Telmisartan duo

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT TELSARTAN DUO (TELSARTAN DUO)

Composition:

Active substances: telmisartan and amlodipine;

1 tablet contains telmisartan 40 mg and amlodipine besylate equivalent to 5 mg of amlodipine,

or

1 tablet contains telmisartan 40 mg and amlodipine besylate equivalent to 10 mg of amlodipine,

or

1 tablet contains telmisartan 80 mg and amlodipine besylate equivalent to 5 mg of amlodipine,

or

1 tablet contains telmisartan 80 mg and amlodipine besylate equivalent to 10 mg of amlodipine;

Excipients:

tablets 40 mg/5 mg and 80 mg/5 mg: sodium hydroxide, meglumine, povidone, polysorbate 80, mannitol (E 421), magnesium stearate, iron oxide red (E 172);

tablets 40 mg/10 mg and 80 mg/10 mg: sodium hydroxide, meglumine, povidone, polysorbate 80, mannitol (E 421), magnesium stearate, iron oxide yellow (E 172).

Pharmaceutical form. Tablets.

Main physico-chemical properties:

tablets 40 mg/5 mg: elongated, biconvex, bilayer uncoated tablets, with a layer from white to almost white on one side and a layer from pale pink to pink with specks on the other side;

tablets 40 mg/10 mg: elongated, biconvex, bilayer uncoated tablets, with a layer from white to almost white on one side and a layer from pale yellow to yellow with specks on the other side;

tablets 80 mg/5 mg: elongated, biconvex, bilayer uncoated tablets, with a layer from white to almost white on one side and a layer from pale pink to pink with specks on the other side;

tablets 80 mg/10 mg: elongated, biconvex, bilayer uncoated tablets, with a layer from white to almost white on one side and a layer from pale yellow to yellow with specks on the other side.

Pharmacotherapeutic group. Agents acting on the renin-angiotensin system, angiotensin II antagonists and calcium channel blockers. ATC code C09DB04.

Pharmacological properties.

Pharmacodynamics.

Telzartan DUO contains two antihypertensive components with complementary mechanisms of blood pressure control in patients with essential hypertension: an angiotensin II receptor antagonist, telmisartan, and a dihydropyridine calcium channel blocker, amlodipine.

The combination of these substances provides an additive antihypertensive effect, reducing blood pressure to a greater extent than either component alone.

Administration of Telzartan DUO once daily ensures effective and sustained reduction of arterial pressure over 24 hours within the therapeutic dose range.

Telmisartan.

Telmisartan is a specific and potent oral angiotensin II receptor (AT1 subtype) antagonist. Telmisartan competitively displaces angiotensin II from its binding site on AT1 receptors, which mediate the known effects of angiotensin II. Telmisartan has no partial agonist activity at the AT1 receptor. It selectively binds to AT1 receptors, 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 induced by telmisartan. Telmisartan reduces plasma aldosterone levels. Telmisartan does not inhibit human plasma renin, does not block ion channels, and does not inhibit angiotensin-converting enzyme (kininase II), the enzyme responsible for bradykinin degradation. Therefore, potentiation of bradykinin-mediated adverse reactions is not expected.

In humans, telmisartan at a dose of 80 mg almost completely inhibits the angiotensin II-induced rise in blood pressure. The blocking effect persists beyond 24 hours and remains detectable up to 48 hours.

After the first dose, antihypertensive activity gradually develops within 3 hours. Maximum blood pressure reduction is usually achieved within 4–8 weeks of treatment initiation and is maintained during long-term therapy.

The antihypertensive effect remains consistent over 24 hours after dosing, including the last 4 hours before the next dose, as confirmed by ambulatory blood pressure monitoring. The ratio of blood pressure reduction at the end of the dosing interval to maximum blood pressure reduction exceeds 80% after administration of 40 mg and 80 mg doses in placebo-controlled clinical trials. There is a clear dose-time relationship regarding the restoration of baseline systolic blood pressure. Data on diastolic blood pressure are inconsistent in this regard.

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 remains to be fully elucidated. The antihypertensive efficacy of telmisartan is comparable to that of other antihypertensive agents from different drug classes (demonstrated in clinical trials comparing telmisartan with amlodipine, atenolol, enalapril, hydrochlorothiazide, and lisinopril).

Upon abrupt discontinuation of telmisartan therapy, blood pressure gradually returns to pretreatment levels over several days, with no evidence of rebound hypertension syndrome.

In clinical trials comparing two antihypertensive drugs, the incidence of dry cough was significantly lower in patients receiving telmisartan compared to those treated with angiotensin-converting enzyme (ACE) inhibitors.

Concomitant use of ACE inhibitors and angiotensin II receptor blockers is not recommended in patients with diabetic nephropathy due to increased risk of hyperkalemia, acute kidney injury, and/or hypotension.

Amlodipine.

Amlodipine is a dihydropyridine calcium channel blocker (inhibitor of calcium ion influx or calcium antagonist) that inhibits transmembrane calcium ion entry into vascular and cardiac smooth muscle cells. The antihypertensive mechanism of amlodipine is due to direct vasodilatory action on vascular smooth muscle, resulting in reduced peripheral vascular resistance and consequent lowering of arterial pressure. Experimental data indicate that amlodipine binds to both dihydropyridine and non-dihydropyridine binding sites. Amlodipine is relatively vascular-selective, exerting greater effects on vascular smooth muscle cells than on cardiac muscle cells.

In patients with arterial hypertension, once-daily dosing provides clinically significant reduction in blood pressure both in supine and standing positions throughout the 24-hour dosing interval. Due to its slow onset of action, amlodipine does not cause acute hypotension.

In hypertensive patients with normal renal function, therapeutic doses of amlodipine reduce renal vascular resistance and increase glomerular filtration rate and effective renal plasma flow without altering filtration fraction or proteinuria.

Amlodipine has not been associated with any adverse metabolic effects or changes in plasma lipid levels and is suitable for patients with asthma, diabetes, and gout.

Patients with heart failure

Clinical studies have shown that amlodipine does not worsen the clinical course of heart failure in patients classified as NYHA class II–IV, as assessed by exercise tolerance, left ventricular ejection fraction, and overall clinical symptoms.

In a long-term, placebo-controlled study in patients with NYHA class III–IV heart failure without clinical or objective signs of ischemic heart disease, who were receiving stable doses of ACE inhibitors, digitalis, and diuretics, amlodipine did not affect overall cardiovascular mortality. However, in this population, amlodipine was associated with a higher number of reported cases of pulmonary edema, despite no significant difference in heart failure progression compared to the placebo group.

Telmisartan/Amlodipine

In an eight-week, multicenter, randomized, double-blind, placebo-controlled study in patients with moderate to severe hypertension (mean seated diastolic blood pressure ≥95 and ≤119 mm Hg), treatment with the telmisartan/amlodipine combination resulted in greater reductions in diastolic and systolic blood pressure and faster achievement of blood pressure control compared to monotherapy with either component.

The telmisartan/amlodipine combination demonstrated dose-dependent reductions in systolic/diastolic blood pressure within the therapeutic dose range: -21.8/-16.5 mm Hg (40 mg/5 mg), -22.1/-18.2 mm Hg (80 mg/5 mg), -24.7/-20.2 mm Hg (40 mg/10 mg), and -26.4/-20.1 mm Hg (80 mg/10 mg). Most antihypertensive effects were achieved within two weeks of treatment initiation. Mean systolic/diastolic blood pressure reductions with combination therapy containing 5 mg amlodipine were comparable to or slightly higher than those with 10 mg amlodipine monotherapy and were associated with significantly fewer cases of edema.

Ambulatory blood pressure monitoring in a subgroup of patients confirmed sustained reductions in systolic and diastolic blood pressure throughout the 24-hour dosing interval.

In a multicenter, randomized, double-blind, active-controlled study in patients with moderate to severe hypertension whose blood pressure was inadequately controlled on amlodipine 5 mg, patients received either telmisartan/amlodipine combination (40 mg/5 mg or 80 mg/5 mg) or amlodipine monotherapy (5 mg or 10 mg). After 8 weeks, both combination regimens were statistically significantly more effective than either amlodipine monotherapy dose in reducing systolic and diastolic blood pressure and achieved higher rates of diastolic blood pressure control. Incidence of edema was significantly lower with the telmisartan/amlodipine combinations (40 mg/5 mg and 80 mg/5 mg) compared to amlodipine 10 mg.

In another multicenter, randomized, double-blind, active-controlled study in patients with moderate to severe hypertension whose blood pressure was inadequately controlled on amlodipine 10 mg, patients received either telmisartan/amlodipine combination (40 mg/10 mg or 80 mg/10 mg) or amlodipine monotherapy (10 mg). After 8 weeks, both combination regimens were statistically superior to amlodipine monotherapy in reducing systolic and diastolic blood pressure and increased the rate of diastolic blood pressure normalization. In two subsequent open-label, long-term observational studies lasting 6 months, the antihypertensive effect of the telmisartan/amlodipine combination was maintained throughout the study period. Furthermore, in some patients who did not achieve adequate blood pressure control with the 40 mg/10 mg combination, additional blood pressure reduction was achieved by dose titration to 80 mg/10 mg.

Pharmacokinetics.

Pharmacokinetics of the fixed-dose combination.

The rate and extent of absorption of the fixed-dose combination are bioequivalent to telmisartan and amlodipine administered as separate tablets.

Absorption. Telmisartan is rapidly absorbed, although absorbed amounts vary. The mean absolute bioavailability of telmisartan is approximately 50%. Food intake reduces the area under the plasma concentration-time curve (AUC0–∞) for telmisartan by approximately 6% (40 mg dose) to 19% (160 mg dose). Plasma concentrations 3 hours after dosing are similar regardless of whether telmisartan is taken fasting or with food.

After oral administration, amlodipine is well absorbed, reaching peak blood levels within 6–12 hours. Absolute bioavailability ranges from 64% to 80%. Food intake does not affect amlodipine bioavailability.

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

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

Biotransformation. Telmisartan is metabolized primarily via conjugation to the glucuronide of the parent compound. The pharmacological activity of the conjugate has not been established.

Amlodipine is extensively metabolized (approximately 90%) in the liver to inactive metabolites.

Elimination. Telmisartan exhibits biexponential pharmacokinetics with a terminal elimination half-life >20 hours. Maximum plasma concentration (Cmax) and, to a lesser extent, the area under the concentration-time curve (AUC) increase disproportionately with dose. There are no data indicating clinically relevant accumulation of telmisartan at recommended doses. Plasma concentrations are higher in women than in men, without significant impact on efficacy.

After oral administration and intravenous infusion, telmisartan is almost entirely excreted in feces, primarily as unchanged compound. Cumulative renal excretion accounts for <1% of the dose. Total plasma clearance (Cltot) is high (approximately 1000 mL/min) compared to hepatic blood flow (approximately 1500 mL/min).

Amlodipine elimination from plasma is biphasic, with a terminal elimination half-life of approximately 30–50 hours, consistent with once-daily dosing. Steady-state plasma levels are achieved after 7–8 days of continuous therapy. Ten percent of amlodipine is excreted unchanged in urine, and 60% as metabolites.

Linearity/Non-linearity. The small reduction in AUC for telmisartan is not expected to reduce therapeutic efficacy. There is no linear relationship between dose and plasma levels. Cmax and, to a lesser extent, AUC increase disproportionately at doses above 40 mg. Amlodipine exhibits linear pharmacokinetics.

Special patient populations.

Children (under 18 years of age). Pharmacokinetic data in children are lacking.

Gender. Differences in telmisartan plasma concentrations were observed; Cmax and AUC were approximately 3 and 2 times higher, respectively, in women than in men.

Elderly patients. Telmisartan pharmacokinetics are not different between young and elderly patients. Time to reach maximum plasma concentration of amlodipine is similar in elderly and younger patients. However, amlodipine clearance tends to be reduced in elderly patients, resulting in increased AUC and prolonged elimination half-life.

Renal impairment. Plasma telmisartan concentrations are doubled in patients with mild, moderate, and severe renal impairment. However, lower plasma concentrations were observed in dialysis-dependent patients. Telmisartan remains highly protein-bound in patients with renal failure and is not removed by dialysis. Elimination half-life is unchanged in patients with renal impairment. Renal impairment does not significantly affect amlodipine pharmacokinetics.

Hepatic impairment. Pharmacokinetic studies in patients with hepatic impairment showed an increase in telmisartan absolute bioavailability to approximately 100%. The elimination half-life of telmisartan is not altered in patients with hepatic impairment. In patients with hepatic insufficiency, amlodipine clearance is reduced, resulting in an approximately 40–60% increase in AUC.

Clinical characteristics.

Indications.

Treatment of essential hypertension in adults.

Add-on therapy. Telzartan DUO, tablets, is indicated for adult patients whose blood pressure is not adequately controlled with amlodipine alone.

Substitution therapy. Adult patients who are taking telmisartan and amlodipine as separate tablets may switch to Telzartan DUO tablets containing the same component doses.

Contraindications.

• Hypersensitivity to the active substances, to dihydropyridine derivatives, or to any excipient.
• Pregnancy or planned pregnancy (see "Use in pregnancy or breastfeeding").
• Breastfeeding period.
• Obstructive biliary disorders and severe hepatic impairment.
• Shock (including cardiogenic shock).
• Left ventricular outflow tract obstruction (e.g., high-grade aortic stenosis).
• Hemodynamically unstable heart failure following acute myocardial infarction.
• Concomitant use of telmisartan/amlodipine with aliskiren-containing products in patients with diabetes or renal dysfunction (eGFR < 60 mL/min/1.73 m²).
• Age under 18 years.

Interaction with other medicinal products and other forms of interaction.

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

Interactions characteristic of the combination.

Interaction studies with other drugs have not been conducted.

Consider when co-administering.

Other antihypertensive medicinal products. The blood pressure-lowering effect of Telzartan DUO may be enhanced when used concomitantly with other antihypertensive agents.

Medicinal products with potential to lower blood pressure. Based on pharmacological properties, certain drugs may potentiate the hypotensive effects of all antihypertensive agents, including this medicinal product, such as baclofen, amifostine, neuroleptics, or antidepressants. Moreover, orthostatic hypotension may be exacerbated by alcohol consumption.

Systemic corticosteroids. Reduced antihypertensive effect.

Interactions related to telmisartan.

Concomitant use not recommended.

Potassium-sparing diuretics or potassium supplements. Angiotensin II receptor antagonists, such as telmisartan, reduce 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 levels. If concomitant use is indicated due to confirmed hypokalemia, it should be done cautiously with frequent monitoring of serum potassium levels.

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

Other antihypertensive agents affecting the renin-angiotensin-aldosterone system (RAAS). Clinical data have shown that dual blockade of the 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 acute renal failure), compared to monotherapy with a single agent acting on the RAAS.

Concomitant use requiring caution.

Nonsteroidal anti-inflammatory drugs (NSAIDs). NSAID therapy (including high-dose acetylsalicylic acid, COX-2 inhibitors, and nonselective NSAIDs) may reduce the antihypertensive effect of angiotensin II receptor antagonists. In some patients with renal impairment (e.g., dehydrated patients or elderly patients with renal dysfunction), concomitant use of angiotensin II receptor antagonists and drugs that inhibit cyclooxygenase may lead to further deterioration of renal function, including possible acute renal failure, which is usually reversible. Therefore, this combination should be used cautiously, particularly in elderly patients. Adequate hydration should be ensured, and careful monitoring of renal function should be performed at the initiation of combination therapy and throughout treatment.

Ramipril. In one study, concomitant 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.

Concomitant use to be considered.

Digoxin. When telmisartan and digoxin are used concomitantly, an average increase in peak digoxin plasma concentration (by 49%) and trough concentration (by 20%) has been observed. Monitoring of digoxin levels should be performed at the start of treatment, during dose adjustments, and upon discontinuation of telmisartan to maintain levels within the therapeutic range.

Interactions related to amlodipine.

Concomitant use requiring 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 lead to a significant increase in amlodipine exposure, potentially increasing the risk of hypotension. The clinical significance of these changes may be more pronounced in elderly patients. Clinical monitoring and dose adjustment may be necessary.

CYP3A4 inducers. Plasma concentrations of amlodipine may change following concomitant use with known CYP3A4 inducers. Therefore, blood pressure should be monitored and dose adjustments made accordingly during and after concomitant therapy, especially with strong CYP3A4 inducers (e.g., rifampicin, St. John’s wort (Hypericum perforatum)).

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, it is recommended to avoid calcium channel blockers such as amlodipine in patients susceptible to malignant hyperthermia and during treatment of malignant hyperthermia.

Grapefruit or grapefruit juice. Concomitant use of amlodipine with grapefruit or grapefruit juice is not recommended, as it may increase amlodipine bioavailability in some patients, thereby enhancing its hypotensive effect.

Concomitant use to be considered.

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, are required in patients receiving both drugs.

Cyclosporine. Interaction studies between cyclosporine and amlodipine have not been conducted in healthy volunteers or other populations, except in kidney transplant patients, where variable increases in cyclosporine trough concentrations (on average 0%–40%) were observed. For kidney transplant patients receiving amlodipine, monitoring of cyclosporine levels and potential dose reduction should be considered.

mTOR (mechanistic target of rapamycin) inhibitors. mTOR inhibitors such as sirolimus, temsirolimus, and everolimus are CYP3A substrates. Amlodipine is a weak CYP3A inhibitor. When used concomitantly with mTOR inhibitors, amlodipine may enhance their effects.

Simvastatin. Long-term concomitant use of amlodipine 10 mg with simvastatin 80 mg resulted in a 77% increase in simvastatin exposure compared to simvastatin alone. Therefore, in patients taking amlodipine, the dose of simvastatin should be limited to 20 mg daily.

Special precautions for use.

Pregnancy. The medicinal product should not be used in pregnant women or women who are planning to become pregnant. If pregnancy is confirmed during treatment with this drug, its use must be discontinued immediately and replaced with another medicinal product permitted for use during pregnancy.

Hepatic impairment.

Telmisartan is predominantly eliminated via bile. A reduced clearance is expected in patients with obstructive biliary disorders or hepatic insufficiency.

In patients with impaired liver function, the elimination half-life of amlodipine is prolonged and AUC parameters are higher; dosage recommendations have not been established. Therefore, amlodipine therapy should be initiated at the lowest dose. Caution is advised both at the beginning of treatment and during dose escalation.

Patients with obstructive biliary disorders

Administration of the drug to patients with obstructive biliary disorders is contraindicated.

Patients with hepatic insufficiency

Telsartan DUO should be used with caution in patients with mild to moderate hepatic impairment. The use of the drug is contraindicated in severe hepatic insufficiency.

Vasorenal hypertension. There is an increased risk of severe arterial hypotension and renal failure when patients with bilateral renal artery stenosis or stenosis in the artery of a single functioning kidney are treated with drugs affecting the RAAS.

Renal impairment and kidney transplantation. In patients with renal function impairment receiving Telsartan DUO tablets, periodic monitoring of serum potassium and creatinine levels is recommended. There is no experience with the use of the drug in patients who have recently undergone kidney transplantation. Telmisartan and amlodipine are not removed from the body by dialysis.

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

Dual blockade of the RAAS. Data indicate that concomitant use of ACE inhibitors, angiotensin II receptor blockers, or aliskiren increases the risk of arterial hypotension, hyperkalemia, and reduced renal function (including acute renal failure). Therefore, dual blockade of the RAAS by combined use of ACE inhibitors, angiotensin II receptor blockers, or aliskiren is not recommended.

If concomitant use is considered absolutely necessary, it should only be performed under specialist supervision and with frequent, careful monitoring of renal function, electrolytes, and blood pressure.

Concomitant use of ACE inhibitors and angiotensin II receptor blockers is not recommended in patients with diabetic nephropathy.

Other conditions requiring RAAS stimulation. In patients in whom vascular tone and renal function primarily depend on RAAS activity (e.g., patients with chronic heart failure or underlying kidney disease, including renal artery stenosis), treatment with drugs affecting this system is associated with acute arterial hypotension, hyperazotemia, oliguria, and rarely, acute renal failure.

Primary hyperaldosteronism. Patients with primary hyperaldosteronism generally do not respond to antihypertensive drugs acting via RAAS inhibition. Therefore, telmisartan is not recommended for use in these patients.

Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy. As with other vasodilators, use with particular caution in patients diagnosed with aortic or mitral valve stenosis or obstructive hypertrophic cardiomyopathy. The drug is contraindicated in high-grade aortic stenosis.

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

Heart failure. In a long-term, placebo-controlled study 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.

Patients with diabetes treated with insulin or antidiabetic agents. Hypoglycemia may develop in such patients during treatment with telmisartan. Therefore, glucose levels should be monitored in these patients; dose adjustment of insulin or antidiabetic agents may be necessary if required.

Hyperkalemia. The use of medicinal products affecting the RAAS may cause hyperkalemia. Hyperkalemia can be fatal in elderly patients, patients with renal impairment, patients with diabetes mellitus, patients concomitantly taking other medicinal products that may increase serum potassium levels, and/or patients with intercurrent diseases.

The benefit-risk ratio should be evaluated before deciding on concomitant use of medicinal products affecting the RAAS.

Main risk factors for hyperkalemia requiring attention include:

• Diabetes mellitus, impaired renal function, advanced age (˃70 years);
• Combination with one or more medicinal products affecting the RAAS, and/or potassium supplements. Medicinal products or therapeutic classes of drugs that may provoke hyperkalemia include potassium-containing salt substitutes, potassium-sparing diuretics, ACE inhibitors, angiotensin II receptor antagonists, NSAIDs including selective COX-2 inhibitors, heparin, immunosuppressants (cyclosporine or tacrolimus), and trimethoprim;
• Intercurrent conditions such as dehydration, acute heart decompensation, metabolic acidosis, worsening renal function, sudden deterioration in kidney function (e.g., due to infections), and cellular lysis (e.g., acute limb ischemia, rhabdomyolysis, severe trauma).

In this category of patients, careful monitoring of serum potassium levels is recommended.

Elderly patients. Dose escalation of amlodipine in this patient group should be performed cautiously (see sections "Dosage and administration" and "Pharmacokinetics").

Other. As with other antihypertensive medicinal products, excessive reduction in blood pressure in patients with ischemic cardiomyopathy or ischemic heart disease may lead to myocardial infarction or stroke.

Intestinal angioedema

Cases of intestinal angioedema have been reported in patients taking angiotensin II receptor blockers (see section "Adverse reactions"). These patients experienced abdominal pain, nausea, vomiting, and diarrhea. Symptoms resolved after discontinuation of angiotensin II receptor blockers. If intestinal angioedema is diagnosed, TELSARTAN DUO should be discontinued and appropriate monitoring initiated until complete resolution of symptoms.

Use during pregnancy or breastfeeding.

Pregnancy.

The medicinal product is contraindicated in pregnant women or women who are planning to become pregnant. If pregnancy is confirmed during treatment with this product, its use must be discontinued immediately and replaced with another medicinal product permitted for use during pregnancy.

Telmisartan.

The use of angiotensin II receptor antagonists is contraindicated during pregnancy.

Animal studies with telmisartan have demonstrated reproductive toxicity.

As long-term therapy with angiotensin II receptor antagonists is considered necessary, female patients planning pregnancy should switch to an alternative antihypertensive treatment with an established safety profile during pregnancy. If pregnancy is confirmed, angiotensin II receptor antagonists should be discontinued immediately and alternative therapy initiated.

It is known that treatment with angiotensin II receptor antagonists during the second and third trimesters of pregnancy causes fetotoxicity in humans (reduced kidney function, oligohydramnios, delayed skull ossification) and neonatal toxicity (renal failure, arterial hypotension, hyperkalemia).

If angiotensin II receptor antagonists were used during the second trimester of pregnancy, ultrasound assessment of kidney function and skull development is recommended.

Newborns whose mothers received angiotensin II receptor antagonists should be closely monitored for arterial hypotension.

Amlodipine.

Data from limited use during pregnancy do not indicate that amlodipine or other calcium channel blockers have harmful effects on the fetus. However, there may be a risk of prolonged labor.

Breastfeeding.

Amlodipine passes into breast milk. The infant's exposure, expressed as a percentage of maternal dose, is estimated to range between 3–7%, with a maximum of 15%. The effects of amlodipine on infants are unknown.

As there is no information on the use of telmisartan during breastfeeding, the use of Telsartan DUO is contraindicated during this period, and patients should switch to an alternative therapy with a better-established safety profile.

Fertility.

There are no data from controlled clinical studies on the use of fixed-dose combinations or individual components of the drug. Reproductive toxicity studies using the combination of telmisartan and amlodipine have not been conducted.

In preclinical studies, no effect of telmisartan on male or female fertility was observed. Similarly, no effects of amlodipine on male or female fertility have been reported.

In preclinical and in vitro studies with calcium channel blockers, reversible biochemical changes in the sperm head have been observed, which may interfere with the fertilization process. Clinical significance has not been established.

Ability to affect reaction rate while driving or operating machinery.

This medicinal product has a moderate effect on the ability to drive or operate machinery. Patients should be informed that adverse reactions such as syncope, somnolence, dizziness, or vertigo may occur during treatment. Therefore, caution is recommended when driving or operating machinery. If patients experience such adverse reactions, they should avoid potentially hazardous activities such as driving or operating machinery.

Method of Administration and Dosage.

Method of Administration.

Telzartan Duo can be taken independently of food intake. It is recommended to take the tablets with a small amount of liquid.

Dosage.

The recommended dose of Telzartan Duo is 1 tablet per day.

The maximum recommended dose is 1 tablet of Telzartan Duo 80 mg/10 mg per day. Telzartan Duo is intended for long-term treatment.

It is not recommended to consume grapefruit or grapefruit juice during treatment with amlodipine, as bioavailability may increase in some patients, leading to an enhanced antihypertensive effect.

Additional Therapy.

Telzartan Duo 80 mg/10 mg tablets may be administered to patients whose blood pressure is not adequately controlled with Telzartan Duo 40 mg/10 mg tablets or Telzartan Duo 80 mg/5 mg tablets.

Telzartan Duo 80 mg/5 mg tablets may be administered to patients whose blood pressure is not adequately controlled with Telzartan Duo 40 mg/5 mg tablets.

Telzartan Duo 40 mg/10 mg tablets may be administered to patients whose blood pressure is not adequately controlled with amlodipine 10 mg.

Telzartan Duo 40 mg/5 mg tablets may be administered to patients whose blood pressure is not adequately controlled with amlodipine 5 mg.

Titration of individual component doses (i.e., amlodipine and telmisartan) is recommended before switching to the fixed-dose combination. If clinically indicated, direct transition from monotherapy to the fixed-dose combination may be considered.

Patients previously receiving 10 mg amlodipine who experienced dose-limiting adverse reactions, such as edema, may be switched to Telzartan Duo 40 mg/5 mg tablets once daily, reducing the amlodipine dose without compromising the expected antihypertensive response.

Substitution Therapy.

Patients currently taking telmisartan and amlodipine as separate tablets may instead take Telzartan Duo, which contains equivalent doses of the components in a single tablet, once daily, for convenience or improved treatment adherence.

Special Patient Populations.

Elderly Patients (>65 years). Dose adjustment is not required for elderly patients. However, limited data are available on the use of the drug in this age group.

The standard amlodipine dosing regimen is recommended for this patient group, but dose escalation should be performed cautiously.

Patients with Renal Impairment. Dose adjustment is not required for patients with mild to moderate renal impairment. Experience with the use of the drug in patients with severe renal impairment or those on hemodialysis is limited. Telzartan Duo should be used with caution in such patients, as neither amlodipine nor telmisartan is dialyzable.

Patients with Hepatic Impairment. Telzartan Duo should be used with caution in patients with mild to moderate hepatic impairment. The telmisartan dose should not exceed 40 mg per day. The use of the drug is contraindicated in patients with severe hepatic impairment.

Children.

Not recommended for use in pediatric practice. Safety and efficacy of the drug in children under 18 years of age have not been established. Data are lacking.

Overdose.

Symptoms. Signs and 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.

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

Rare cases of non-cardiogenic pulmonary edema have been reported following amlodipine overdose, 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 elapsed since drug intake and the severity of symptoms. Recommended interventions include induction of emesis and/or gastric lavage. Activated charcoal may be beneficial in cases of overdose with both telmisartan and 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 maintained. Intravenous calcium gluconate may be effective in counteracting calcium channel blockade effects. Neither telmisartan nor amlodipine is dialyzable by hemodialysis.

Adverse reactions

Adverse reactions are categorized by frequency as follows: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1000 to < 1/100); rare (≥ 1/10000 to < 1/1000); very rare (< 1/10000); frequency not known (cannot be estimated from the available data).

Within each frequency group, adverse reactions are listed in order of decreasing severity.

List of adverse reactions in the table.

Classification by systems and organs	Telzartan DUO	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		anaemia
Rare		thrombocytopenia, eosinophilia
Very rare			leukopenia, thrombocytopenia
Immune system disorders
Rare		hypersensitivity, anaphylactic reaction
Very rare			hypersensitivity
Metabolism and nutrition disorders
Uncommon		hyperkalaemia
Rare		hypoglycaemia (in patients with diabetes mellitus), hyponatraemia
Very rare			hyperglycaemia
Psychiatric disorders
Uncommon			mood alteration
Rare	depression, anxiety, insomnia		confusion
Nervous system disorders
Common	dizziness
Uncommon	drowsiness, migraine, headache, paraesthesia
Rare	syncope, peripheral neuropathy, hypaesthesia, dysgeusia, tremor
Very rare			extrapyramidal disorder, hypertonia
Eye disorders
Common			vision disorders (including diplopia)
Uncommon			visual disturbance
Rare		vision 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	dyspnoea	dyspnoea, rhinitis
Very rare	interstitial lung disease3
Gastrointestinal disorders
Common			intestinal motility disorders (including diarrhoea and constipation)
Uncommon	abdominal pain, diarrhoea, nausea	flatulence
Rare	vomiting, gingival hyperplasia, dyspepsia, dry mouth	gastric discomfort
Very rare			pancreatitis, gastritis
Hepatobiliary disorders
Rare		liver function abnormalities, liver disorder2
Very rare			hepatitis, jaundice, increased liver enzymes (in most cases due to cholestasis)
Skin and subcutaneous tissue disorders
Uncommon	pruritus	hyperhidrosis	alopecia, purpura, skin discoloration, hyperhidrosis
Rare	eczema, erythema, rash	angioedema (also with fatal outcome), drug eruption, toxic skin eruption, urticaria
Very rare			angioedema, erythema multiforme, urticaria, exfoliative dermatitis, Stevens-Johnson syndrome, photosensitivity
Frequency unknown			toxic epidermal necrolysis
Musculoskeletal and connective tissue disorders
Common			ankle swelling
Uncommon	arthralgia, muscle cramps (leg cramps), myalgia
Rare	back pain, limb pain (leg pain)	tendon pain (symptoms similar to manifestations of tendinitis)
Renal and urinary disorders
Uncommon		renal function abnormalities, including acute renal failure	urinary disorders, polyuria
Rare	nocturia
Reproductive system and breast disorders
Uncommon	erectile dysfunction		gynaecomastia
General disorders and administration site conditions
Common	peripheral oedema
Uncommon	asthenia, chest pain, fatigue, oedema		pain
Rare	malaise	influenza-like illness
Investigations
Uncommon	increased liver enzymes	increased blood creatinine	increased body weight, decreased body weight
Rare	increased blood uric acid	increased blood creatine phosphokinase, decreased haemoglobin
1: the event may be coincidental or related to an unknown mechanism at present. 2: most cases of liver function abnormalities/liver diseases were observed during post-marketing use of the drug in Japanese patients. Such adverse reactions were more frequently reported in these patients. 3: during post-marketing use of telmisartan, cases of interstitial lung disease (mainly interstitial pneumonia and eosinophilic pneumonia) have been reported.

Description of selected adverse reactions

Cases of intestinal angioneurotic edema have been reported following the use of angiotensin II receptor blockers (see section "Special precautions").

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after a medicinal product is authorized is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients are encouraged to report any suspected adverse reactions and lack of efficacy of the medicinal product via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life. 2 years.

Storage conditions. Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of the reach of children.

Packaging. 7 tablets in a blister, 4 blisters in a cardboard box,

or 10 tablets in a blister, 3 blisters in a cardboard box.

Prescription status. Prescription only.

Manufacturer. Dr. Reddy’s Laboratories Limited

Manufacturer's address and location of operations.

Manufacturing site - Vl Village Khol, Nalagarh Road, Baddi, Solan District, Himachal Pradesh, 173205, India