Teldipin tablets 5 mg + 80 mg No. 30

Instructions for Teldipin tablets 5 mg + 80 mg No. 30

Composition

active ingredients: telmisartan, amlodipine;

1 tablet contains 40 mg of telmisartan and 5 mg of amlodipine (as amlodipine besylate) or 40 mg of telmisartan and 10 mg of amlodipine (as amlodipine besylate), or 80 mg of telmisartan and 5 mg of amlodipine (as amlodipine besylate), or 80 mg of telmisartan and 10 mg of amlodipine (as amlodipine besylate);

excipients: meglumine, sodium hydroxide, povidone K30, lactose monohydrate, sorbitol (E 420), iron oxide yellow (E 172), magnesium stearate, sodium stearyl fumarate, mannitol (E 421), colloidal anhydrous silicon dioxide, stearic acid.

Dosage form

Pills.

Main physicochemical properties:

Teldipine, 40 mg/5 mg tablets: oval, slightly biconvex, two-layer tablets, brownish-yellow on one side, marbled, white to almost white on the other side, engraved with K3;

Teldipine, 40 mg/10 mg tablets: oval, slightly biconvex, two-layer tablets, brownish-yellow on one side, marbled, white to almost white on the other side, engraved with K2;

Teldipine, 80 mg/5 mg tablets: oval, slightly biconvex, two-layer tablets, brownish-yellow on one side, marbled, white to almost white on the other side;

Teldipine, 80 mg/10 mg tablets: oval, slightly biconvex, two-layer tablets, brownish-yellow on one side, marbled, white to off-white on the other side, engraved with K1.

Pharmacotherapeutic group

Drugs acting on the renin-angiotensin system. Angiotensin II antagonists and calcium channel blockers. Telmisartan and amlodipine.

ATX code C09D B04.

Pharmacological properties

Pharmacodynamics. Telmisartan

Mechanism of action

Telmisartan is a specific and effective antagonist of angiotensin II receptors (type AT1). Telmisartan displaces angiotensin II with very high affinity at its binding sites on the AT1 receptor subtype, which are responsible for the activity of angiotensin II. Telmisartan does not exhibit any partial agonist effect on the AT1 receptor. Telmisartan selectively binds the AT1 receptor. Binding is long-lasting. Telmisartan does not exhibit affinity for other receptors, including AT2 and other, less studied AT receptors. The functional role of these receptors is unknown, as is the effect of their possible "overstimulation" by angiotensin II, the level of which increases under the influence of telmisartan. Telmisartan reduces plasma aldosterone levels. Telmisartan does not inhibit human plasma renin, does not block ion channels. Telmisartan does not inhibit angiotensin-converting enzyme (kininase II), an enzyme that also degrades bradykinin. Therefore, potentiation of bradykinin-mediated side effects should not be expected.

In humans, telmisartan at a dose of 80 mg almost completely inhibits the increase in blood pressure induced by angiotensin II. The blocking effect is maintained for 24 hours and remains significant for up to 48 hours.

Clinical efficacy and safety

Treatment of essential hypertension

After the first dose of telmisartan, antihypertensive activity gradually develops within 3 hours. The maximum reduction in blood pressure is achieved 4-8 weeks after the start of treatment and is maintained during long-term therapy.

The antihypertensive effect is maintained continuously for 24 hours after administration of the drug, including the last 4 hours before the next dose, as confirmed by ambulatory blood pressure monitoring. This was confirmed by the ratio of the blood pressure reduction before the next dose to the maximum blood pressure reduction of more than 80% after taking 40 and 80 mg of telmisartan in placebo-controlled clinical trials. There is a clear relationship between dose and time to recovery to baseline systolic blood pressure. Similar data for diastolic blood pressure are contradictory.

In patients with arterial hypertension, telmisartan reduces both systolic and diastolic blood pressure without affecting pulse rate. The influence of the diuretic and natriuretic effects of the drug on its hypotensive effect has not yet been determined. The antihypertensive efficacy of telmisartan is comparable to that of drugs belonging to other classes of antihypertensive drugs (demonstrated by clinical studies comparing telmisartan with amlodipine, atenolol, enalapril, hydrochlorothiazide and lisinopril).

When treatment with telmisartan is abruptly discontinued, blood pressure gradually returns to pre-treatment values within a few days, without withdrawal symptoms.

In clinical trials comparing two antihypertensive drugs, the incidence of dry cough was significantly lower in patients taking telmisartan than in patients taking ACE inhibitors.

The ONTARGET study (Ongoing International Trial of Telmisartan Alone and in Combination with Ramipril) compared the effects of telmisartan, ramipril, and the combination of telmisartan/ramipril on cardiovascular outcomes in 25,620 patients aged 55 years and older with coronary heart disease, stroke, transient ischemic attack, history of peripheral arterial disease, or type 2 diabetes with target organ damage (e.g., retinopathy, left ventricular hypertrophy, macro- or microalbuminuria). These patients were at risk for cardiovascular disease.

Patients were randomized to one of three treatment groups: telmisartan 80 mg (n = 8542), ramipril 10 mg (n = 8576), or the combination of telmisartan 80 mg and ramipril 10 mg (n = 8502). The median follow-up was 4.5 years.

The effect of telmisartan was similar to that of ramipril in reducing the primary composite endpoint of cardiac death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for congestive heart failure. The incidence of the primary endpoint was similar in the telmisartan (16.7%) and ramipril (16.5%) groups. The hazard ratio for telmisartan compared with ramipril was 1.01 (97.5% CI 0.93–1.10, p (no benefit) = 0.0019 at a cut-off value of 1.13). The all-cause mortality rate was 11.6% and 11.8% for patients receiving telmisartan and ramipril, respectively.

Telmisartan was as effective as ramipril on the pre-specified secondary endpoint (fatal cardiovascular event, non-fatal myocardial infarction, and non-fatal stroke) [0.99 (97.5% CI 0.90–1.08), p (no benefit) = 0.0004], the primary endpoint in the landmark HOPE (The HeartOutcomes Prevention Evaluation Study) study that compared ramipril with placebo.

In the TRANSCEND study, patients with ACE-I intolerance were randomized to telmisartan 80 mg (n = 2954) or placebo (n = 2972), with the same other inclusion criteria as in the ONTARGET study. Both drugs were added to standard therapy.

The median follow-up was 4 years and 8 months. There was no significant difference in the incidence of the primary composite endpoint (cardiac death, non-fatal myocardial infarction, non-fatal stroke, or hospitalization for congestive heart failure) [15.7% for telmisartan and 17% for placebo, relative risk 0.92 (95% CI 0.81–1.05, p = 0.22)]. There was evidence of superiority of telmisartan over placebo for the pre-specified secondary composite endpoint (cardiac death, non-fatal myocardial infarction, and non-fatal stroke [0.87 (95% CI 0.76–1.00, p = 0.048)]). There was no evidence of benefit in terms of cardiovascular mortality (relative risk 1.03, 95% CI 0.85–1.24).

Cough and angioedema were reported less frequently in patients taking telmisartan than in patients taking ramipril, although hypotension was reported more frequently with telmisartan.

The combination of telmisartan and ramipril did not provide a better effect compared with ramipril or telmisartan used separately. With the combination of drugs, cardiovascular mortality and mortality from any cause were quantitatively higher. In addition, a significantly higher incidence of hyperkalemia, renal failure, hypotension and dizziness was recorded in the combination treatment group. Therefore, the use of the combination of telmisartan and ramipril is not recommended for this population.

In the Preventive Treatment to Effectively Prevent Re-Stroke (PRoFESS) study, in patients aged 50 years and older with a recent stroke, sepsis was more common with telmisartan compared to placebo, 0.70% and 0.49% respectively [RR 1.43 (95% confidence interval 1.00–2.06)]; the incidence of fatal sepsis was higher in patients taking telmisartan (0.33%) compared to patients taking placebo (0.16%) [RR 2.07 (95% confidence interval 1.14–3.76)].

The established increased incidence of sepsis with telmisartan may be coincidental or depend on a mechanism that has not yet been established.

Two large randomized controlled trials (ONTARGET and VA NEPHRON-D (Diabetic Nephropathy in the Elderly Study)) examined the use of a combination of ACE inhibitors with angiotensin II receptor blockers.

The ONTARGET study was conducted in patients with cardiovascular and cerebrovascular diseases or type 2 diabetes mellitus with evidence of target organ damage. The VA NEPHRON-D study was conducted in patients with type 2 diabetes mellitus and diabetic nephropathy.

These studies did not show a strong positive effect on the kidneys and/or cardiovascular system and a reduction in mortality, but there was an increased risk of hyperkalemia, acute renal failure and/or hypotension compared with monotherapy.

Therefore, ACE inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy.

The ALTITUDE (Aliskiren in Type 2 Diabetes Using Kidney and Cardiovascular Endpoints) trial assessed the benefit of adding aliskiren to standard therapy with ACE inhibitors or angiotensin II receptor blockers in patients with type 2 diabetes and chronic kidney disease or cardiovascular disease, or both. The trial was stopped early due to an increased risk of adverse events.

Fatal outcomes due to cardiovascular failure and stroke were more frequently observed in the aliskiren group than in the placebo group, as were adverse reactions, including serious ones, related to the diseases (hyperkalemia, hypotension, and renal dysfunction).

Amlodipine

Amlodipine is a calcium ion flux inhibitor belonging to the dihydropyridine group (slow calcium channel blocker or calcium ion antagonist) and blocks the transmembrane flow of calcium ions into myocardial and vascular smooth muscle cells.

The mechanism of antihypertensive action of amlodipine is due to a direct relaxant effect on vascular smooth muscle. The exact mechanism by which amlodipine reduces angina is not fully understood, but amlodipine reduces overall exercise ischemia through the following actions:

• Amlodipine dilates peripheral arterioles and thus reduces total peripheral resistance (afterload). Since the heart rate is unchanged, the reduction in work load on the heart reduces myocardial energy consumption and oxygen demand.
• Amlodipine also partially dilates the main coronary arteries and coronary arterioles in both intact and ischemic areas of the myocardium. This dilation increases the supply of oxygen to the myocardium in patients with vasospastic angina (Prinzmetal's angina or variant angina).

In patients with hypertension, once-daily administration of amlodipine provides clinically significant reductions in supine and standing blood pressure over 24 hours. Due to its slow onset of action, amlodipine does not cause acute hypotension.

In patients with angina, once-daily administration of amlodipine increases total exercise time, time to angina attack, and time to 1 mm ST-segment depression, reduces the frequency of angina attacks, and reduces the need for nitroglycerin.

Amlodipine is not associated with any negative metabolic effects or changes in plasma lipid levels, so it can be used in patients with asthma, diabetes, and gout.

Patients with coronary heart disease (CHD)

The efficacy of amlodipine in preventing clinical events in patients with coronary heart disease (CHD) was evaluated in the independent multicenter, randomized, double-blind, placebo-controlled CAMELOT study involving 1997 patients (comparison of amlodipine and enalapril in reducing thrombosis). Over 2 years, 663 patients received amlodipine at a dose of 5–10 mg, 673 patients received enalapril at a dose of 10–20 mg, and 655 patients received placebo in addition to standard therapy with statins, β-blockers, diuretics, and aspirin. The main efficacy results are shown in Table 1. The results indicate that treatment with amlodipine was associated with fewer hospitalizations for angina and fewer revascularization procedures in patients with CHD.

Table 1

Efficacy indicators in the CAMELOT study

Use in patients with heart failure

Haemodynamic studies and exercise-controlled clinical trials in patients with heart failure, NYHA functional class II–IV, have shown that amlodipine did not lead to clinical deterioration in terms of exercise tolerance, left ventricular ejection fraction, and clinical symptoms.

The aim of the placebo-controlled PRAISE trial was to evaluate the effect of amlodipine in patients with NYHA functional class III–IV heart failure who were receiving digoxin, diuretics, and ACE inhibitors. The study showed that amlodipine did not increase the risk of mortality or morbidity/mortality related to heart failure.

PRAISE-2 is a long-term, placebo-controlled study. The aim of the study was to evaluate the effect of amlodipine in patients with heart failure, NYHA functional class III–IV, without clinical symptoms or objective data confirming or underlying ischemic disease. Patients participating in the study were taking ACE inhibitors, digitalis drugs and diuretics for a long time. The study showed that amlodipine did not affect all-cause cardiovascular mortality. In the study, amlodipine was associated with an increased number of reports of pulmonary edema.

A study (ALLHAT) evaluating different types of treatments to prevent heart attacks

The ALLHAT (Antihypertensive and Lipid-lowering Treatment for Heart Attack Prevention) randomized, double-blind, morbidity/mortality trial was conducted to compare current therapeutic agents: amlodipine 2.5–10 mg/day (calcium channel blocker) or lisinopril 10–40 mg/day (ACE inhibitor) as first-line therapy and the thiazide diuretic chlorthalidone 12.5–25 mg/day in patients with mild to moderate hypertension.

The study included 33,357 hypertensive patients aged 55 years and older who were followed for a mean of 4.9 years. Patients had at least one additional cardiovascular risk factor, including: previous myocardial infarction or stroke >6 months before study entry or evidence of other atherosclerotic cardiovascular disease (overall 51.5%), type 2 diabetes mellitus (36.1%), dyslipidemia with high-density lipoprotein (HDL) <35 mg/dL (11.6%), left ventricular hypertrophy as determined by electrocardiogram or echocardiography (20.9%), and smoking (21.9%).

The primary endpoint was a composite of fatal CHD or nonfatal myocardial infarction. There was no statistically significant difference in the primary endpoint between amlodipine-based and chlorthalidone-based therapy: relative risk 0.98, 95% CI (0.90–1.07), p = 0.65. As a secondary endpoint, the incidence of heart failure (a component of the composite cardiovascular endpoint) was significantly higher in the amlodipine group compared with the chlorthalidone group (10.2% vs. 7.7%, relative risk 1.38, 95% CI [1.25–1.52], p < 0.001). However, there was no significant difference in all-cause mortality between amlodipine-based and chlorthalidone-based therapy (relative risk 0.96, 95% CI [0.89–1.02], p = 0.20).

Pharmacokinetics.

Telmisartan

Absorption

Telmisartan is rapidly absorbed, but the amount absorbed is variable. The mean absolute bioavailability of telmisartan is approximately 50%. When telmisartan is administered with food, the area under the concentration-time curve (AUC) for telmisartan decreases from approximately 6% (40 mg dose) to approximately 19% (160 mg dose). 3 hours after administration, plasma concentrations are similar to those observed when telmisartan is administered in the fasted state.

Linearity/nonlinearity

It is believed that a slight decrease in AUC does not reduce the therapeutic efficacy of the drug. There is no linear relationship between doses and plasma levels. The maximum plasma concentration (Cmax) and, to a lesser extent, the AUC increase disproportionately at doses above 40 mg.

Distribution

Telmisartan is highly bound to plasma proteins (more than 99.5%), mainly to albumin and alpha-1-acid glycoprotein. The mean volume of distribution (Vss) at steady state is approximately 500 l.

Biotransformation

Telmisartan is metabolized by conjugation to the glucuronide of the parent compound, which has no pharmacological activity.

Breeding

Telmisartan is characterized by a biexponential pharmacokinetic curve with a terminal half-life of more than 20 hours. The maximum plasma concentration (Cmax) and, to a lesser extent, the AUC increase disproportionately with dose. When using telmisartan at recommended doses, no clinically significant accumulation has been observed. Plasma concentrations are higher in women than in men, without a corresponding effect on efficacy.

After oral and intravenous administration, telmisartan is almost completely excreted in the feces, mainly unchanged. Cumulative urinary excretion is less than 1% of the dose. Total plasma clearance (Cltot) is high (approximately 1000 ml/min) compared with hepatic blood flow (approximately 1500 ml/min).

Special categories of patients

There was a difference in plasma drug concentrations depending on the patient's gender, with Cmax and AUC being 3- and 2-fold higher in women compared to men, respectively.

Elderly patients

The pharmacokinetics of telmisartan do not differ in elderly patients and patients under 65 years of age.

Patients with renal impairment

In patients with mild, moderate and severe renal impairment, plasma concentrations of telmisartan were doubled. However, lower plasma concentrations were observed in patients with renal failure undergoing dialysis. Telmisartan is highly bound to plasma proteins in patients with renal failure and is not removed by dialysis. The elimination half-life is not altered in patients with renal impairment.

Patients with liver dysfunction

Pharmacokinetic studies in patients with hepatic impairment have shown an increase in absolute bioavailability of almost 100%. The elimination half-life is not altered in these patients.

Amlodipine

Absorption, distribution, plasma protein binding

After oral administration of therapeutic doses, amlodipine is well absorbed with peak blood levels occurring 6–12 hours after administration. Absolute bioavailability is 64–80%.

The volume of distribution of amlodipine is approximately 21 l/kg. In vitro studies have shown that approximately 97.5% of amlodipine circulating in the general circulation is bound to plasma proteins.

Food intake does not affect the bioavailability of amlodipine.

Biotransformation/excretion

The terminal half-life of amlodipine from plasma is approximately 30–50 hours, which corresponds to once-daily dosing. Amlodipine is extensively metabolized in the liver to inactive metabolites. 10% of the parent amlodipine and 60% of the metabolites of amlodipine are excreted in the urine.

Special categories of patients

Patients with liver dysfunction

Clinical data on the use of amlodipine in patients with hepatic impairment are limited. In patients with hepatic impairment, amlodipine clearance is reduced, resulting in a prolonged half-life and an increase in AUC by approximately 40-60%.

Elderly patients

The time to reach maximum plasma concentrations of amlodipine is similar in young and elderly patients. In elderly patients, amlodipine clearance tends to be reduced, resulting in an increase in AUC and half-life. The increase in AUC and prolongation of half-life in patients with congestive heart failure were within the expected range for patients of the age group studied.

Indication

Teldipine is indicated as replacement therapy for the treatment of patients with arterial hypertension who are already treated with telmisartan and amlodipine, administered simultaneously at the same dose as in the combination.

Contraindication

Hypersensitivity to the active substance or to any of the components of the drug.

Pregnancy or planning to become pregnant (see section "Use during pregnancy or breastfeeding").

Biliary obstructive disorders.

Severe liver dysfunction.

Severe arterial hypotension.

Shock (including cardiogenic).

Left ventricular outflow tract obstruction (e.g., due to severe aortic stenosis).

Hemodynamically unstable heart failure after acute myocardial infarction.

The simultaneous use of Teldipine with aliskiren-containing drugs is contraindicated in patients with diabetes mellitus or renal insufficiency (GFR < 60 ml/min/1.73 m2) (see sections “Interaction with other medicinal products and other types of interactions”, “Pharmacodynamics”).

Interaction with other medicinal products and other types of interactions

No interactions between the two components of this fixed combination were observed during clinical studies.

Interactions inherent to the combination

No studies have been conducted on interactions with other drugs.

Should be taken into account when used concomitantly

Other antihypertensive drugs. The blood pressure lowering effect of Teldipine may be enhanced by concomitant use of other antihypertensive drugs.

Medicinal products with blood pressure lowering potential. Based on the pharmacological properties, it can be expected that some medicinal products may enhance the hypotensive effects of all antihypertensive medicinal products, including Teldipine, e.g. baclofen, amifostine. Furthermore, orthostatic hypotension may be exacerbated by alcohol, barbiturates, narcotics or antidepressants.

Corticosteroids (systemic use). Decreased antihypertensive effect.

Interactions related to telmisartan

Potassium-sparing diuretics or potassium supplements. Angiotensin II receptor antagonists such as telmisartan attenuate diuretic-induced potassium loss. Potassium-sparing diuretics such as spironolactone, eplerenone, triamterene or amiloride, potassium supplements or potassium-containing salt substitutes may lead to significant increases 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 angiotensin II receptor antagonists, including telmisartan. If the combination is considered necessary, serum lithium levels should be closely monitored during concomitant use.

Other antihypertensive agents acting on the renin-angiotensin-aldosterone system (RAAS): Clinical data have shown that dual blockade of the renin-angiotensin-aldosterone system (RAAS) with a combination of ACE inhibitors, angiotensin II receptor blockers or aliskiren is associated with a higher incidence of adverse events such as hypotension, hyperkalaemia and decreased renal function (up to acute renal failure) compared with the use of a single RAAS-acting agent (see sections 4.4, 4.3 and 5.1).

Concomitant use requires caution

Nonsteroidal anti-inflammatory drugs (NSAIDs): NSAIDs (i.e. acetylsalicylic acid at anti-inflammatory doses, 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 combination of angiotensin II receptor antagonists and cyclooxygenase inhibitors may lead to further deterioration of renal function, including possible acute renal failure, which is usually reversible. Therefore, this combination should be administered with caution, especially in the elderly. Patients should be adequately hydrated; in addition, renal function should be monitored after initiation of combination therapy and periodically thereafter.

Ramipril: In one study, the combination of telmisartan and ramipril was reported to result in a 2.5-fold increase in AUC0-24 and Cmax of ramipril and ramiprilat. The clinical significance of this observation is unknown.

This should be taken into account when used concomitantly.

Digoxin: When telmisartan was co-administered with digoxin, an increase in mean peak (49%) and trough (20%) plasma digoxin concentrations was observed. Digoxin levels should be monitored at the start of treatment, during dose adjustments and when telmisartan therapy is discontinued to maintain them within the therapeutic range.

Interactions related to amlodipine

Concomitant use requires caution

CYP3A4 inhibitors: Concomitant use of amlodipine with strong or moderate CYP3A4 inhibitors (protease inhibitors, azole antifungals, macrolides such as erythromycin or clarithromycin, verapamil or diltiazem) may result in significant increases in amlodipine concentrations, which may increase the risk of hypotension. These pharmacokinetic changes are clinically more pronounced in elderly patients. Therefore, clinical monitoring and dose adjustment may be necessary.

CYP3A4 inducers: When used concomitantly with known CYP3A4 inducers, the plasma concentration of amlodipine may change. Therefore, blood pressure should be monitored and the dose adjusted both during and after concomitant use, particularly with potent CYP3A4 inducers (such as rifampicin, St. John's wort).

Dantrolene (infusion): Fatal ventricular fibrillation and cardiovascular collapse associated with hyperkalemia have been observed in animals following intravenous administration of verapamil and dantrolene. Because of the risk of hyperkalemia, it is recommended that calcium channel blockers, such as amlodipine, be avoided in patients predisposed to malignant hyperthermia and in the treatment of malignant hyperthermia.

Grapefruit or grapefruit juice. Co-administration of 240 ml of grapefruit juice with a single oral dose of 10 mg amlodipine in 20 healthy volunteers did not show any significant effect on the pharmacokinetics of amlodipine. The concomitant use of amlodipine with grapefruit or grapefruit juice is still not recommended because bioavailability may be increased in some patients, leading to increased antihypertensive effect.

Should be taken into account when used concomitantly

Cyclosporine: Interaction studies between cyclosporine and amlodipine have not been conducted in healthy volunteers or other populations, except in renal transplant patients, where a variable increase in cyclosporine trough concentrations (mean 0-40%) was observed. In renal transplant patients receiving amlodipine, monitoring of cyclosporine concentrations should be considered and, if necessary, a reduction in the cyclosporine dose.

Simvastatin: Coadministration of multiple doses of amlodipine 10 mg and simvastatin 80 mg resulted in a 77% increase in simvastatin exposure compared to simvastatin alone. For patients taking amlodipine, the dose of simvastatin should be limited to 20 mg daily.

Others. Amlodipine has been safely used with digoxin, warfarin, atorvastatin, sildenafil, antacids (aluminum hydroxide, magnesium hydroxide, simethicone), cimetidine, cyclosporine, antibiotics, and oral hypoglycemic drugs. When amlodipine and sildenafil were combined, each drug independently exerted its own blood pressure-lowering effect.

Application features

Pregnancy: Angiotensin II receptor antagonists (ARBs) should not be initiated during pregnancy. Unless continued ARB 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, ARBs should be stopped immediately, and, if appropriate, alternative therapy should be started (see sections 4.3 and 4.8).

Hepatic impairment: Teldipine should not be administered to patients with cholestasis, biliary obstructive disorders or severe hepatic insufficiency (see section 4.3) as telmisartan is excreted mainly in the bile. In these patients, a decrease in the hepatic clearance of telmisartan is expected.

In patients with hepatic impairment, the half-life of amlodipine is prolonged and AUC values are increased: dosage recommendations for such patients have not been established. Therefore, Teldipine should be used with caution in patients with mild to moderate hepatic impairment.

Renal hypertension: There is an increased risk of severe hypotension and renal failure when patients with bilateral renal artery stenosis or stenosis of the artery to a solitary kidney are treated with drugs that affect the renin-angiotensin-aldosterone system.

Renal insufficiency and kidney transplantation. When taking Teldipine in patients with impaired renal function, periodic monitoring of serum potassium and creatinine levels is recommended. There is no experience of the safe use of Teldipine in patients with recent kidney transplantation. Telmisartan and amlodipine are not removed by dialysis.

Intravascular hypovolemia. Symptomatic hypotension, especially after the first dose, may occur in patients with reduced fluid volume and/or sodium due to diuretic therapy, dietary salt restriction, diarrhea or vomiting. Such conditions should be corrected before using telmisartan. If hypotension occurs while taking Teldipine, the patient should be placed in the horizontal position and, if necessary, an intravenous infusion of saline solution should be given. After stabilization of blood pressure, treatment can be continued.

Dual blockade of the renin-angiotensin-aldosterone system (RAAS)

There is evidence that concomitant use of angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers or aliskiren increases the risk of hypotension,