Telmiста® trio
UkraineTable of Contents
INSTRUCTIONS for medical use of the medicinal product Telmista® Trio (Telmista® Trio)
Composition:
Active substances: telmisartan, amlodipine, hydrochlorothiazide;
One tablet contains 40 mg telmisartan, 5 mg amlodipine (as amlodipine besylate) and 12.5 mg hydrochlorothiazide, or 80 mg telmisartan, 5 mg amlodipine (as amlodipine besylate) and 12.5 mg hydrochlorothiazide, or 80 mg telmisartan, 10 mg amlodipine (as amlodipine besylate) and 12.5 mg hydrochlorothiazide, or 80 mg telmisartan, 10 mg amlodipine (as amlodipine besylate) and 25 mg hydrochlorothiazide;
Excipients: povidone K30, sodium hydroxide, lactose monohydrate, meglumine, crospovidone, microcrystalline cellulose, sodium stearyl fumarate, pregelatinized starch, sodium starch glycolate type A, magnesium stearate, colloidal anhydrous silicon dioxide, iron oxide yellow (E 172) – for tablets only,
40 mg/5 mg/12.5 mg,
80 mg/10 mg/12.5 mg, 80 mg/10 mg/25 mg; iron oxide red (E 172) – for tablets only,
80 mg/5 mg/12.5 mg, 80 mg/10 mg/12.5 mg.
Medicinal form. Tablets.
Main physicochemical properties:
Telmista® Trio, tablets, 40 mg/5 mg/12.5 mg: round, biconvex, bilayer tablets, one side from white to almost white with engraving L1, the other side brownish-yellow, mottled;
Telmista® Trio, tablets, 80 mg/5 mg/12.5 mg: oval, biconvex, bilayer tablets, one side from white to almost white with engraving L2, the other side pink, mottled;
Telmista® Trio, tablets, 80 mg/10 mg/12.5 mg: oval, biconvex, bilayer tablets, one side from white to almost white with engraving L3, the other side orange, mottled;
Telmista® Trio, tablets, 80 mg/10 mg/25 mg: oval, biconvex, bilayer tablets, one side from white to almost white with engraving L4, the other side brownish-yellow, mottled.
Pharmacotherapeutic group. Agents acting on the renin-angiotensin system. Angiotensin II antagonists and calcium channel blockers, other combinations.
ATC code C09DX08.
Pharmacological Properties.
Pharmacodynamics.
Telista® Trio is a combination of the angiotensin II receptor antagonist telmisartan, the calcium influx inhibitor amlodipine, and the thiazide diuretic hydrochlorothiazide.
Mechanism of Action
Telmisartan is a specific and effective oral antagonist of angiotensin II receptors type 1 (AT1). Telmisartan displaces angiotensin II with very high affinity from its binding sites on AT1 receptors, which mediate the known effects of angiotensin II. Telmisartan has no partial agonist activity at the AT1 receptor. Telmisartan selectively binds to AT1 receptors. Binding is long-lasting. Telmisartan has no affinity for other receptors, including AT2 and other less-characterized AT receptors. The functional role of these receptors is unknown, as is the effect of their potential "overstimulation" by angiotensin II, whose levels increase 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), the enzyme that also degrades bradykinin. Therefore, potentiation of bradykinin-mediated adverse effects is not expected.
Amlodipine is a dihydropyridine calcium influx inhibitor (a slow calcium channel blocker or calcium antagonist) that inhibits transmembrane influx of calcium ions into cardiac and vascular smooth muscle. The antihypertensive mechanism of action of amlodipine is due to its vasodilatory effect on vascular smooth muscle.
Hydrochlorothiazide is a thiazide diuretic. The mechanism of the antihypertensive action of thiazide diuretics is not fully understood. Thiazides affect electrolyte reabsorption mechanisms in renal tubules, directly increasing the excretion of sodium and chloride in approximately equivalent amounts. The diuretic effect of hydrochlorothiazide reduces plasma volume, increases plasma renin activity, increases aldosterone secretion, leading to increased potassium excretion in urine, loss of bicarbonate, and decreased serum potassium levels. It is likely that due to blockade of the renin-angiotensin-aldosterone system, concomitant use with telmisartan reduces potassium loss associated with these diuretics.
Pharmacodynamic Effects
In healthy volunteers, telmisartan at a dose of 80 mg almost completely inhibits the increase in blood pressure induced by angiotensin II. The blocking effect persists for 24 hours and remains evident up to 48 hours.
After the first dose of telmisartan, antihypertensive activity gradually develops within 3 hours. Maximum reduction in blood pressure is usually achieved within 4–8 weeks of starting treatment and is maintained during long-term therapy. The antihypertensive effect remains consistently over 24 hours after drug administration, including the last 4 hours before the next dose, as confirmed by ambulatory blood pressure monitoring. This is supported by measurements taken at peak effect and immediately before the next dose (the minimum/maximum effect ratio remains stably above 80% after doses of 40 and 80 mg telmisartan in placebo-controlled clinical trials).
In patients with arterial hypertension, telmisartan reduces both systolic and diastolic blood pressure without affecting pulse rate. The antihypertensive efficacy of telmisartan is comparable to that of agents from other classes of antihypertensive drugs (demonstrated in clinical trials comparing telmisartan with amlodipine, atenolol, enalapril, hydrochlorothiazide, and lisinopril).
Upon abrupt discontinuation of telmisartan therapy, blood pressure gradually returns to pre-treatment levels over several days, without risk of withdrawal syndrome.
In clinical trials comparing two antihypertensive agents, the incidence of dry cough was significantly lower in patients taking telmisartan than in those receiving ACE inhibitors.
In patients with arterial hypertension, once-daily administration of amlodipine provides clinically significant reduction in blood pressure in both supine and standing positions over a 24-hour interval. Due to its slow onset of action, acute arterial hypotension is not typical with amlodipine. Amlodipine has not been associated with any adverse metabolic effects or changes in plasma lipids and is suitable for patients with asthma, diabetes, and gout.
After administration of hydrochlorothiazide, diuresis begins within 2 hours, maximum effect is reached approximately within 4 hours, while the effect lasts for approximately 6–12 hours.
Clinical Efficacy and Safety of Triple Combination
In a study (N = 393) evaluating the efficacy and safety of telmisartan 80 mg/amlodipine 5 mg/hydrochlorothiazide 12.5 mg (TAH 80/5/12.5 mg) in the treatment of arterial hypertension uncontrolled by the combination telmisartan 80 mg/amlodipine 5 mg (TA 80/5 mg), patients with persistent elevated blood pressure underwent an 8-week double-blind treatment period. Patients who did not achieve target values after a 6-week run-in period were randomized to the TAH 80/5/12.5 mg or TA 80/5 mg group. After 8 weeks of treatment, the triple combination group showed significantly greater adjusted mean reduction in seated DBP and SBP compared to the dual combination group, with differences of -3.9 mm Hg (95% CI: -5.3 to -2.4; P < 0.0001) and -5.3 mm Hg (95% CI: -7.6 to -3.1; P < 0.0001), respectively.
The objective of another study (N = 132) was to compare the effect of TAH 80/5/12.5 mg with the combination telmisartan 80 mg/hydrochlorothiazide 12.5 mg (TG 80/12.5 mg) on blood pressure reduction in patients with essential hypertension with inadequate control. Patients were randomized to double-blind treatment with TAH or TA for 8 weeks after a 6-week run-in period with TG 80/12.5 mg. After 8 weeks of treatment, the triple combination group showed significantly greater adjusted mean reduction in seated DBP and SBP compared to the dual combination group, with differences of -6.2 mm Hg (95% CI: -8.6 to -3.8; P < 0.0001) and -8.6 mm Hg (95% CI: -13.0 to -4.1; P = 0.0002), respectively.
In an 8-week study (N = 310), patients with arterial hypertension underwent a 4-week run-in period with TA 40/5 mg. Then, patients with uncontrolled arterial hypertension after 4 weeks despite TA treatment were randomized to TAH 40/5/12.5 mg or TA 40/5 mg for 2 weeks. Subsequently, patients underwent a 6-week treatment period with higher-dose TAH 80/10/12.5 mg and TA 80/10 mg. In the TAH group, significantly greater reduction in mean seated SBP was observed compared to the TA group (-18.7 [1.1] vs. -12.2 [1.1] mm Hg, P < 0.001). Similar results were observed for changes in mean seated DBP (-9.3 [0.6] vs. -7.0 [0.6] mm Hg; P = 0.013).
Clinical Efficacy and Safety of Triple Combination
In a double-blind, placebo-controlled clinical trial (n = 687 patients evaluated for efficacy) in patients who did not respond to the combination telmisartan/hydrochlorothiazide 80 mg/12.5 mg, an additional effect of the combination 80 mg/25 mg on blood pressure reduction (2.7/1.6 mm Hg (SBP/DBP)) was observed compared to continuing treatment with the combination 80 mg/12.5 mg (difference in adjusted mean changes from baseline). In a subsequent study with the combination 80 mg/25 mg, blood pressure decreased further (resulting in a total reduction of 11.5/9.9 mm Hg (SBP/DBP)).
In a pooled analysis of two similar 8-week double-blind, placebo-controlled clinical trials compared to the combination valsartan/hydrochlorothiazide 160 mg/25 mg (n = 2121 patients evaluated for efficacy), the combination telmisartan/hydrochlorothiazide 80 mg/25 mg showed significantly greater blood pressure reduction (2.2/1.2 mm Hg (SBP/DBP)) (difference in adjusted mean changes from baseline).
Prevention of Cardiovascular Diseases
In the ONTARGET (Ongoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial) study, the effects of telmisartan, ramipril, and the combination telmisartan/ramipril on cardiovascular outcomes were compared in 25,620 patients aged 55 years or older with a history of ischemic heart disease, stroke, transient ischemic attack, peripheral arterial disease, or type 2 diabetes with evidence of target organ damage (e.g., retinopathy, left ventricular hypertrophy, macro- or microalbuminuria), who were at risk for cardiovascular events.
Patients were randomized into one of three treatment groups: telmisartan 80 mg (n = 8542), ramipril 10 mg (n = 8576), or combination telmisartan 80 mg/ramipril 10 mg (n = 8502) and followed for a median of 4.5 years.
Telmisartan demonstrated effects on reducing the primary composite endpoint of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, or hospitalization for heart failure similar to those of ramipril. The rate 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 rates were 11.6% and 11.8% in the telmisartan and ramipril groups, respectively.
Telmisartan was as effective as ramipril regarding the predefined secondary composite endpoint of cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke [0.99 (97.5% CI 0.90–1.08), p (non-inferiority) = 0.0004], the primary endpoint in the comparative HOPE (Heart Outcomes Prevention Evaluation) study, which evaluated the effect of ramipril versus placebo.
In the TRANSCEND study, patients with ACE inhibitor intolerance (with similar inclusion criteria as in the ONTARGET study) were randomized to telmisartan 80 mg (n = 2954) or placebo (n = 2972), in addition to standard therapy. The median follow-up duration was 4 years and 8 months. No statistically significant difference was observed in the rate of the primary composite endpoint (cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, or hospitalization for heart failure) [15.7% in the telmisartan group and 17.0% in the placebo group, risk ratio 0.92 (95% CI 0.81–1.05, p = 0.22)]. There is evidence of benefit with telmisartan versus placebo regarding the predefined secondary composite endpoint of 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 regarding cardiovascular mortality (risk ratio 1.03, 95% CI 0.85–1.24).
Cough and angioedema were observed less frequently in patients in the telmisartan group than in the ramipril group, whereas arterial hypotension was observed more frequently with telmisartan.
The combination of telmisartan and ramipril provided no additional benefit compared to either ramipril or telmisartan alone. Cardiovascular and all-cause mortality rates were numerically higher with the combination. Furthermore, the combination group showed significantly higher incidences of hyperkalemia, renal impairment, arterial hypotension, and syncope. Therefore, the use of the telmisartan/ramipril combination is not recommended in this patient group.
In the "Prevention Regimen for Effectively avoiding Second Strokes" (PRoFESS) study in patients aged 50 years or older who had recently experienced a stroke, the incidence of sepsis with telmisartan compared to placebo was 0.70% and 0.49%, respectively [RR (response rate) 1.43 (95% CI 1.00–2.06)], and the incidence of fatal sepsis in patients taking telmisartan compared to placebo was 0.33% and 0.16% [RR 2.07 (95% CI 1.14–3.76)]. Reports indicated a higher incidence of sepsis in patients taking telmisartan than in those receiving placebo. This may be due to chance or may indicate a process whose nature is currently unknown.
Concomitant use of angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers was investigated in two large-scale randomized controlled trials (ONTARGET (Ongoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial) and VA NEPHRON-D (Nephropathy in Diabetes, sponsored by the Department of Veterans Affairs)).
ONTARGET was a study conducted in patients with a history of cardiovascular or cerebrovascular disease or type 2 diabetes with evidence of target organ damage.
VA NEPHRON-D was a study conducted in patients with type 2 diabetes and diabetic nephropathy.
These studies did not demonstrate a significant favorable effect on renal and/or cardiovascular outcomes or mortality, while an increased risk of hyperkalemia, acute kidney injury, and/or hypotension was observed compared to monotherapy. Given the similarity of pharmacodynamic properties, these results are also applicable to other ACE inhibitors and angiotensin II receptor blockers.
Concomitant use of ACE inhibitors and angiotensin II receptor blockers is contraindicated in patients with diabetic nephropathy.
ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints) was a study designed to evaluate the benefit of adding aliskiren to standard therapy with an ACE inhibitor or angiotensin II receptor blocker in patients with type 2 diabetes and chronic kidney disease, cardiovascular disease, or both. This study was terminated early due to an increased risk of adverse outcomes. Cardiovascular mortality and stroke incidence were higher in the aliskiren group than in the placebo group, and reports of adverse events and serious adverse events (hyperkalemia, arterial hypotension, and renal function impairment) were more frequent in the aliskiren group than in the placebo group.
Epidemiological studies have shown that long-term treatment with hydrochlorothiazide reduces the risk of cardiovascular mortality and morbidity.
The effect of the fixed-dose combination of telmisartan/hydrochlorothiazide on mortality and cardiovascular morbidity is currently unknown.
Clinical Trial of Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack (ALLHAT)
A randomized, double-blind clinical trial on morbidity and mortality, the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), was conducted to compare newer treatment approaches: amlodipine 2.5–10 mg/day (calcium channel blocker) or lisinopril 10–40 mg/day (ACE inhibitor) as first-line therapy versus treatment with the thiazide diuretic chlorthalidone 12.5–25 mg/day in mild to moderate hypertension.
Overall, 33,357 hypertensive patients aged 55 years or older were randomized and followed for a median of 4.9 years. Patients had at least one additional risk factor for ischemic heart disease, including myocardial infarction or stroke (>6 months before enrollment) or documented other atherosclerotic cardiovascular diseases (overall 51.5%), type 2 diabetes (36.1%), HDL-cholesterol <35 mg/dL (11.6%), left ventricular hypertrophy diagnosed by electrocardiogram or echocardiography (20.9%), or current cigarette smoking (21.9%).
The primary endpoint was fatal ischemic heart disease or non-fatal myocardial infarction. The primary endpoint did not differ significantly between amlodipine-based and chlorthalidone-based therapies: RR 0.98 (95% CI 0.90–1.07), p = 0.65. Among secondary endpoints, 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%, HR 1.38, 95% CI [1.25–1.52], p < 0.001). However, there was no significant difference between amlodipine and chlorthalidone in all-cause mortality: RR 0.96 (95% CI [0.89–1.02]), p = 0.20.
Non-melanoma Skin Cancer
Based on available data from epidemiological studies, a cumulative dose-dependent association between HCTZ and NMSC was observed. One study included a population of 71,533 BCC cases and 8,629 SCC cases, corresponding to 1,430,833 and 172,462 control populations, respectively. High use of HCTZ (≥50,000 mg cumulative) was associated with an adjusted OR (odds ratio) of 1.29 (95% CI: 1.23–1.35) for BCC and 3.98 (95% CI: 3.68–4.31) for SCC. A clear cumulative dose-response relationship was observed for both BCC and SCC. Another study suggested a possible association between lip cancer (SCC) and HCTZ exposure: 633 lip cancer cases were matched with a control population of 63,067 using a risk-set sampling strategy. A cumulative dose-response relationship was demonstrated with an adjusted OR of 2.1 (95% CI: 1.7–2.6), increasing to OR 3.9 (3.0–4.9) at high dose (~25,000 mg) and OR 7.7 (5.7–10.5) at the highest cumulative dose (~100,000 mg) (see also section "Special Warnings and Precautions for Use").
Pharmacokinetics.
Concomitant administration of amlodipine, hydrochlorothiazide, and telmisartan does not affect the pharmacokinetics of either substance in healthy volunteers.
Absorption
Telmisartan: After oral administration, maximum telmisartan concentration is reached within 0.5–1.5 hours. Absolute bioavailability of telmisartan at doses of 40 mg and 160 mg was 42% and 58%, respectively. Food slightly reduces telmisartan bioavailability, decreasing the area under the concentration-time curve (AUC) by approximately 6% after a 40 mg tablet and by approximately 19% after a 160 mg dose. Three hours after administration, plasma concentration is the same regardless of whether telmisartan is taken fasting or with food. The slight reduction in AUC is not considered to cause a reduction in therapeutic efficacy. Telmisartan does not accumulate in plasma with repeated administration.
Amlodipine: After oral administration of therapeutic doses, amlodipine is well absorbed, with peak plasma concentration observed within 6–12 hours. Absolute bioavailability is 64–80%. Amlodipine bioavailability is not affected by food intake.
Hydrochlorothiazide: After oral administration of Telista® Trio, maximum hydrochlorothiazide concentration is reached approximately within 1–3 hours. Based on cumulative urinary excretion of hydrochlorothiazide, absolute bioavailability is approximately 60%.
Distribution
Telmisartan is highly bound to plasma proteins (>99.5%), primarily to albumin and alpha-1 acid glycoprotein. The theoretical volume of distribution of telmisartan is approximately 500 L, indicating additional tissue binding.
Amlodipine: Volume of distribution is approximately 21 L/kg. In vitro studies demonstrated that approximately 97.5% of circulating amlodipine is bound to plasma proteins.
Hydrochlorothiazide is 68% bound to plasma proteins, and its theoretical volume of distribution is 0.83–1.14 L/kg.
Metabolism
Telmisartan is metabolized via conjugation, forming a pharmacologically inactive acylglucuronide. The glucuronide of the parent compound is the only metabolite detected in humans. After a single dose of 14C-labeled telmisartan, the glucuronide accounts for approximately 11% of measured radioactivity in plasma. Cytochrome P450 isoenzymes are not involved in telmisartan metabolism.
Amlodipine: The terminal plasma half-life is 35–50 hours, consistent with once-daily dosing.
Hydrochlorothiazide is not metabolized in the human body.
Elimination
Telmisartan: After intravenous or oral administration of 14C-labeled telmisartan, the majority of the administered dose (>97%) was excreted in feces via biliary excretion. Only a minor amount was detected in urine. Total plasma clearance of telmisartan after oral administration is >1500 mL/min. The terminal elimination half-life exceeds 20 hours.
Amlodipine is extensively metabolized by the liver into inactive metabolites, with 10% of the parent compound and 60% of metabolites excreted in urine.
Hydrochlorothiazide is excreted almost entirely unchanged in urine. Approximately 60% of an oral dose is excreted unchanged within 48 hours. Renal clearance is approximately 250–300 mL/min. The terminal elimination half-life of hydrochlorothiazide is 10–15 hours.
Linearity/Non-linearity
Telmisartan: The pharmacokinetics of telmisartan for oral administration are non-linear when increasing the dose from 20 to 160 mg, with more than proportional increases in plasma concentration (Cmax and AUC) with dose escalation. Telmisartan does not accumulate significantly in plasma with repeated administration.
Amlodipine and hydrochlorothiazide have linear pharmacokinetics.
Pharmacokinetics in Specific Patient Populations
Elderly
The pharmacokinetics of telmisartan do not differ between elderly patients and patients under 65 years of age.
Time to peak plasma concentrations of amlodipine is the same in young and elderly patients. Clearance of amlodipine tends to decrease in elderly individuals, resulting in increased AUC and half-life. Increases in AUC and prolonged half-life in patients with heart failure were within the expected range for the age group studied.
Gender
Plasma telmisartan concentrations are generally 2–3 times higher in women than in men. However, clinical trial data show that blood pressure reduction in women does not increase significantly, nor does the incidence of orthostatic hypotension. Dose adjustment is not necessary.
Higher hydrochlorothiazide concentrations are observed in women compared to men, but this has no clinical significance.
Patients with Renal Impairment
Lower plasma concentrations were observed in patients with dialysis-dependent renal failure. In patients with renal impairment, telmisartan is highly bound to plasma proteins and is not removed by dialysis. The half-life remains unchanged in patients with renal impairment.
Elimination of hydrochlorothiazide is reduced in patients with renal impairment. In typical studies in patients with a mean creatinine clearance of 90 mL/min, the half-life of hydrochlorothiazide increases. In patients with absent or removed kidneys, the half-life is approximately 34 hours.
Patients with Hepatic Impairment
Pharmacokinetic studies in patients with hepatic impairment showed an increase in absolute bioavailability to approximately 100%. The half-life does not change in patients with renal impairment.
Very limited clinical data are available on amlodipine use in patients with hepatic impairment. In patients with hepatic insufficiency, reduced clearance of amlodipine is observed, leading to prolonged half-life and increased AUC by approximately 40–60%.
Children
A population pharmacokinetic study was conducted in 74 children with arterial hypertension aged 1–17 years (including 34 patients aged 6–12 years and 28 patients aged 13–17 years), who received amlodipine at doses of 1.25–20 mg once or twice daily. In children aged 6–12 years and adolescents aged 13–17 years, typical oral clearance (CL/F) was 22.5 and 27.4 L/h in males and 16.4 and 21.3 L/h in females, respectively. There was considerable inter-individual variability in exposure. Data in children under 6 years of age are limited.
Clinical characteristics.
Indications.
Telmita® Trio is indicated for the treatment of essential hypertension as a replacement therapy in adult patients whose blood pressure is adequately controlled with the combination of telmisartan/hydrochlorothiazide and amlodipine as separate tablets administered at the same doses as those contained in the fixed-dose combination.
Contraindications.
- Hypersensitivity to any of the active substances or to any of the excipients of the medicinal product.
- Hypersensitivity to other sulfonamide derivatives (since hydrochlorothiazide is a sulfonamide derivative).
- Pregnancy or planned pregnancy (see sections "Special precautions for use" and "Use in pregnancy or lactation").
- Cholestasis or obstructive biliary disorders.
- Severe hepatic impairment.
- Severe renal impairment (creatinine clearance <30 mL/min), anuria.
- Refractory hypokalemia/hyponatremia, hypercalcemia.
- Lactation.
- Symptomatic hyperuricemia (gout).
- Pediatric population (under 18 years of age).
- Severe arterial hypotension.
- Shock (including cardiogenic shock).
- Obstruction of the left ventricular outflow tract (e.g., high-grade aortic stenosis).
- Hemodynamically unstable heart failure following acute myocardial infarction.
- Concomitant use of Telmita® Trio with medicinal products containing aliskiren is contraindicated in patients with diabetes mellitus or renal impairment (GFR < 60 mL/min/1.73 m²) (see sections "Interaction with other medicinal products and other forms of interaction", "Pharmacological properties").
Interaction with other medicinal products and other forms of interaction.
Interactions related to telmisartan and hydrochlorothiazide
Lithium preparations
Reversible increases in serum lithium concentrations and lithium toxicity have been reported when lithium is used concomitantly with ACE inhibitors. Such effects have also very rarely been reported with angiotensin II receptor antagonists (including Telmita® Trio). Combination of lithium with Telmita® Trio is not recommended (see section). If such combination is considered necessary, careful monitoring of serum lithium levels is recommended during combined treatment.
Medicinal products associated with potassium loss and hypokalemia (e.g., other potassium-wasting diuretics, laxatives, corticosteroids, ACTH, amphotericin, carbenoxolone, sodium penicillin G, salicylic acid and derivatives)
If these agents are prescribed concomitantly with the hydrochlorothiazide/telmisartan combination, monitoring of plasma potassium levels is recommended. These medicinal products may potentiate the effect of hydrochlorothiazide on serum potassium levels (see section "Special precautions for use").
Iodinated contrast agents
In cases of diuretic-induced dehydration, there is an increased risk of acute renal failure, particularly when high doses of iodinated contrast agents are administered. Patients require rehydration prior to administration of iodinated contrast agents.
Medicinal products that may increase potassium levels or cause hyperkalemia (e.g., ACE inhibitors, potassium-sparing diuretics, potassium supplements, potassium-containing salt substitutes, cyclosporine, or other medicinal products such as sodium heparin).
If these medicinal products are prescribed concomitantly with the hydrochlorothiazide/telmisartan combination, monitoring of plasma potassium levels is recommended. Based on experience with other agents that inhibit the renin-angiotensin system, concomitant use of the above-mentioned medicinal products may lead to increased serum potassium levels; therefore, such combination is not recommended (see section "Special precautions for use").
Medicinal products affected by changes in serum potassium levels
Periodic monitoring of serum potassium levels and ECG is recommended when Telmita® Trio is used concomitantly with medicinal products whose effects are influenced by changes in serum potassium levels (e.g., cardiac glycosides and antiarrhythmic agents), as well as with the following agents (including antiarrhythmics) that may induce torsades de pointes, with hypokalemia being a predisposing factor for this arrhythmia.
- Class Ia antiarrhythmic agents (e.g., quinidine, hydroquinidine, disopyramide);
- Class III antiarrhythmic agents (e.g., amiodarone, sotalol, dofetilide, ibutilide);
- Certain antipsychotics (e.g., thioridazine, chlorpromazine, levomepromazine, trifluphenazine, zuclopenthixol, sulpiride, sultopride, amisulpride, tiapride, pimozide, haloperidol, droperidol);
- Other agents (e.g., bepridil, cisapride, difemanyl, intravenous erythromycin, halofantrine, mizolastine, pentamidine, terfenadine, intravenous vincamine).
Cardiac glycosides
Hypokalemia or hypomagnesemia induced by thiazide use may predispose to cardiac glycoside-induced arrhythmias (see section "Special precautions for use").
Digoxin
Concomitant use of telmisartan with digoxin has been associated with increased mean peak (49%) and trough (20%) digoxin plasma concentrations. Digoxin levels should be maintained within the therapeutic range at the initiation, adjustment, and discontinuation of telmisartan.
Other antihypertensive medicinal products
Telmisartan may enhance the hypotensive effect of other antihypertensive agents.
Clinical trial data indicate 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 events such as hypotension, hyperkalemia, and impaired renal function (including renal failure), compared to treatment with a single RAAS-acting agent (see sections "Contraindications", "Special precautions for use", and "Pharmacological properties").
Antidiabetic agents (oral hypoglycemics and insulin)
Dosage adjustment of antidiabetic agents may be required (see section "Special precautions for use").
Metformin
Metformin should be used with caution due to the risk of lactic acidosis resulting from possible hydrochlorothiazide-induced functional renal impairment.
Cholestyramine and colestipol resins
Ion-exchange resins may reduce the absorption of hydrochlorothiazide.
Nonsteroidal anti-inflammatory drugs (NSAIDs)
NSAID therapy (including acetylsalicylic acid at anti-inflammatory doses, COX-2 inhibitors, and non-selective NSAIDs) may reduce the diuretic, natriuretic, and antihypertensive effects of thiazide diuretics and angiotensin II receptor antagonists.
In some patients with impaired renal function (e.g., dehydrated patients or elderly patients with renal impairment), concomitant use 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, such combination should be used with caution, especially in elderly patients. Patients should maintain adequate fluid intake, and monitoring of renal function should be considered after initiation and periodically during concomitant therapy.
In one study, concomitant administration of telmisartan and ramipril resulted in a 2.5-fold increase in AUC0-24 and Cmax of ramipril and ramiprilat. The clinical significance of these findings is unknown.
Pressor amines (e.g., noradrenaline)
The response to pressor amines may be reduced.
Non-depolarizing muscle relaxants (e.g., tubocurarine)
The effect of non-depolarizing muscle relaxants may be potentiated by hydrochlorothiazide.
Medicinal products used for the treatment of gout (e.g., probenecid, sulfinpyrazone, and allopurinol)
Dosage adjustment of uricosuric agents may be required, as hydrochlorothiazide may increase serum uric acid levels. Higher doses of probenecid or sulfinpyrazone may be needed. Concomitant use of thiazides may increase the frequency of hypersensitivity reactions to allopurinol.
Calcium salts
Thiazide diuretics may increase serum calcium levels by reducing calcium excretion. When calcium-containing preparations or calcium-sparing agents (e.g., vitamin D) are prescribed, serum calcium levels should be monitored and calcium dosage adjusted accordingly.
Beta-blockers and diazoxide
The hyperglycemic effect of beta-blockers and diazoxide may be enhanced by thiazides.
Anticholinergic agents (e.g., atropine, biperiden) increase the bioavailability of thiazide diuretics due to reduced gastrointestinal motility and delayed gastric emptying.
Amantadine
Thiazides may increase the risk of adverse reactions associated with amantadine.
Cytotoxic agents (e.g., cyclophosphamide, methotrexate)
Thiazides may reduce renal excretion of cytotoxic drugs and enhance their myelosuppressive effects.
Based on the pharmacological properties of baclofen and amifostine, these medicinal products may be expected to enhance the hypotensive effect of all antihypertensive agents, including telmisartan.
In addition, alcohol, barbiturates, narcotics, or antidepressants may exacerbate orthostatic hypotension.
Salicylates. When high doses of salicylates are used, hydrochlorothiazide may enhance their toxic effects on the central nervous system.
Methyldopa. Isolated cases of hemolytic anemia have been reported with concomitant use of hydrochlorothiazide and methyldopa.
Cyclosporine. Concomitant use of cyclosporine may potentiate hyperuricemia and increase the risk of complications such as gout.
Effect of medicinal products on laboratory test results. Due to its effect on calcium metabolism, thiazides may affect the assessment of parathyroid function (see section "Special precautions for use").
Carbamazepine. Due to the risk of symptomatic hyponatremia, clinical and biological monitoring is required.
Amphotericin B (parenteral), corticosteroids, ACTH, and stimulant laxatives. Hydrochlorothiazide potentiates electrolyte imbalances, primarily hypokalemia.
Interactions related to amlodipine
Effect of other medicinal products on amlodipine
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 a significant increase in amlodipine concentration, 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. When used concomitantly with known CYP3A4 inducers, plasma concentrations of amlodipine may be altered. Therefore, blood pressure should be monitored and dosage adjusted both during and after concomitant use of such agents, particularly with potent CYP3A4 inducers (e.g., rifampicin, St. John's wort-containing products).
Concomitant use of amlodipine with grapefruit or grapefruit juice is not recommended, as bioavailability may be increased in some patients, leading to enhanced antihypertensive effects.
Dantrolene (infusions). In animal studies, ventricular fibrillation with fatal outcome and cardiovascular collapse associated with hyperkalemia were observed 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.
Effect of amlodipine on other medicinal products
The blood pressure-lowering effects of amlodipine are additive to those of other antihypertensive agents.
Tacrolimus. There is a risk of increased tacrolimus blood levels when used concomitantly with amlodipine, although the pharmacokinetic mechanism of this interaction is not fully understood. To avoid tacrolimus toxicity, regular monitoring of tacrolimus blood levels and dose adjustment, if necessary, are recommended in patients receiving both amlodipine and tacrolimus.
Clarithromycin: Clarithromycin is a CYP3A4 inhibitor. There is an increased risk of hypotension in patients receiving clarithromycin with amlodipine. Close monitoring of patients is recommended when amlodipine is used concomitantly with clarithromycin.
mTOR inhibitors (mechanistic target of rapamycin): mTOR inhibitors such as sirolimus, temsirolimus, and everolimus are CYP3A substrates. Amlodipine is a weak CYP3A inhibitor. Concomitant use of mTOR inhibitors with amlodipine may increase exposure to mTOR inhibitors.
Cyclosporine. Interaction studies between cyclosporine and amlodipine have not been conducted in healthy volunteers or other populations, 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, with dose reduction 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 receiving amlodipine, the simvastatin dose should be limited to 20 mg daily.
In clinical studies, amlodipine did not affect the pharmacokinetics of atorvastatin, digoxin, or warfarin.
Special precautions for use.
Pregnancy. Angiotensin II receptor antagonists (ARBs) should not be initiated during pregnancy. Women planning pregnancy should switch to alternative antihypertensive therapy with an established safety profile during pregnancy. If pregnancy is confirmed, ARB therapy should be discontinued immediately and alternative treatment initiated if necessary (see sections "Contraindications" and "Use in pregnancy or breastfeeding").
Hepatic impairment. Telmista® Trio should not be administered to patients with cholestasis, biliary obstructive disorders, or severe hepatic insufficiency (see section "Contraindications"), as telmisartan is primarily eliminated via bile. Reduced hepatic clearance of telmisartan is expected in these patients.
Furthermore, Telmista® Trio should be used with caution in patients with hepatic impairment or progressive liver disease, as even minor disturbances in fluid and electrolyte balance may precipitate hepatic encephalopathy. There is no clinical experience with the use of Telmista® Trio in patients with hepatic impairment.
In patients with hepatic impairment, the elimination half-life of amlodipine is prolonged and AUC values are increased. Dose escalation of amlodipine should be performed cautiously.
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 intestinal angioneurotic edema is diagnosed, the drug should be discontinued and appropriate monitoring initiated until complete symptom resolution.
Renovascular hypertension. There is an increased risk of severe arterial hypotension and renal failure in patients with bilateral renal artery stenosis or stenosis of the artery to a single kidney when treated with drugs affecting the renin-angiotensin-aldosterone system.
Renal impairment and kidney transplantation. Telmista® Trio should not be administered to patients with severe renal impairment (creatinine clearance <30 mL/min) (see section "Special precautions for use"). There is no experience with the use of Telmista® Trio in patients who have recently undergone kidney transplantation. Experience with Telmista® Trio in patients with mild to moderate renal impairment is limited; therefore, periodic monitoring of serum potassium, creatinine, and uric acid levels is recommended. Azotemia associated with thiazide diuretics may occur in patients with renal impairment.
Telmisartan is not removed from blood by hemofiltration or dialysis.
Plasma concentrations of amlodipine do not correlate with the degree of renal impairment. Amlodipine is not dialyzable.
Patients with reduced intravascular volume and/or sodium. 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, especially reduced intravascular volume and/or sodium, should be corrected before initiating Telmista® Trio.
Hyponatremia, accompanied by neurological symptoms (nausea, progressive disorientation, apathy), has been reported with hydrochlorothiazide use.
Dual blockade of the renin-angiotensin-aldosterone system (RAAS)
Evidence indicates that concomitant use of ACE inhibitors, angiotensin II receptor blockers, or aliskiren increases the risk of hypotension, hyperkalemia, and reduced renal function (including acute renal failure). Therefore, dual blockade of the 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 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 renin-angiotensin-aldosterone system stimulation. In patients whose vascular tone and renal function depend primarily on the activity of the renin-angiotensin-aldosterone system (e.g., patients with 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 Telmista® Trio is not recommended.
Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy. As with other vasodilators, special caution is required when treating patients with aortic or mitral valve stenosis or obstructive hypertrophic cardiomyopathy.
Metabolic and endocrine effects
Thiazide therapy may impair glucose tolerance, while hypoglycemia may occur in diabetic patients receiving insulin or antidiabetic therapy and telmisartan. Therefore, blood glucose monitoring should be considered in these patients; dose adjustment of insulin or antidiabetic agents may be necessary. Latent diabetes mellitus may manifest during thiazide therapy.
Elevated cholesterol and triglyceride levels have been associated with thiazide diuretic therapy; however, at the 12.5 mg dose contained in Telmista® Trio, minimal or no effects have been reported. Hyperuricemia or overt gout may occur in some patients receiving thiazide therapy.
Electrolyte imbalance
As with any patient receiving diuretics, serum electrolyte concentrations should be monitored periodically.
Thiazides (including hydrochlorothiazide) may cause fluid and electrolyte imbalance (including hypokalemia, hyponatremia, and hypochloremic alkalosis). Warning signs of fluid and electrolyte imbalance include dry mouth, thirst, weakness, lethargic sleep, drowsiness, fatigue, muscle pain or cramps, muscle weakness, arterial hypotension, oliguria, tachycardia, and gastrointestinal disturbances (nausea, vomiting) (see section "Adverse reactions").
- Hypokalemia
Although hypokalemia may occur during thiazide diuretic therapy, concomitant therapy with telmisartan may mitigate diuretic-induced hypokalemia. The risk of hypokalemia may be increased in patients with hepatic cirrhosis, those with high diuresis, inadequate oral electrolyte intake, or those receiving concomitant corticosteroid or adrenocorticotropic hormone (ACTH) therapy (see section "Interaction with other medicinal products and other forms of interaction").
- Hyperkalemia
Conversely, due to the antagonism of telmisartan at angiotensin II (AT1) receptors, hyperkalemia may occur with Telmista® Trio. Although clinically significant hyperkalemia has not been observed with Telmista® Trio, risk factors for hyperkalemia include renal and/or cardiac insufficiency and diabetes mellitus. Potassium-sparing diuretics, potassium-containing dietary supplements, or potassium-containing salt substitutes should be used with caution in combination with Telmista® Trio (see section "Interaction with other medicinal products and other forms of interaction").
- Hypochloremic alkalosis
Chloride deficiency is usually mild and generally does not require treatment.
- Hypercalcemia
Thiazides may reduce urinary calcium excretion and cause transient, slight increases in serum calcium levels in the absence of known calcium metabolism disorders. Marked hypercalcemia may indicate occult hyperparathyroidism. Thiazide diuretics should be discontinued before assessing parathyroid function.
- Hypomagnesemia
Thiazides have been shown to increase urinary magnesium excretion, potentially leading to hypomagnesemia (see section "Interaction with other medicinal products and other forms of interaction").
Race. As with other angiotensin II receptor antagonists, telmisartan is less effective in reducing blood pressure in patients with dark skin, likely due to the prevalent low-renin state in this hypertensive population.
Ischemic heart disease. As with any other antihypertensive agent, significant blood pressure reduction in patients with ischemic heart disease or myocardial ischemia may lead to myocardial infarction or stroke.
General information
Hypersensitivity reactions to hydrochlorothiazide may occur in patients with or without a history of allergy or bronchial asthma, but are more likely in patients with such a history. Exacerbation or activation of systemic lupus erythematosus has been observed during thiazide diuretic (hydrochlorothiazide) therapy.
Cases of photosensitivity reactions with thiazide diuretics have been reported (see section 4.8). If a photosensitivity reaction occurs during treatment, discontinuation is recommended. If re-administration of the diuretic is necessary, protection of exposed areas from sunlight or artificial UV radiation is advised.
Choroidal effusion, acute myopia (short-sightedness), and secondary angle-closure glaucoma
Medicinal products containing sulfonamides or sulfonamide derivatives may cause an idiosyncratic reaction leading to choroidal effusion with visual field defects, transient myopia, and acute angle-closure glaucoma. Symptoms include sudden decrease in visual acuity or eye pain and usually occur within hours to weeks after starting the drug. Untreated acute angle-closure glaucoma may result in permanent vision loss. Primary treatment is prompt discontinuation of the drug. If intraocular pressure remains uncontrolled, prompt medical or surgical treatment may be required. A history of allergy to sulfonamides or penicillin may be a risk factor for acute angle-closure glaucoma.
Non-melanoma skin cancer (NMSC)
An increased risk of non-melanoma skin cancer (NMSC) [basal cell carcinoma (BCC) and squamous cell carcinoma (SCC)] with increasing cumulative dose of hydrochlorothiazide (HCTZ) was observed in two epidemiological studies based on data from the Danish National Cancer Registry. The photosensitizing effects of HCTZ may represent a possible mechanism for NMSC.
Patients taking HCTZ should be informed about the risk of NMSC and advised to regularly check their skin for new lesions and promptly report any suspicious skin changes. To minimize skin cancer risk, patients should be advised about preventive measures such as limiting exposure to sunlight and UV radiation and using appropriate protection when exposed. Suspicious skin lesions should be promptly evaluated, including histological examination of biopsy specimens. HCTZ use may also be reconsidered in patients with a history of NMSC (see also section "Adverse reactions").
Acute respiratory toxicity
Very rare, severe cases of acute respiratory toxicity, including acute respiratory distress syndrome (ARDS), have been reported after hydrochlorothiazide administration. Pulmonary edema usually develops within minutes or hours after hydrochlorothiazide intake. Initial symptoms include dyspnea, fever, worsening pulmonary function, and hypotension. Hydrochlorothiazide should be discontinued and appropriate treatment initiated if ARDS is suspected. Hydrochlorothiazide should not be prescribed to patients who previously experienced ARDS after hydrochlorothiazide.
Patients with heart failure
This medicinal product should be used with caution in patients with heart failure. In a long-term placebo-controlled study in patients with severe heart failure (NYHA class III and IV), the incidence of pulmonary edema was higher in the amlodipine group than in the placebo group. Calcium channel blockers, including amlodipine, should be used with caution in patients with congestive heart failure, as these drugs may increase the risk of future cardiovascular complications and mortality.
Lactose
Telista® Trio contains lactose; therefore, patients with rare hereditary galactose intolerance, Lapp lactase deficiency, or glucose/galactose malabsorption should not take this product.
Sodium. The medicinal product contains less than 1 mmol (23 mg)/dose of sodium, i.e., essentially sodium-free.
The drug may affect the results of the following laboratory tests:
- the drug may reduce plasma protein-bound iodine levels;
- treatment should be discontinued before laboratory testing to assess parathyroid function;
- the drug may increase free bilirubin concentration in serum.
Use in pregnancy or breastfeeding.
Pregnancy
Telista® Trio is contraindicated in pregnant women or women planning pregnancy. If pregnancy is confirmed during treatment with this medicinal product, its use must be discontinued and replaced with another medicinal product approved for use (see sections "Contraindications" and "Special precautions for use").
There are no adequate data on the use of telmisartan and hydrochlorothiazide in pregnant women. Animal studies have shown reproductive toxicity.
Epidemiological evidence regarding teratogenic risk after 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 drugs. While long-term ARB therapy is considered necessary, patients planning pregnancy should switch to alternative antihypertensive therapy with an established safety profile during pregnancy. If pregnancy is confirmed, ARB use should be discontinued 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 (impaired 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 monitored for arterial hypotension (see sections "Contraindications" and "Special precautions for use").
Experience with hydrochlorothiazide use during pregnancy is limited, especially during the first trimester. Animal studies are insufficient. Hydrochlorothiazide crosses the placenta. Based on the pharmacological mechanism of action of hydrochlorothiazide, its use during the second and third trimesters may worsen fetoplacental perfusion and cause effects in the fetus and newborn such as jaundice, electrolyte imbalance, and thrombocytopenia.
Hydrochlorothiazide should not be used for gestational edema, gestational hypertension, or preeclampsia due to the risk of reduced plasma volume and placental hypoperfusion without beneficial effect on disease course.
Hydrochlorothiazide should not be used for essential hypertension in pregnant women except in rare situations when no other treatment is possible.
The safety of amlodipine use in pregnant women has not been established. Reproductive toxicity was observed in animal studies at high doses.
Breastfeeding
Telista® Trio should not be used during breastfeeding; alternative therapy with better-established safety profiles should be preferred, especially when nursing newborns or preterm infants.
Information on the use of telmisartan during breastfeeding is lacking.
Hydrochlorothiazide is excreted in small amounts in breast milk. High-dose thiazides causing intense diuresis may suppress breast milk production. Use of telmisartan/hydrochlorothiazide during breastfeeding is contraindicated.
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
No fertility studies have been conducted in humans with fixed-dose combination or individual components.
Preclinical studies did not reveal effects of telmisartan and hydrochlorothiazide on male or female fertility.
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. Adverse effects on male fertility were observed in a rat study.
Ability to affect reaction speed when driving or operating machinery.
Telista® Trio may affect the ability to drive or operate machinery. Treatment with antihypertensive agents, particularly Telista® Trio, may cause dizziness, syncope, or vertigo.
Patients experiencing these adverse effects should avoid potentially hazardous tasks such as driving or operating machinery.
Method of Administration and Dosage.
Dosage
The recommended daily dose is 1 tablet of the specified strength.
This medicinal product is not suitable for initial therapy.
Before switching to Telmista® Trio, patients must have achieved the expected therapeutic effect while receiving stable doses of the individual monocomponents administered concomitantly. Dose selection should be based on the doses of the individual components at the time of transition.
If dosage adjustment is required, it should be performed by individual titration of the components in free combination.
Special Patient Populations
Patients with renal impairment. Telmista® Trio is contraindicated in patients with severe renal impairment (see section "Contraindications"). Experience with the telmisartan/hydrochlorothiazide combination in patients with mild to moderate renal impairment is limited but does not indicate adverse renal effects; therefore, dose adjustment is not considered necessary. Periodic monitoring of renal function is recommended (see section "Special Warnings and Precautions for Use"). Plasma concentrations of amlodipine do not correlate with the degree of renal impairment, so standard dosing is recommended. Amlodipine is not dialyzable.
Patients with hepatic impairment. Telmista® Trio is contraindicated in patients with severe hepatic impairment (see section "Contraindications"). For patients with mild to moderate hepatic impairment, the dose should not exceed 40/5/12.5 mg once daily.
Thiazides should be used with caution in patients with impaired liver function (see section "Special Warnings and Precautions for Use").
Caution should be exercised when increasing the dose of amlodipine. The pharmacokinetics of amlodipine in patients with severe hepatic insufficiency have not been studied.
Elderly patients. No dose adjustment is required for elderly patients.
Method of Administration
Telmista® Trio can be taken independently of food intake. It is recommended to swallow Telmista® Trio tablets with a small amount of liquid.
Children. The safety and efficacy of Telmista® Trio in children (under 18 years of age) have not been established. The use of Telmista® Trio in children is not recommended.
Overdose.
Information regarding overdose with telmisartan is limited. Human experience with intentional overdose of amlodipine is limited.
Symptoms
The most prominent manifestations of telmisartan overdose were hypotension and tachycardia; bradycardia, dizziness, vomiting, increased serum creatinine levels, and acute renal failure have also been reported. Overdose with hydrochlorothiazide is associated with electrolyte depletion (hypokalemia, hypochloremia) and hypovolemia due to excessive diuresis. The most common signs and symptoms of overdose are nausea and somnolence. Hypokalemia may cause muscle cramps and/or may exacerbate arrhythmias associated with concomitant use of cardiac glycosides or certain antiarrhythmic drugs. Available data suggest that significant overdose of amlodipine may lead to excessive peripheral vasodilation and possibly reflex tachycardia. With amlodipine use, marked and potentially prolonged systemic hypotension has been reported, up to and including shock, with fatal outcomes.
Rare cases of non-cardiogenic pulmonary edema have been reported as a consequence of amlodipine overdose, which may present with delayed onset (24–48 hours after ingestion) and may require mechanical ventilation. Early resuscitation measures (including fluid loading) to support perfusion and cardiac output may be precipitating factors.
Treatment
Telmisartan and amlodipine are not removed by hemodialysis. The extent of hydrochlorothiazide removal by hemodialysis has not been established.
Treatment depends on the time elapsed since ingestion and the severity of symptoms. Careful monitoring of cardiac and respiratory function is required, and treatment should be symptomatic and supportive. Recommended measures include induction of emesis and/or gastric lavage. Activated charcoal may be beneficial in treating overdose if administered within 2 hours of ingestion.
Serum electrolytes and creatinine levels should be monitored frequently, and attention should be paid to circulating fluid volume and urine output. If arterial hypotension occurs, the patient should be placed in a supine position and treated with therapy aimed at rapid restoration of salt and fluid volume. A vasoconstrictor may help restore vascular tone and arterial pressure, provided there are no contraindications to its use. Intravenous administration of calcium gluconate may be beneficial in counteracting the effects of calcium channel blockade.
Adverse reactions.
Short description of the safety profile
During treatment, the most frequently reported adverse reactions were: somnolence, dizziness, headache, palpitations, flushing, abdominal pain, nausea, leg swelling, edema, and increased fatigue. Serious angioneurotic edema is rare (frequency from ≥ 1/10,000 to < 1/1,000).
Summary table of adverse reactions
Frequencies are defined as: very common (≥ 1/10); common (from ≥ 1/100 to < 1/10); uncommon (from ≥ 1/1,000 to < 1/100); rare (from ≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000); not known (cannot be estimated from available data).
Within each frequency category, adverse reactions are listed in decreasing order of severity.
| MedDRA System Organ Class |
Adverse Reactions |
Frequency |
|||
| Telmisartan + HCTZ |
Telmisartan |
HCTZ |
Amlodipine |
||
| Infections and infestations |
Sepsis, including fatal outcome |
uncommon2 |
|||
| Bronchitis |
uncommon |
||||
| Pharyngitis |
uncommon |
||||
| Sinusitis |
uncommon |
||||
| Upper respiratory tract infections |
uncommon |
||||
| Urinary tract infections |
uncommon |
||||
| Cystitis |
uncommon |
||||
| Benign, malignant and unspecified neoplasms (including cysts and polyps) |
Non-melanoma skin cancer (basal cell carcinoma and squamous cell carcinoma) |
unknown2 |
|||
| Blood and lymphatic system disorders |
Anemia |
uncommon |
|||
| Eosinophilia |
uncommon |
||||
| Thrombocytopenia |
uncommon |
uncommon |
very rare |
||
| Thrombocytopenia with purpura |
uncommon |
||||
| Aplastic anemia |
unknown |
||||
| Hemolytic anemia |
very rare |
||||
| Bone marrow function suppression |
very rare |
||||
| Leukopenia |
very rare |
very rare |
|||
| Agranulocytosis |
very rare |
||||
| Immune system disorders |
Anaphylactic reactions |
uncommon |
|||
| Hypersensitivity |
uncommon |
very rare |
|||
| Allergic reactions |
very rare |
||||
| Metabolism and nutrition disorders |
Hypokalemia |
uncommon |
very common |
||
| Hyperuricemia |
uncommon |
common |
|||
| Hyponatremia |
uncommon |
uncommon |
common |
||
| Hyperkalemia |
uncommon |
||||
| Hypoglycemia (in patients with diabetes) |
uncommon |
||||
| Hypomagnesemia |
common |
||||
| Hypercalcemia |
uncommon |
||||
| Hypochloremic alkalosis |
very rare |
||||
| Decreased appetite |
common |
||||
| Hyperlipidemia |
very common |
||||
| Hyperglycemia |
uncommon |
very rare |
|||
| Loss of control of diabetes |
uncommon |
||||
| Psychiatric disorders |
Anxiety |
uncommon |
uncommon |
uncommon |
|
| Depression |
uncommon |
uncommon |
uncommon |
uncommon |
|
| Insomnia |
uncommon |
uncommon |
uncommon |
||
| Sleep disorders |
uncommon |
uncommon |
|||
| Confusion |
uncommon |
||||
| Nervous system disorders |
Dizziness |
common |
uncommon |
common |
|
| Syncope |
uncommon |
uncommon |
uncommon |
||
| Paresthesia |
uncommon |
uncommon |
uncommon |
||
| Somnolence |
uncommon |
common |
|||
| Headache |
uncommon |
common |
|||
| Tremor, dysgeusia, hypoesthesia |
uncommon |
||||
| Hypertonia, peripheral neuropathy |
very rare |
||||
| Extrapyramidal disorder |
unknown |
||||
| Eye disorders |
Vision disorders |
uncommon |
uncommon |
uncommon |
common |
| Blurred vision |
uncommon |
||||
| Acute angle-closure glaucoma |
unknown |
||||
| Choroidal effusion |
unknown |
||||
| Ear and labyrinth disorders |
Vertigo |
uncommon |
uncommon |
||
| Tinnitus |
uncommon |
||||
| Cardiac disorders |
Tachycardia |
uncommon |
uncommon |
uncommon |
|
| Arrhythmia |
uncommon |
uncommon |
uncommon |
||
| Bradycardia |
uncommon |
uncommon |
|||
| Palpitations |
common |
||||
| Atrial fibrillation |
uncommon |
||||
| Myocardial infarction |
very rare |
||||
| Vascular disorders |
Arterial hypotension |
uncommon |
uncommon |
uncommon |
|
| Orthostatic hypotension |
uncommon |
uncommon |
common |
||
| Necrotizing vasculitis |
very rare |
||||
| Flushing |
common |
||||
| Vasculitis |
very rare |
||||
| Respiratory, thoracic and mediastinal disorders |
Dyspnea |
uncommon |
uncommon |
common |
|
| Respiratory distress syndrome |
uncommon |
very rare |
|||
| Pneumonitis |
uncommon |
very rare |
|||
| Pulmonary edema |
uncommon |
very rare |
|||
| Cough |
uncommon |
uncommon |
|||
| Interstitial lung disease |
very rare1,2 |
||||
| Acute respiratory distress syndrome (ARDS) (see section "Special precautions") |
very rare |
||||
| Rhinitis |
uncommon |
||||
| Gastrointestinal disorders |
Diarrhea |
uncommon |
uncommon |
common |
common |
| Dry mouth |
uncommon |
uncommon |
uncommon |
||
| Flatulence |
uncommon |
uncommon |
|||
| Abdominal pain |
uncommon |
uncommon |
common |
||
| Constipation |
uncommon |
uncommon |
common |
||
| Dyspepsia |
uncommon |
uncommon |
common |
||
| Vomiting |
uncommon |
uncommon |
common |
uncommon |
|
| Gastritis |
uncommon |
very rare |
|||
| Gastric discomfort |
uncommon |
uncommon |
|||
| Nausea |
common |
common |
|||
| Pancreatitis |
very rare |
very rare |
|||
| Change in defecation rhythm |
common |
||||
| Gingival hyperplasia |
very rare |
||||
| Hepatobiliary disorders |
Liver function abnormalities / hepatic disorders |
uncommon2 |
uncommon2 |
||
| Jaundice |
uncommon |
very rare |
|||
| Cholestasis |
uncommon |
||||
| Hepatitis |
very rare |
||||
| Skin and subcutaneous tissue disorders |
Angioedema |
uncommon |
uncommon |
very rare |
|
| Erythema |
uncommon |
uncommon |
|||
| Pruritus |
uncommon |
uncommon |
uncommon |
||
| Rash |
uncommon |
uncommon |
common |
uncommon |
|
| Hyperhidrosis |
uncommon |
uncommon |
uncommon |
||
| Urticaria |
uncommon |
uncommon |
common |
uncommon |
|
| Eczema |
uncommon |
||||
| Drug-induced dermatitis |
uncommon |
||||
| Toxic dermatitis |
uncommon |
||||
| Lupus-like syndrome |
very rare |
||||
| Photosensitivity reaction |
uncommon |
very rare |
|||
| Toxic epidermal necrolysis |
very rare |
unknown |
|||
| Erythema multiforme |
unknown |
very rare |
|||
| Alopecia, purpura, skin discoloration, exanthema |
uncommon |
||||
| Stevens-Johnson syndrome, Quincke's edema |
very rare |
||||
| Musculoskeletal and connective tissue disorders |
Back pain |
uncommon |
uncommon |
uncommon |
|
| Muscle cramps (leg cramps) |
uncommon |
uncommon |
unknown |
common |
|
| Myalgia |
uncommon |
uncommon |
uncommon |
||
| Arthralgia |
uncommon |
uncommon |
uncommon |
||
| Limb pain (leg pain) |
uncommon |
uncommon |
|||
| Tendon pain (tendonitis symptoms) |
uncommon |
||||
| Systemic lupus erythematosus |
uncommon1 |
very rare |
|||
| Ankle swelling |
common |
||||
| Renal and urinary disorders |
Renal function abnormalities |
uncommon |
unknown |
||
| Acute renal failure |
uncommon |
uncommon |
|||
| Glucosuria |
uncommon |
||||
| Urinary disorders, nocturia, increased frequency of urination |
uncommon |
||||
| Reproductive system and breast disorders |
Erectile dysfunction |
uncommon |
common |
uncommon |
|
| Gynecomastia |
uncommon |
||||
| General disorders and administration site conditions |
Chest pain |
uncommon |
uncommon |
uncommon |
|
| Influenza-like symptoms |
uncommon |
uncommon |
|||
| Pain |
uncommon |
uncommon |
|||
| Asthenia (weakness) |
uncommon |
unknown |
common |
||
| Chills |
unknown |
||||
| Edema |
very common |
||||
| Fatigue |
common |
||||
| Malaise |
uncommon |
||||
| Investigations |
Increased plasma uric acid levels |
uncommon |
uncommon |
||
| Increased plasma creatinine levels |
uncommon |
uncommon |
|||
| Increased plasma creatine kinase levels |
uncommon |
uncommon |
|||
| Increased liver enzymes |
uncommon |
uncommon |
very rare3 |
||
| Decreased hemoglobin levels |
uncommon |
||||
| Increase or decrease in body weight |
uncommon |
||||
1See additional description in the section "Description of selected adverse reactions"
2Based on post-marketing experience
3Predominantly corresponds to cholestasis
Description of selected adverse reactions
Hepatic function disorders/liver disorders
Based on post-marketing experience, most cases of hepatic function disorders/liver disorders were observed in patients of Japanese nationality. Patients of Japanese nationality are more prone to these adverse reactions.
Sepsis
In the PRoFESS study, a higher incidence of sepsis was observed among patients receiving telmisartan compared to those receiving placebo. This may be due to chance or may reflect a process with a mechanism currently unknown (see section "Pharmacological properties").
Interstitial lung disease
Cases of interstitial lung disease have been reported after marketing authorization, occurring in temporal association with telmisartan use. However, a causal relationship has not been established.
Non-melanoma skin cancer
Based on available data from epidemiological studies, a cumulative dose-dependent association has been observed between ARBs and non-melanoma skin cancer (NMSC) (see also sections "Special warnings and precautions for use" and "Pharmacological properties").
Intestinal angioneurotic edema
Cases of intestinal angioneurotic edema have been reported following administration of angiotensin II receptor antagonists (see section "Special warnings and precautions for use").
Reporting of suspected adverse reactions.
Reporting suspected adverse reactions after medicine authorization is important. It allows continued monitoring of the benefit-risk balance of the medicine. Healthcare professionals and patients, as well as their legal representatives, are encouraged to report any suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.
Shelf life. 2 years.
Storage conditions.
This medicinal product requires no special storage temperature conditions. Store in the original packaging to protect from moisture and light.
Keep out of the reach and sight of children.
Packaging.
7 tablets in a blister; 4 or 12 blisters in a carton.
Prescription status. Prescription only.
Manufacturer.
KRKA, d.d., Novo mesto, Slovenia / KRKA, d.d., Novo mesto, Slovenia.
Manufacturer's address and location of operations.
Smarjeska cesta 6, 8501 Novo mesto, Slovenia / Smarjeska cesta 6, 8501 Novo mesto, Slovenia.