Atera a

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ATERA A (ATERA A)

Composition:

Active substances: telmisartan, amlodipine;

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

Excipients: sodium hydroxide, meglumine, povidone K25, iron oxide yellow (E 172) – only for tablets of 40 mg/10 mg and 80 mg/10 mg, iron oxide red (E 172) – only for tablets of 40 mg/5 mg and 80 mg/5 mg, mannitol (E 421), microcrystalline cellulose, crospovidone, magnesium stearate, pregelatinized starch, corn starch, colloidal anhydrous silicon dioxide.

Pharmaceutical form. Tablets.

Main physicochemical properties:

Atéra A, tablets 40 mg/5 mg: bilayer tablets, elongated, biconvex, white to almost white on one side and pink on the other, slight specks on the pink side may occur;

Atéra A, tablets 40 mg/10 mg: bilayer tablets, elongated, biconvex, white to almost white on one side and yellow on the other, slight specks on the yellow side may occur;

Atéra A, tablets 80 mg/5 mg: bilayer tablets, elongated, biconvex, white to almost white on one side and pink on the other, slight specks on the pink side may occur;

Atéra A, tablets 80 mg/10 mg: bilayer tablets, elongated, biconvex, white to almost white on one side and yellow on the other, slight specks on the yellow side may occur.

Pharmacotherapeutic group. Angiotensin II receptor blockers, combinations. Telmisartan and amlodipine. ATC code: C09DB04.

Pharmacological properties.

Pharmacodynamics.

Athera A contains two antihypertensive components with complementary mechanisms of action for controlling blood pressure in patients with essential hypertension: an angiotensin II receptor antagonist, telmisartan, and a dihydropyridine calcium channel blocker, amlodipine.

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

Administration of Athera A once daily ensures effective and sustained reduction of blood pressure over 24 hours within the therapeutic dose range.

Telmisartan

Telmisartan is a specific and potent angiotensin II receptor antagonist (AT1 subtype) effective after oral administration. Telmisartan binds with very high affinity to the angiotensin II binding site on AT1 receptors, which mediate the known effects of angiotensin II, thereby displacing angiotensin II. Telmisartan does not exhibit 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 and other less-characterized AT receptors. The functional role of these receptors is unknown, as is the potential effect of their possible "overstimulation" by elevated angiotensin II levels, which increase under the influence of telmisartan. Telmisartan reduces plasma aldosterone levels. It does not inhibit plasma renin activity, 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 for over 24 hours and remains evident up to 48 hours.

After the first dose, antihypertensive activity of telmisartan gradually develops within 3 hours. Maximum reduction in blood pressure is usually achieved within 4–8 weeks of initiating treatment 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 just before the next dose to the maximum reduction exceeds 80% after administration of 40 mg and 80 mg in placebo-controlled clinical trials. There is a clear dose-response relationship regarding the time to recovery of initial systolic blood pressure. Data on diastolic blood pressure in this context are inconsistent.

In patients with arterial hypertension, telmisartan reduces both systolic and diastolic blood pressure without affecting pulse rate. The contribution of diuretic and natriuretic effects of the drug to its hypotensive action remains to be fully elucidated. The antihypertensive efficacy of telmisartan is comparable to that of other antihypertensive agents from different 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 pre-treatment levels over several days, with no evidence of a withdrawal syndrome.

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

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

Amlodipine

Amlodipine is a dihydropyridine calcium channel blocker (influx inhibitor of calcium ions or calcium antagonist) that inhibits transmembrane influx of calcium ions into vascular and cardiac smooth muscle cells. The antihypertensive mechanism of amlodipine is due to a direct vasodilatory effect on vascular smooth muscle, resulting in reduced peripheral vascular resistance and consequent lowering of arterial blood pressure. Experimental data indicate that amlodipine binds to both dihydropyridine and non-dihydropyridine binding sites. Amlodipine is relatively vascular-selective, exerting a greater effect 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 (GFR) and effective renal plasma flow without altering filtration fraction or proteinuria.

Amlodipine is not associated with any adverse metabolic effects or changes in plasma lipid levels, making it suitable for use in 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 involving patients with NYHA class III–IV heart failure without clinical or objective signs of ischemic heart disease, receiving stable doses of ACE inhibitors, digitalis, and diuretics, amlodipine did not affect overall cardiovascular mortality. In this same population, amlodipine was associated with a higher incidence of pulmonary edema reports, despite no significant difference in heart failure progression compared to the placebo group.

Telmsartan/amlodipine

In an eight-week, multicenter, randomized, double-blind, placebo-controlled study involving patients with moderate to severe hypertension (mean seated diastolic blood pressure ≥95 mm Hg and ≤119 mm Hg), the telmisartan/amlodipine combination reduced diastolic and systolic blood pressure more effectively and achieved blood pressure control faster than either component used as monotherapy.

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 of the antihypertensive effect was 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 reports of edema.

Automated ambulatory blood pressure monitoring in a subgroup of patients confirmed the consistent reduction in systolic and diastolic blood pressure throughout the 24-hour dosing period.

In a multicenter, randomized, double-blind, active-controlled study involving 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 telmisartan/amlodipine 40 mg/5 mg and 80 mg/5 mg compared to amlodipine 10 mg.

In another multicenter, randomized, double-blind, active-controlled study involving patients with moderate to severe hypertension inadequately controlled on amlodipine 10 mg, patients received either telmisartan/amlodipine (40 mg/10 mg or 80 mg/10 mg) or amlodipine monotherapy (10 mg). After 8 weeks, both combination regimens showed statistically greater efficacy than amlodipine monotherapy in reducing systolic and diastolic blood pressure and improved diastolic blood pressure normalization rates. In two subsequent open-label, long-term observational studies lasting 6 months, the antihypertensive effect of telmisartan/amlodipine combination was maintained throughout the study period. Additionally, in some patients who did not achieve adequate blood pressure control with telmisartan/amlodipine 40 mg/10 mg, further 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 combination are equivalent to the bioavailability of telmisartan and amlodipine administered as separate tablets.

Absorption. Telmisartan is rapidly absorbed, although the extent of absorption varies. The mean absolute bioavailability of telmisartan is approximately 50%. When telmisartan is taken with food, the area under the plasma concentration-time curve (AUC0–∞) decreases 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 concentrations 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 have shown that about 97.5% of circulating amlodipine in patients with arterial hypertension is protein-bound.

Metabolism. Telmisartan is metabolized primarily by conjugation to the glucuronide of the parent substance. 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 of >20 hours. Maximum plasma concentration (Cmax) and, to a lesser extent, 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 eliminated via 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).

Plasma elimination of amlodipine 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 administration. Approximately 10% of amlodipine is excreted unchanged in urine and 60% as metabolites.

Linearity/non-linearity. The slight decrease 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). 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 peak 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 concentrations of telmisartan are doubled in patients with mild, moderate, and severe renal impairment. However, lower plasma concentrations were observed in dialysis-dependent patients. Telmisartan is highly protein-bound in patients with renal failure and is not removed by dialysis. Elimination half-life is not altered 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 increase in AUC by approximately 40–60%.

Clinical characteristics.

Indications

Treatment of essential hypertension in adults.

Additional therapy. The medicinal product Athera A is indicated for adult patients whose blood pressure is not adequately controlled with amlodipine or telmisartan alone.

Substitution therapy. Adult patients who are taking telmisartan and amlodipine as separate tablets may switch to Athera A tablets containing the same doses of the components.

Contraindications

• Hypersensitivity to the active substances, to dihydropyridine derivatives, or to any excipients of the medicinal product.
• Pregnancy or planned pregnancy (see section "Use in pregnancy or breast-feeding").
• Breast-feeding 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 mellitus or renal impairment (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 typical for 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 ATERA A may be enhanced when used concomitantly with other antihypertensive medicinal products.

Medicinal products with potential to lower blood pressure. Based on pharmacological properties, it can be expected that certain medicinal products may enhance the hypotensive effects of all antihypertensive agents, including this medicinal product, for example baclofen, amifostine, neuroleptics, or antidepressants. In addition, orthostatic hypotension may be exacerbated by alcohol consumption.

Systemic corticosteroids. Reduction of antihypertensive effect.

Interactions related to telmisartan

Concomitant use not recommended

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

Lithium. Cases of reversible increases in serum lithium concentrations and increased lithium toxicity have been reported with concomitant use of lithium and ACE inhibitors or angiotensin II receptor antagonists, including 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 arterial hypotension, hyperkalemia, and impaired renal function (including acute renal failure), compared to treatment with a single agent acting on the RAAS.

Concomitant use requiring caution

Nonsteroidal anti-inflammatory drugs (NSAIDs). NSAID therapy (including acetylsalicylic acid at anti-inflammatory doses, COX-2 inhibitors, and non-selective NSAIDs) may reduce the antihypertensive effect of angiotensin II receptor antagonists. In some patients with impaired renal function (e.g., dehydrated patients or elderly patients with renal impairment), 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 with caution, especially in elderly patients. Adequate hydration should be ensured. Careful monitoring of renal function at the start of combination therapy and during treatment is also required.

Ramipril. In one study, concomitant use 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. Concomitant use of telmisartan and digoxin was associated with a mean increase in plasma digoxin C_max (by 49%) and minimum concentration (by 20%). Monitoring of digoxin levels should be performed at the initiation, dose adjustment, and discontinuation of telmisartan to maintain levels within the therapeutic range.

Interactions related to amlodipine

Concomitant use requiring caution

CYP3A4 inhibitors. When co-administered with the CYP3A4 inhibitor erythromycin in young patients or with diltiazem in elderly patients, plasma concentrations of amlodipine increased by 22% and 50%, respectively. However, the clinical significance of this observation is not established. It cannot be excluded that strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, ritonavir) may increase plasma concentrations of amlodipine to a greater extent than diltiazem. Amlodipine should be used with caution when co-administered with CYP3A4 inhibitors. However, no adverse reactions specific to such interactions have been reported.

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

Grapefruit or grapefruit juice. Concomitant administration of 240 mL of grapefruit juice with a single 10 mg oral dose of amlodipine in 20 healthy volunteers did not show a significant effect on the pharmacokinetic properties of amlodipine. However, concomitant use of amlodipine with grapefruit or grapefruit juice is not currently recommended, as in some patients it may increase amlodipine bioavailability, leading to an enhanced antihypertensive 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 in patients receiving tacrolimus, regular monitoring of blood tacrolimus levels and, if necessary, dose adjustment are required when amlodipine is administered.

Cyclosporine. Interaction studies between cyclosporine and amlodipine have not been conducted in healthy volunteers or other groups, 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, if necessary, reduction of cyclosporine dose should be considered.

Simvastatin. Long-term concomitant use of amlodipine with 80 mg simvastatin 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.

Others. Amlodipine has been safely co-administered with digoxin, warfarin, atorvastatin, sildenafil, antacids (aluminum hydroxide, magnesium hydroxide, simethicone), cimetidine, antibiotics, and oral hypoglycemic agents. When amlodipine and sildenafil were used together, each drug independently contributed to blood pressure reduction.

Special precautions for use.

Pregnancy. Therapy with angiotensin II receptor antagonists (ARBs) should not be initiated during pregnancy. Patients who are planning pregnancy and for whom ongoing ARB therapy is considered necessary should switch to an alternative antihypertensive treatment with an established safety profile for use in pregnancy. If pregnancy is confirmed, ARB therapy should be discontinued immediately and alternative therapy initiated if necessary (see sections "Contraindications" and "Use during pregnancy or breastfeeding").

Hepatic impairment

Telmisartan is predominantly excreted via bile. In patients with obstructive biliary disorders or hepatic insufficiency, administration of the drug may lead to reduced telmisartan clearance. In addition, as with all calcium antagonists, the elimination half-life of amlodipine is prolonged in patients with hepatic impairment, and dosage recommendations have not been established.

Patients with obstructive biliary disorders

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

Patients with hepatic insufficiency

Atera A should be administered with caution to patients with mild to moderate hepatic insufficiency. The use of the drug is contraindicated in severe hepatic insufficiency.

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

Renal impairment and kidney transplantation. Periodic monitoring of serum potassium and creatinine levels is recommended in patients with renal impairment receiving Atera A tablets. 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 intravascular volume and/or sodium levels due to excessive diuretic therapy, dietary salt restriction, diarrhea, or vomiting. Such conditions should be corrected prior to initiating telmisartan. If hypotension occurs during treatment, the patient should be placed in a supine position and, if necessary, receive intravenous infusion of physiological saline. Therapy may be continued after blood pressure stabilization.

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

If concomitant use is considered absolutely necessary, it should be performed only under specialist supervision with frequent and 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 renal disease, including renal artery stenosis), treatment with drugs affecting this system may be associated with acute 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, the drug should be used with particular caution in patients diagnosed with aortic or mitral valve stenosis or obstructive hypertrophic cardiomyopathy. The drug is contraindicated in patients with high-grade aortic stenosis.

Unstable angina, acute myocardial infarction. There are no data on the use of Atera A in patients with 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 increased 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 telmisartan therapy. Therefore, glucose levels should be monitored in these patients; dose adjustment of insulin or antidiabetic agents may be necessary.

Hyperkalemia. Drugs affecting the RAAS may cause hyperkalemia. Hyperkalemia can be life-threatening in elderly patients, patients with renal impairment, patients with diabetes mellitus, patients concomitantly taking other drugs that may increase serum potassium levels, and/or patients with intercurrent illnesses.

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

Key risk factors for hyperkalemia requiring attention include:

• Diabetes mellitus, renal dysfunction, advanced age (>70 years).
• Combination with one or more RAAS-affecting drugs and/or potassium supplements. Medicinal products or therapeutic classes 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, renal dysfunction, sudden worsening of renal function (e.g., due to infections), and cellular lysis (e.g., acute limb ischemia, rhabdomyolysis, severe trauma).

Careful monitoring of serum potassium levels is recommended in these patient groups.

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

This medicinal product contains less than 1 mmol (23 mg)/dose of sodium, i.e., essentially "sodium-free".

Use during pregnancy or breastfeeding.

Pregnancy

The medicinal product is contraindicated in pregnant women or women planning to become pregnant. If pregnancy is confirmed during treatment with Atera A, therapy should be discontinued immediately and replaced with another medicinal product approved for use in pregnancy.

Telmisartan

Angiotensin II receptor antagonists are contraindicated during pregnancy.

Animal studies with telmisartan have demonstrated reproductive toxicity.

Patients planning pregnancy and for whom ongoing therapy with angiotensin II receptor antagonists is considered necessary should switch to an alternative antihypertensive treatment with an established safety profile for use 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 fetal toxicity in humans (reduced renal function, oligohydramnios, delayed skull ossification) and neonatal toxicity (renal failure, hypotension, hyperkalemia).

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

Infants born to mothers who took angiotensin II receptor antagonists should be closely monitored for hypotension.

Amlodipine

Limited data on 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 period

Amlodipine is excreted in breast milk. The dose received by the infant from the mother is estimated to be 3–7% in the interquartile range, with a maximum of 15%. The effect of amlodipine on infants is unknown.

As there is no information on the use of telmisartan during breastfeeding, Atera A is contraindicated during this period; alternative therapy with a better-established safety profile should be used.

Fertility

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

In preclinical studies, no effects of telmisartan on male or female fertility were 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. The clinical significance of this has not been established.

Ability to affect reaction speed when driving vehicles or operating machinery.

This medicinal product has a moderate effect on reaction speed when driving vehicles or operating 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 vehicles 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

Athera A 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 Athera A is 1 tablet per day.

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

Concomitant use of amlodipine with grapefruit or grapefruit juice is not recommended, as bioavailability may increase in some patients, leading to an enhanced antihypertensive effect.

Additional Therapy

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

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

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

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

Titration of individual doses of the components (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 amlodipine 10 mg who experienced dose-limiting adverse reactions, such as edema, may be switched to Athera A 40 mg/5 mg tablets once daily, reducing the amlodipine dose without reducing the overall expected antihypertensive response.

Substitution Therapy

Patients currently taking telmisartan and amlodipine as separate tablets may instead receive Athera A, containing the corresponding doses of these components in a single tablet, once daily, for example, to improve convenience or treatment adherence.

Special Patient Populations

Elderly Patients. Dose adjustment is not required in elderly patients. However, information on the use of the drug in elderly patients is limited.

Patients with Renal Impairment. Dose adjustment is not required in patients with mild to moderate renal impairment. Experience with the use of Athera A in patients with severe renal impairment or those on hemodialysis is limited. The drug should be used with caution in such patients, as neither amlodipine nor telmisartan is removed from the body by dialysis.

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

Children.

Not recommended for use in pediatric practice. Safety and efficacy of Athera A 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 hypotension and tachycardia; bradycardia, dizziness, increased serum creatinine levels, and acute renal failure have also been reported.

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

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

Treatment. Close monitoring of the patient is required; treatment should be symptomatic and supportive. Therapeutic measures depend on the time elapsed since drug intake and the severity of symptoms. Recommended measures 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 hypotension, the patient should be placed in a supine position with legs elevated, and intravascular volume and electrolyte balance should be promptly corrected. Supportive therapy is necessary. Intravenous administration of calcium gluconate may be effective in counteracting calcium channel blockade effects. Neither telmisartan nor amlodipine is removed by hemodialysis.

Side effects

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

Within each frequency group, side effects are listed in order of decreasing severity.

System Organ Class		Athera A		Telmisartan		Amlodipine
Infections and infestations
Uncommon				upper respiratory tract infections, including pharyngitis and sinusitis, urinary tract infections, including cystitis
Rare		cystitis		sepsis, including fatal outcome1
Blood and lymphatic system disorders
Uncommon				anemia
Rare				thrombocytopenia, eosinophilia
Very rare						leukopenia, thrombocytopenia
Immune system disorders
Rare				hypersensitivity, anaphylactic reaction
Very rare						hypersensitivity
Metabolism and nutrition disorders
Uncommon				hyperkalemia
Rare				hypoglycemia (in patients with diabetes mellitus)
Very rare						hyperglycemia
Psychiatric disorders
Uncommon						mood changes
Rare		depression, anxiety, insomnia				confusion
Nervous system disorders
Common		dizziness
Uncommon		sleepiness, migraine, headache, paresthesia
Rare		syncope, peripheral neuropathy, hypaesthesia, dysgeusia, tremor
Very rare						extrapyramidal disorder
Eye disorders
Uncommon						vision disorders
Rare				visual disturbances
Ear and labyrinth disorders
Uncommon		vertigo				tinnitus
Cardiac disorders
Uncommon		bradycardia, palpitations
Rare				tachycardia
Very rare						myocardial infarction, arrhythmia, ventricular tachycardia, atrial fibrillation
Vascular disorders
Uncommon		arterial hypotension, orthostatic hypotension, flushing
Very rare						vasculitis
Respiratory, thoracic and mediastinal disorders
Uncommon		cough		dyspnea		dyspnea, rhinitis
Very rare		interstitial lung disease3
Gastrointestinal disorders
Uncommon		abdominal pain, diarrhea, nausea		flatulence		intestinal motility disorder
Rare		vomiting, gingival hyperplasia, dyspepsia, dry mouth		gastric discomfort
Very rare						pancreatitis, gastritis
Hepatobiliary disorders
Rare				liver function abnormalities, hepatic 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 (with fatal outcome), drug eruption, toxic skin eruption, urticaria
Very rare					angioedema, erythema multiforme, urticaria, exfoliative dermatitis, Stevens-Johnson syndrome, photosensitivity
Frequency not known					toxic epidermal necrolysis
Musculoskeletal and connective tissue disorders
Uncommon	arthralgia, muscle cramps (leg cramps), myalgia
Rare	back pain, limb pain (leg pain)		tendon pain (symptoms similar to 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				gynecomastia
General disorders and administration site conditions
Common	peripheral edema
Uncommon	asthenia, chest pain, fatigue, swelling				pain
Rare	malaise		influenza-like illness
Investigations
Uncommon	increased liver enzymes		increased blood creatinine		weight increased, weight decreased
Rare	increased blood uric acid		increased blood creatine phosphokinase, decreased hemoglobin
1: the event may be coincidental or related to an unknown mechanism; 2: most cases of liver function abnormalities/liver disorders were observed during post-marketing use of the drug in Japanese patients; such adverse reactions were more frequently observed in these patients; 3: during post-marketing use of telmisartan, cases of interstitial lung disease (mainly interstitial pneumonia and eosinophilic pneumonia) have been reported.

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions after registration of a medicinal product plays an important role. This allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals should report any suspected adverse reactions.

Shelf life.

2 years.

Storage conditions.

Store in the original packaging to protect from light.

Keep out of reach and sight of children.

Packaging.

14 tablets in a blister pack, 2 blisters in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

Pharmaceutical Works "Polpharma" S.A., Poland.

Manufacturer's address and location of operations.

19, Pelplinska Str., 83-200 Starogard Gdanski, Poland.