Teldipine

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT TELDIPIN (Teldipin®)

Composition:

Active substances: telmisartan, amlodipine;

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

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.

Medicinal form: Tablets.

Main physicochemical properties:

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

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

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

Teldipin, 80 mg/10 mg tablets: oval, slightly biconvex, two-layered tablets, marbled, brownish-yellow on one side, white to almost white on the other side, with engraving K1.

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

ATC code C09DB04.

Pharmacological properties.

Pharmacodynamics.

Telmisartan

Mechanism of action

Telmisartan is a specific and potent antagonist of angiotensin II receptors (AT1 subtype). Telmisartan competitively displaces angiotensin II from its binding sites on AT1 receptors, which mediate the vasoconstrictor and other actions of angiotensin II. Telmisartan exhibits no partial agonist activity at the AT1 receptor. It selectively binds to AT1 receptors with high affinity, and this binding is long-lasting. Telmisartan has no affinity for other receptors, including AT2 receptors and other less-characterized angiotensin receptors. The functional role of these receptors is unknown, as is the potential effect of their possible "overstimulation" by elevated angiotensin II levels resulting from telmisartan treatment. Telmisartan reduces plasma aldosterone levels. It does not affect plasma renin activity and does not block ion channels. Telmisartan does not inhibit angiotensin-converting enzyme (kininase II), the enzyme responsible for bradykinin degradation. Therefore, potentiation of bradykinin-mediated adverse effects is unlikely.

In humans, telmisartan at a dose of 80 mg almost completely inhibits the blood pressure increase induced by angiotensin II. The blocking effect persists for 24 hours and remains evident 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. Maximum reduction in blood pressure is achieved within 4–8 weeks of treatment initiation and is maintained during long-term therapy.

The antihypertensive effect is sustained over 24 hours after dosing, including the last 4 hours before the next dose, as confirmed by ambulatory blood pressure monitoring. This has been demonstrated by the ratio of blood pressure reduction just before the next dose to the maximum blood pressure reduction, which exceeds 80% after 40 mg and 80 mg of telmisartan in placebo-controlled clinical trials. There is a clear dose- and time-dependent relationship for the return of baseline systolic blood pressure. Similar data for diastolic blood pressure are inconsistent.

In patients with arterial hypertension, telmisartan reduces both systolic and diastolic blood pressure without affecting pulse rate. The contribution of diuretic and natriuretic effects to its antihypertensive action has not been clearly established. The antihypertensive efficacy of telmisartan is comparable to that of antihypertensive drugs from other classes (as demonstrated in clinical trials comparing telmisartan with amlodipine, atenolol, enalapril, hydrochlorothiazide, and lisinopril).

Upon abrupt discontinuation of telmisartan, blood pressure gradually returns to pre-treatment levels over several days without a withdrawal syndrome.

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

Prevention of cardiovascular disease

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

Patients were randomized into one of three treatment groups: telmisartan 80 mg (n = 8,542), ramipril 10 mg (n = 8,576), or combination of telmisartan 80 mg and ramipril 10 mg (n = 8,502). The mean duration of follow-up was 4.5 years.

The effect of telmisartan was non-inferior to ramipril in reducing the primary composite endpoint of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, or hospitalization for heart failure. The incidence of the primary endpoint was similar in the telmisartan (16.7%) and ramipril (16.5%) groups. The risk ratio for telmisartan versus ramipril was 1.01 (97.5% CI 0.93–1.10; p [non-inferiority] = 0.0019 with a margin of 1.13). All-cause mortality was 11.6% and 11.8% in the telmisartan and ramipril groups, respectively.

Telmisartan demonstrated non-inferiority to ramipril regarding the pre-specified secondary endpoint (cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke) [0.99 (97.5% CI 0.90–1.08), p (non-inferiority) = 0.0004], which was the primary endpoint in the reference HOPE (Heart Outcomes Prevention Evaluation) study comparing ramipril with placebo.

In the TRANSCEND study, patients intolerant to ACE inhibitors were randomized to telmisartan 80 mg (n = 2,954) or placebo (n = 2,972), with similar inclusion criteria as in ONTARGET. Both treatments were administered in addition to standard therapy.

The mean duration of follow-up was 4 years and 8 months. No significant difference was observed in the incidence of the primary composite endpoint (cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, or hospitalization for heart failure) [15.7% for telmisartan vs. 17% for placebo; relative risk 0.92 (95% CI 0.81–1.05, p = 0.22)]. However, evidence of benefit was observed for the pre-specified secondary composite endpoint (cardiovascular 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 cardiovascular mortality (relative risk 1.03, 95% CI 0.85–1.24).

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

The combination of telmisartan and ramipril did not provide additional benefit compared to either agent alone. In fact, numerically higher rates of cardiovascular and all-cause mortality were observed in the combination group. Furthermore, significantly higher incidences of hyperkalemia, renal impairment, hypotension, and dizziness were reported in the combination group. Therefore, the use of telmisartan and ramipril in combination is not recommended in this patient population.

In the PRoFESS (Prevention Regimen for Effectively Avoiding Second Strokes) trial, among patients aged 50 years or older who had recently experienced a stroke, sepsis occurred more frequently with telmisartan than with placebo (0.70% vs. 0.49%, respectively [RR 1.43 (95% CI 1.00–2.06)]); fatal sepsis was also higher in the telmisartan group (0.33%) compared to placebo (0.16%) [RR 2.07 (95% CI 1.14–3.76)].

The observed increased incidence of sepsis with telmisartan may be due to chance or to an as-yet-undefined mechanism.

Two large randomized controlled trials (ONTARGET and VA NEPHRON-D) evaluated the use of combined ACE inhibitors with angiotensin receptor blockers.

ONTARGET included patients with cardiovascular or cerebrovascular disease or type 2 diabetes with target organ damage. VA NEPHRON-D included patients with type 2 diabetes and diabetic nephropathy.

These studies did not demonstrate a significant benefit on renal or cardiovascular outcomes or mortality reduction. Instead, they showed an increased risk of hyperkalemia, acute kidney injury, and/or hypotension compared to monotherapy.

Given the similar pharmacodynamic profiles, these findings are also relevant to other ACE inhibitors and angiotensin receptor blockers.

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

The ALTITUDE trial (Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Endpoints) evaluated the benefit of adding aliskiren to standard therapy with ACE inhibitors or angiotensin receptor blockers in patients with type 2 diabetes and chronic kidney disease or cardiovascular disease, or both. The trial was prematurely terminated due to an increased risk of adverse outcomes.

Cardiovascular and stroke-related deaths occurred more frequently in the aliskiren group than in the placebo group, as did adverse events, including serious ones related to disease (hyperkalemia, hypotension, and renal dysfunction).

Amlodipine

Amlodipine is a calcium channel blocker of the dihydropyridine group (a slow-channel calcium antagonist) that inhibits the transmembrane influx of calcium ions into vascular smooth muscle and cardiac muscle cells.

The antihypertensive mechanism of amlodipine is due to direct vasodilatory effects on vascular smooth muscle. The exact mechanism by which amlodipine reduces angina symptoms is not fully understood, but it reduces myocardial oxygen demand through the following actions:

• Amlodipine dilates peripheral arterioles, thereby reducing total peripheral resistance (afterload). Since heart rate is unaffected, this reduces cardiac workload, myocardial energy consumption, and oxygen demand.
• Amlodipine also causes partial dilation of major coronary arteries and coronary arterioles, both in normal and ischemic myocardial regions. This improves oxygen delivery to the myocardium in patients with vasospastic angina (Prinzmetal's or variant angina).

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

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

Amlodipine has no adverse metabolic effects or changes in plasma lipid levels, making it suitable for use in patients with asthma, diabetes, and gout.

Patients with ischemic heart disease (IHD)

The efficacy of amlodipine in preventing clinical events in patients with ischemic heart disease (IHD) was evaluated in the CAMELOT trial, a multicenter, randomized, double-blind, placebo-controlled study involving 1,997 patients (comparing amlodipine and enalapril in preventing thrombotic events). Over 2 years, 663 patients received amlodipine 5–10 mg, 673 received enalapril 10–20 mg, and 655 received placebo, all in addition to standard therapy with statins, β-blockers, diuretics, and aspirin. The key efficacy outcomes are presented in Table 1. The results indicate that amlodipine treatment was associated with fewer hospitalizations for angina and fewer revascularization procedures in patients with IHD.

Table 1

Efficacy outcomes in the CAMELOT study

Frequency of cardiovascular events, number (%)				Amlodipine vs placebo
Outcome	Amlodipine	Placebo	Enalapril	Relative risk (95 % Cl)	p-value
Primary endpoint Adverse cardiovascular events	110 (16.6)	151 (23.1)	136 (20.0)	0.69 (0.54–0.88)	0.003
Individual components Coronary revascularization Hospitalizations due to angina Non-fatal myocardial infarction Stroke or transient ischemic attack Cardiovascular mortality Hospitalizations due to congestive heart failure Cardiac arrest with subsequent resuscitation Newly diagnosed peripheral vascular disease	78 (11.8) 51 (17.7) 14 (2.1) 6 (0.9) 5 (0.8) 3 (0.5) 0 5 (0.8)	103 (15.7) 84 (12.8) 19 (2.9) 12 (1.8) 2 (0.3) 5 (0.8) 4 (0.6) 2 (0.3)	95 (14.1) 86 (12.8) 11 (1.6) 8 (1.2) 5 (0.7) 4 (0.6) 1 (0.1) 8 (1.2)	0.73 (0.54–0.98) 0.58 (0.41–0.82) 0.73 (0.37–1.46) 0.50 (0.19–1.32) 2.46 (0.48–12.7) 0.59 (0.14–2.47) ̶ 2.6 (0.5–13.4)	0.03 0.002 0.37 0.15 0.27 0.46 0.04 0.24

Use in patients with heart failure

Hemodynamic studies and clinical exercise tolerance studies in patients with heart failure, NYHA functional class II–IV, have shown that amlodipine does not lead to clinical worsening in terms of exercise tolerance, left ventricular ejection fraction, or clinical symptoms.

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

PRAISE-2 was a long-term, placebo-controlled study. The objective was to evaluate the effect of amlodipine in patients with heart failure, NYHA functional class III–IV, without clinical symptoms or objective evidence of underlying ischemic heart disease. Patients enrolled in the study were on long-term treatment with ACE inhibitors, digitalis preparations, and diuretics. The study showed that amlodipine had no effect on overall cardiovascular mortality. However, during the study, amlodipine administration was associated with an increased number of reports of pulmonary edema.

ALLHAT study – evaluation of different treatment types for prevention of heart attacks

The randomized, double-blind ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial) morbidity/mortality study was conducted to compare modern therapeutic agents: amlodipine at a dose of 2.5–10 mg/day (calcium channel blocker) or lisinopril at a dose of 10–40 mg/day (ACE inhibitor) as first-line therapy versus the thiazide diuretic chlorthalidone at a dose of 12.5–25 mg/day, in patients with mild to moderate arterial hypertension.

The study included 33,357 hypertensive patients aged 55 years and older, with a mean follow-up of 4.9 years. Patients had at least one additional cardiovascular risk factor, including: prior myocardial infarction or stroke >6 months before enrollment, or documented other atherosclerotic cardiovascular disease (51.5% total), type 2 diabetes (36.1%), low HDL (high-density lipoprotein) cholesterol <35 mg/dL (11.6%), left ventricular hypertrophy confirmed by electrocardiography or echocardiography (20.9%), or smoking (21.9%).

The primary endpoint was a composite of fatal coronary heart disease or non-fatal myocardial infarction. There was no statistically significant difference in the primary endpoint between amlodipine-based therapy 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 to 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 extent of absorption varies. The mean absolute bioavailability of telmisartan is approximately 50%. Administration with food reduces the area under the concentration-time curve (AUC) for telmisartan by approximately 6% (40 mg dose) to 19% (160 mg dose). Plasma concentrations 3 hours after dosing are similar to those observed under fasting conditions.

Linearity/non-linearity

The slight reduction in AUC is not considered to diminish the therapeutic efficacy of the drug. There is no linear relationship between dose and plasma levels. Maximum plasma concentration (Cmax) and, to a lesser extent, AUC increase disproportionately at doses above 40 mg.

Distribution

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

Biotransformation

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

Elimination

Telmisartan exhibits biphasic pharmacokinetics with a terminal elimination half-life of over 20 hours. Maximum plasma concentration (Cmax) and, to a lesser extent, AUC increase disproportionately with dose. With recommended doses of telmisartan, no clinically relevant accumulation has been observed. Plasma concentrations are higher in women than in men, without a corresponding impact on efficacy.

After both oral and intravenous administration, telmisartan is almost entirely eliminated via feces, primarily in unchanged form. Cumulative urinary excretion accounts for less than 1% of the administered dose. Total plasma clearance (Cltot) is high (approximately 1000 mL/min) compared to hepatic blood flow (approximately 1500 mL/min).

Special patient populations

Gender

A difference in plasma drug concentrations by gender was observed, with Cmax and AUC approximately 3 and 2 times higher, respectively, in women compared to men.

Elderly patients

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

Patients with renal impairment

Plasma concentrations of telmisartan were doubled in patients with mild, moderate, and severe renal impairment. However, in dialysis-dependent patients with renal failure, lower plasma concentrations were observed. Telmisartan is highly protein-bound in patients with renal failure and is not removed by dialysis. The elimination half-life is unchanged in patients with renal impairment.

Patients with hepatic impairment

Pharmacokinetic studies in patients with hepatic impairment showed an increase in absolute bioavailability by nearly 100%. The elimination half-life in these patients is unchanged.

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 dosing. Absolute bioavailability ranges from 64% to 80%.

The volume of distribution of amlodipine is approximately 21 L/kg. In vitro studies have shown that about 97.5% of circulating amlodipine is bound to plasma proteins.

Food intake does not affect the bioavailability of amlodipine.

Biotransformation/elimination

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

Special patient populations

Patients with hepatic impairment

Clinical data on amlodipine use in patients with hepatic impairment are limited. In patients with liver disease, reduced clearance of amlodipine is observed, leading to a prolonged elimination 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 younger and elderly patients. In elderly patients, amlodipine clearance tends to be reduced, resulting in increased AUC and prolonged elimination half-life. Increases in AUC and prolonged elimination half-life in patients with congestive heart failure were consistent with those expected for the age group studied.

Clinical characteristics.

Indications.

Teldipine is indicated as replacement therapy for the treatment of patients with arterial hypertension who have previously been treated with telmisartan and amlodipine administered concomitantly at the same doses as in the combination.

Contraindications.

• Hypersensitivity to the active substance or to any of the excipients.
• Pregnancy or planned pregnancy (see section "Use in pregnancy or breastfeeding").
• Biliary obstructive disorders.
• Severe hepatic impairment.
• Severe arterial hypotension.
• Shock (including cardiogenic shock).
• Left ventricular outflow tract obstruction (e.g., due to severe aortic stenosis).
• Hemodynamically unstable heart failure following acute myocardial infarction.
• Concomitant use of Teldipine with medicinal products containing aliskiren is contraindicated in patients with diabetes mellitus or patients with renal impairment (GFR < 60 mL/min/1.73 m²) (see sections "Interaction with other medicinal products and other forms of interaction", "Pharmacodynamics").

Interaction with other medicinal products and other forms of interaction.

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

Interactions inherent to the combination

No studies on interactions with other drugs have been conducted.

Consider when co-administering

Other antihypertensive medicinal products. The antihypertensive effect of Teldipine may be enhanced by concomitant use of other antihypertensive agents.

MEDICINAL PRODUCTS WITH POTENTIAL TO REDUCE BLOOD PRESSURE. Based on pharmacological properties, it can be expected that certain medicinal products may enhance the hypotensive effects of all antihypertensive agents, including Teldipine, e.g., baclofen, amifostine. Moreover, orthostatic hypotension may be intensified by alcohol consumption, barbiturates, narcotics, or antidepressants.

Systemic corticosteroids. Reduction of antihypertensive effect.

Interactions related 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 significant increases in serum potassium concentration. If concomitant use is indicated due to documented hypokalemia, they should be used with caution and serum potassium levels should be monitored frequently.

Lithium. Cases of reversible increases in serum lithium concentrations and toxicity have been reported during concomitant use of lithium with ACE inhibitors and angiotensin II receptor antagonists, including telmisartan. If combination therapy is considered necessary, serum lithium levels should be monitored closely during concomitant use.

Other antihypertensive agents affecting the renin-angiotensin-aldosterone system (RAAS). Clinical data have shown that dual blockade of the renin-angiotensin-aldosterone system (RAAS) by combining ACE inhibitors, angiotensin II receptor blockers, or aliskiren is associated with a higher incidence of adverse effects such as arterial hypotension, hyperkalemia, and decreased renal function (up to acute renal failure), compared to using a single RAAS-acting agent (see sections "Special precautions for use", "Contraindications", and "Pharmacological properties").

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 impaired renal function (e.g., dehydrated patients or elderly patients with impaired renal function), concomitant use of angiotensin II receptor antagonists and cyclooxygenase-inhibiting agents may lead to further deterioration of renal function, including possible acute renal failure, which is usually reversible. Therefore, this combination should be used with caution, especially in elderly patients. Adequate hydration should be ensured; in addition, renal function should be monitored after initiation of combined therapy and periodically thereafter.

Ramipril. In one study, co-administration of telmisartan and ramipril resulted in a 2.5-fold increase in AUC_0–24 and C_max of ramipril and ramiprilat. The clinical significance of this observation is unknown.

Consider when co-administering

Digoxin. Increased mean peak (49%) and trough (20%) plasma digoxin concentrations have been observed when telmisartan is co-administered with digoxin. Digoxin levels should be monitored at the start of treatment, during dose adjustments, and upon discontinuation of telmisartan therapy to maintain levels 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 significantly increased amlodipine concentrations, increasing 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. Plasma concentrations of amlodipine may change when used concomitantly with known CYP3A4 inducers. Therefore, blood pressure should be monitored and dosage adjusted both during and after concomitant use of such agents, particularly strong CYP3A4 inducers (e.g., rifampicin, products containing St. John's wort).

Dantrolene (infusions). Ventricular fibrillation with fatal outcome and cardiovascular collapse associated with hyperkalemia have been observed in animals after intravenous administration of verapamil and dantrolene. Due to the risk of hyperkalemia, calcium channel blockers such as amlodipine should be avoided in patients susceptible to malignant hyperthermia and during treatment of malignant hyperthermia.

Grapefruit or grapefruit juice. Concomitant administration of 240 mL of grapefruit juice with a single oral dose of 10 mg amlodipine in 20 healthy volunteers did not show a significant effect on the pharmacokinetic properties of amlodipine. However, concomitant use of amlodipine with grapefruit or grapefruit juice is not recommended, as bioavailability may increase in some patients, leading to enhanced antihypertensive effects.

Consider when co-administering

Tacrolimus. There is a risk of increased blood levels of tacrolimus when used concomitantly with amlodipine, although the pharmacokinetic mechanism of this interaction is not fully understood. To avoid tacrolimus toxicity, regular monitoring of blood tacrolimus levels and dose adjustment, if necessary, should be performed when amlodipine is co-administered with tacrolimus.

Cyclosporine. Interaction studies between cyclosporine and amlodipine have not been conducted in healthy volunteers or other patient groups, except in kidney transplant recipients, in whom variable increases in cyclosporine trough concentrations (on average 0–40%) were observed. In kidney transplant recipients receiving amlodipine, monitoring of cyclosporine concentrations should be considered, and cyclosporine dosage reduced if necessary.

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

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

Special precautions for use.

Intestinal angioneurotic edema

Cases of intestinal angioneurotic edema have been reported in patients receiving angiotensin II receptor antagonists (see section "Adverse reactions"). These patients experienced symptoms such as abdominal pain, nausea, vomiting, and diarrhea. Symptoms resolved after discontinuation of angiotensin II receptor antagonists. If a patient is diagnosed with intestinal angioneurotic edema, treatment with the medicinal product should be discontinued and appropriate monitoring initiated until complete resolution of symptoms.

Pregnancy. Therapy with angiotensin II receptor antagonists (ARBs) should not be initiated during pregnancy. While ARB therapy is considered necessary, patients planning pregnancy should switch to alternative antihypertensive treatment with an established safety profile during pregnancy. If pregnancy is confirmed, ARB use should be stopped immediately and alternative therapy initiated if necessary (see sections "Contraindications" and "Use in pregnancy or lactation").

Hepatic impairment. Teldepin should not be prescribed to patients with cholestasis, biliary obstructive disorders, or severe hepatic insufficiency (see section "Contraindications"), as telmisartan is primarily excreted via bile. Reduced hepatic clearance of telmisartan is expected in these patients.

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

Renovascular hypertension. There is an increased risk of severe arterial hypotension and renal failure when drugs affecting the renin-angiotensin-aldosterone system (RAAS) are administered to patients with bilateral renal artery stenosis or stenosis of the artery of a solitary kidney.

Renal impairment and kidney transplantation. Periodic monitoring of serum potassium and creatinine levels is recommended in patients with impaired renal function receiving Teldepin. There is no experience with the safe use of Teldepin in patients who have recently undergone kidney transplantation. Telmisartan and amlodipine are not removed by dialysis.

Intravascular hypovolemia. Symptomatic hypotension, particularly after the first dose, may occur in patients with reduced fluid and/or sodium volume due to diuretic therapy, dietary salt restriction, diarrhea, or vomiting. Such conditions should be corrected before initiating telmisartan. If arterial hypotension occurs during Teldepin treatment, the patient should be placed in a supine position and, if necessary, receive intravenous infusion of physiological saline. Therapy may be continued after stabilization of blood pressure.

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

Evidence indicates that concomitant use of angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers, or aliskiren increases the risk of hypotension, hyperkalemia, and reduced renal function (up to acute renal failure). Therefore, dual blockade of RAAS by combining ACE inhibitors, angiotensin II receptor blockers, or aliskiren is not recommended (see sections "Interaction with other medicinal products and other forms of interaction" and "Pharmacological properties").

If dual blockade is considered absolutely necessary, it should be performed only under specialist supervision and with continuous careful monitoring of renal function, electrolyte levels, and blood pressure.

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

Other conditions requiring stimulation of the renin-angiotensin-aldosterone system. In patients whose vascular tone and renal function primarily depend on the activity of the renin-angiotensin-aldosterone system (e.g., patients with congestive heart failure or severe renal disease, including renal artery stenosis), treatment with drugs affecting this system, such as telmisartan, may be associated with acute arterial hypotension, hyperazotemia, oliguria, or rarely acute renal failure (see section "Adverse reactions").

Primary hyperaldosteronism. Patients with primary hyperaldosteronism generally do not respond to antihypertensive drugs acting via blockade of the renin-angiotensin system. Therefore, use of Teldepin is not recommended.

Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy. As with other vasodilators, particular caution is required when treating patients with aortic or mitral valve stenosis or obstructive hypertrophic cardiomyopathy.

Unstable angina, acute myocardial infarction. There are no data on the use of Teldepin in unstable angina or during and within one month following myocardial infarction.

Heart failure. In a long-term placebo-controlled study (PRAISE-2) involving patients with NYHA class III and IV non-ischemic heart failure, amlodipine use was associated with an increased number of reports of pulmonary edema, despite no significant difference in the frequency of worsening heart failure compared to placebo.

Diabetic patients treated with insulin or antidiabetic medicinal products

Hypoglycemia may develop in such patients during telmisartan treatment. Appropriate monitoring of blood glucose levels should be considered in these patients. Dose adjustment of insulin or antidiabetic medicinal products may be required.

Hyperkalemia. Hyperkalemia may occur during treatment with drugs affecting the renin-angiotensin-aldosterone system.

In elderly individuals, patients with renal impairment, diabetes, those concurrently treated with other medicinal products that may increase potassium levels, and/or those with concomitant diseases, hyperkalemia may lead to fatal outcomes.

Before considering concomitant use of medicinal products that inhibit the renin-angiotensin system, the benefit-risk ratio must be carefully evaluated.

Major risk factors for hyperkalemia that require attention:

• Diabetes mellitus, renal impairment, age over 70 years;
• Combination therapy with one or more other drugs affecting the renin-angiotensin system and/or potassium supplements. Medicinal products or therapeutic groups that may provoke hyperkalemia include potassium-containing salt substitutes, potassium-sparing diuretics, ACE inhibitors, angiotensin II receptor antagonists, non-steroidal anti-inflammatory drugs (NSAIDs, including selective COX-2 inhibitors), heparin, immunosuppressants (cyclosporine or tacrolimus), and trimethoprim;
• Concomitant diseases, especially dehydration, acute heart decompensation, metabolic acidosis, worsening renal function, sudden deterioration in kidney status (e.g., infections), cell lysis (e.g., acute limb ischemia, rhabdomyolysis, extensive trauma).

Patients at risk require close monitoring of serum potassium concentration (see section "Interaction with other medicinal products and other forms of interaction").

Ethnic differences. As with all other angiotensin II receptor antagonists, telmisartan is less effective in reducing blood pressure in black patients compared to other racial groups. This may be explained by the higher prevalence of low-renin states in black patients with arterial hypertension.

Other. As with any other antihypertensive agent, significant reduction in blood pressure in patients with ischemic heart disease or myocardial ischemia may lead to myocardial infarction or stroke.

Lactose

Teldepin contains lactose; therefore, patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency, or glucose/galactose malabsorption should not take this medicinal product.

Sorbitol. The medicinal product contains sorbitol (E 420). Patients with rare hereditary fructose intolerance should not use this medicinal product.

Sodium. The medicinal product contains less than 1 mmol (23 mg)/dose of sodium, i.e., it is practically sodium-free.

Use during pregnancy or lactation.

Pregnancy

Use of Teldepin is contraindicated in pregnant women and women planning pregnancy (see sections "Contraindications" and "Special precautions for use").

Telmisartan

There are no data on the use of telmisartan in pregnant women. Animal studies have shown reproductive toxicity.

Epidemiological evidence on teratogenic risk following ACE inhibitor use during the first trimester of pregnancy is inconclusive; however, a small increased risk cannot be excluded. There are no controlled epidemiological data on the risk of angiotensin II receptor antagonists, but similar risks may exist for this class of medicinal products. While ARB therapy is considered necessary, patients planning pregnancy should switch to alternative antihypertensive treatment with an established safety profile during pregnancy. If pregnancy is confirmed, ARB use should be stopped immediately and alternative therapy initiated if necessary.

Treatment with angiotensin II receptor antagonists during the second and third trimesters of pregnancy causes fetotoxicity in humans (reduced renal function, oligohydramnios, delayed skull ossification) and neonatal toxicity (renal failure, arterial hypotension, hyperkalemia). If angiotensin II receptor antagonists are used from the second trimester of pregnancy, ultrasound monitoring of fetal renal function and skull condition is recommended. Newborns whose mothers received angiotensin II receptor antagonists should be closely observed for arterial hypotension (see sections "Contraindications" and "Special precautions for use").

Amlodipine

The safety of amlodipine use in pregnant women has not been established. Reproductive toxicity was observed in animal studies at high doses.

Lactation

Use of Teldepin during lactation is contraindicated; alternative therapy with medicinal products with a better-established safety profile should be preferred, especially when breastfeeding newborns or preterm infants.

Amlodipine can pass into breast milk. The fraction of maternal dose received by infants was estimated at an interquartile range of 3–7%, maximum 15%. The effect of amlodipine on infants is unknown.

Fertility

Telmisartan

Preclinical studies did not reveal any effect of telmisartan on fertility in males or females.

Amlodipine

In some patients treated with calcium channel blockers, reversible biochemical changes in sperm heads have been observed. Clinical data on the effect of amlodipine on fertility are insufficient. In one rat study, adverse effects on male fertility were observed.

Ability to affect reaction speed when driving or operating machinery.

Teldepin has a moderate effect on reaction speed when driving or operating machinery. Patients should be informed that adverse reactions such as syncope, somnolence, dizziness, or vertigo may occur during treatment (see section "Adverse reactions"). Therefore, caution should be exercised when driving or operating machinery. If patients experience such adverse reactions, they should avoid potentially hazardous activities such as driving or operating mechanical equipment.

Method of Administration and Dosage

Dosage

The recommended dose of Teldipin is 1 tablet per day.

Fixed-dose combination is not suitable for initial therapy.

Before switching to Teldipin, patients should have achieved the desired therapeutic effect while receiving stable doses of the individual monocomponents. The dosage of Teldipin should be selected based on the doses of both components that were used prior to switching to the fixed combination.

The maximum recommended dose of amlodipine is 10 mg per day, and the maximum recommended dose of telmisartan is 80 mg per day. The drug is intended for long-term treatment.

Concomitant use of amlodipine with grapefruit or grapefruit juice is not recommended, as bioavailability may increase in some patients, leading to an enhanced antihypertensive effect (see section "Interaction with Other Medicinal Products and Other Forms of Interaction").

Special Patient Populations

Elderly patients. Dose adjustment is not required in elderly patients. Caution should be exercised when increasing the dose in elderly patients (see sections "Special Warnings and Precautions for Use" and "Pharmacokinetics").

Patients with renal impairment. Dose adjustment is not necessary in patients with mild to moderate renal impairment. Experience with the use of Teldipin in patients with severe renal impairment and those undergoing hemodialysis is limited. Teldipin should be administered with caution in such patients, as neither amlodipine nor telmisartan is dialyzable.

Patients with hepatic impairment. Teldipin is contraindicated in patients with severe hepatic impairment (see section "Contraindications"). The drug should be used with caution in patients with mild to moderate hepatic impairment. The dose of telmisartan in these patients should not exceed 40 mg per day (see section "Special Warnings and Precautions for Use").

Method of Administration

Teldipin may be taken independently of food intake. It is recommended to take Teldipin tablets with a small amount of liquid.

Children. Safety and efficacy of Teldipin in pediatric patients (under 18 years of age) have not been established. Data are lacking.

Overdose.

Symptoms. Symptoms of overdose are expected to reflect exaggerated pharmacological effects. The most prominent manifestations of telmisartan overdose are arterial hypotension and tachycardia; bradycardia, dizziness, increased serum creatinine levels, and acute renal failure have also been reported.

Overdose with amlodipine may lead to excessive peripheral vasodilation and possibly reflex tachycardia. Marked and potentially prolonged systemic hypotension has been reported, including shock with fatal outcome.

Rare cases of non-cardiogenic pulmonary edema following amlodipine overdose have been reported, which may present with delayed onset (24–48 hours after ingestion) and may require mechanical ventilation. Contributing factors to the development of non-cardiogenic pulmonary edema may include early resuscitation measures (including fluid overload) aimed at maintaining perfusion and cardiac output.

Treatment. Close monitoring of the patient is required; treatment should be symptomatic and supportive. Therapeutic measures depend on the time of ingestion and severity of symptoms.

Recommended measures include induction of emesis and/or gastric lavage. Activated charcoal may be beneficial in cases of overdose with either telmisartan or amlodipine.

Serum electrolytes and creatinine levels should be monitored regularly. In case of arterial hypotension, the patient should be placed in a supine position with legs elevated, and intravascular volume and electrolyte balance should be rapidly corrected. Supportive therapy should be provided. Intravenous calcium gluconate may be considered to counteract calcium channel blockade effects. Neither telmisartan nor amlodipine is removed by hemodialysis.

Adverse reactions.

Safety profile characterization

The most common adverse reactions are dizziness and peripheral edema. Complete loss of consciousness may rarely occur (less than 1 case per 1000 patients).

Adverse reactions previously reported for either component of the medicinal product (telmisartan or amlodipine) may potentially also occur with Teldepin, even if they were not observed during clinical trials or in the post-marketing period.

Characterization of adverse reactions

Adverse reactions are listed by frequency as follows: very common (≥ 1/10), common (≥ 1/100 – <1/10), uncommon (≥ 1/1000 – < 1/100), rare (≥1/10000 – < 1/1000), very rare (<1/10000), and not known (cannot be estimated from available data).

Within each frequency category, adverse effects are listed in order of decreasing severity.

Table 2

MedDRA System Organ Class			Telmisartan/Amlodipine	Telmisartan	Amlodipine
Infections and infestations
Uncommon				Upper respiratory tract infections, including pharyngitis and sinusitis, urinary tract infections, including cystitis
Rare			Cystitis	Sepsis, including fatal outcome1
Blood and lymphatic system disorders
Uncommon				Anemia
Rare				Thrombocytopenia, eosinophilia
Very rare					Leukopenia, thrombocytopenia
Immune system disorders
Rare				Hypersensitivity, anaphylactic reaction
Very rare					Hypersensitivity
Metabolism and nutrition disorders
Uncommon				Hyperkalemia
Rare				Hypoglycemia (in patients with diabetes mellitus)
Very rare					Hyperglycemia
Psychiatric disorders
Uncommon					Mood changes
Rare		Depression, anxiety, insomnia			Confusion
Nervous system disorders
Common		Dizziness
Uncommon		Somnolence, migraine, headache, paresthesia
Rare		Syncope, peripheral neuropathy, hypesthesia, dysgeusia, tremor
Very rare					Extrapyramidal disorder
Eye disorders
Uncommon					Visual disturbance
Rare				Visual disorders
Ear and labyrinth disorders
Uncommon		Vertigo			Tinnitus
Cardiac disorders
Uncommon		Bradycardia, palpitations
Rare				Tachycardia
Very rare					Myocardial infarction, arrhythmia, ventricular tachycardia, atrial fibrillation
Vascular disorders
Uncommon		Arterial hypotension, orthostatic hypotension, flushing
Very rare					Vasculitis
Respiratory, thoracic and mediastinal disorders
Uncommon		Cough		Dyspnea	Dyspnea, rhinitis
Very rare		Interstitial lung disease3
Gastrointestinal disorders
Uncommon		Abdominal pain, diarrhea, nausea		Flatulence	Changes in defecation rhythm
Rare		Vomiting, dyspepsia, dry mouth		Epigastric discomfort
Very rare					Pancreatitis, gastritis, gingival hyperplasia
Hepatobiliary disorders
Rare				Liver function abnormalities/liver disorders2
Very rare					Hepatitis, jaundice, increased liver transaminases (mainly cholestasis-related)
Skin and subcutaneous tissue disorders
Uncommon		Pruritus		Increased sweating	Alopecia, purpura, skin color changes, increased sweating
Rare		Eczema, erythema, rash		Angioedema (with fatal outcome), drug eruption, toxic skin eruption, urticaria
Very rare					Angioedema, erythema multiforme, urticaria, exfoliative dermatitis, Stevens-Johnson syndrome, Quincke's edema, photosensitivity
Unknown					Toxic epidermal necrolysis
Musculoskeletal and connective tissue disorders
Uncommon		Arthralgia, muscle spasms (leg cramps), myalgia
Rare		Back pain, limb pain (leg pain)		Tendon pain (symptoms similar to tendinitis)
Renal and urinary disorders
Uncommon				Renal function impairment, including acute renal failure	Urinary disorders, increased urinary frequency
Rare		Nocturia
Reproductive system and breast disorders
Uncommon		Erectile dysfunction			Gynecomastia
General disorders
Common		Peripheral edema
Uncommon		Asthenia, chest pain, increased fatigue, swelling			Pain
Rare		Malaise		Influenza-like symptoms
Investigations
Uncommon	Elevated liver enzymes			Increased blood creatinine	Increased body weight, decreased body weight
Rare	Elevated blood uric acid			Elevated blood creatine phosphokinase, decreased hemoglobin

1This adverse reaction may be coincidental or may indicate a process whose nature is currently unknown.

2Most cases of hepatic function disorders/hepatic disorders were observed in patients of Japanese nationality. Patients of Japanese nationality are more prone to these adverse reactions.

3Interstitial lung disease (mainly interstitial pneumonia and eosinophilic pneumonia) has been reported during the post-marketing period with telmisartan use and was transient.

Description of selected adverse reactions

Intestinal angioneurotic edema

Cases of intestinal angioneurotic edema have been reported following the use of angiotensin II receptor antagonists (see section "Dosage and administration").

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the Automated Information System for Pharmacovigilance at the following link: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions.

Store at temperatures not exceeding 30°C, in the original packaging to protect from light.

Keep out of reach of children.

Packaging.

10 tablets in a blister; 3 or 9 blisters in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

KRKA, d.d., Novo mesto, Slovenia / KRKA, d.d., Novo mesto, Slovenia.

Manufacturer's address and location of operations.

Šmarješka cesta 6, 8501 Novo mesto, Slovenia / Smarjeska cesta 6, 8501 Novo mesto, Slovenia.