to the class of angiotensin II receptor blockers (ARBs) and calcium channel blockers. Used in the treatment of cardiovascular disease.

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