Attento plus 20/5/12,5

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ATTENTO® PLUS 20/5/12.5, ATTENTO® PLUS 40/10/12.5, ATTENTO® PLUS 40/10/25 (ATTENTO® PLUS 20/5/12.5, ATTENTO® PLUS 40/10/12.5, ATTENTO® PLUS 40/10/25)

Composition:

Active substances: olmesartan medoxomil; amlodipine besylate; hydrochlorothiazide.

ATTENTO® PLUS 20/5/12.5:

One film-coated tablet contains olmesartan medoxomil 20 mg, amlodipine besylate 6.944 mg (equivalent to amlodipine 5 mg), and hydrochlorothiazide 12.5 mg.

ATTENTO® PLUS 40/10/12.5:

One film-coated tablet contains olmesartan medoxomil 40 mg, amlodipine besylate 13.888 mg (equivalent to amlodipine 10 mg), and hydrochlorothiazide 12.5 mg.

ATTENTO® PLUS 40/10/25:

One film-coated tablet contains olmesartan medoxomil 40 mg, amlodipine besylate 13.888 mg (equivalent to amlodipine 10 mg), and hydrochlorothiazide 25 mg.

Excipients:

Tablet core: pregelatinized starch (corn), silicified microcrystalline cellulose, sodium croscarmellose, magnesium stearate (of plant origin).

Film coating:

ATTENTO® PLUS 20/5/12.5:

Opadry II 85F24118 (polyvinyl alcohol, polyethylene glycol, talc, titanium dioxide (E 171), yellow iron oxide (E 172), red iron oxide (E 172), black iron oxide (E 172)).

ATTENTO® PLUS 40/10/12.5 and ATTENTO® PLUS 40/10/25:

Opadry II 85F25437 (polyvinyl alcohol, polyethylene glycol, talc, titanium dioxide (E 171), yellow iron oxide (E 172), red iron oxide (E 172)).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties.

ATTENTO® PLUS 20/5/12.5:

Orange-white, round, film-coated tablets (tablet diameter approximately 8 mm) with "C51" embossed on one side.

ATTENTO® PLUS 40/10/12.5:

Grayish-red, round, film-coated tablets (tablet diameter approximately 9.5 mm) with "C55" embossed on one side.

ATTENTO® PLUS 40/10/25:

Grayish-red, oval, film-coated tablets (tablet dimensions approximately 15 × 7 mm) with "C57" embossed on one side.

Pharmacotherapeutic group. Angiotensin II antagonists, calcium channel blockers and diuretics. ATC code C09DX03.

Pharmacological properties.

Pharmacodynamics.

ATTENTO® PLUS is a combination medicinal product containing olmesartan medoxomil – an angiotensin II receptor antagonist, amlodipine besylate – a calcium channel blocker, and hydrochlorothiazide – a thiazide diuretic. The combination of these three active substances demonstrates a synergistic effect and provides greater reduction in arterial blood pressure than each active substance alone.

Olmesartan medoxomil is a selective antagonist of angiotensin II receptors (type AT1), intended for oral administration. Angiotensin II is the main vasoactive hormone of the renin-angiotensin-aldosterone system, playing a key role in the pathophysiology of arterial hypertension. Angiotensin II causes vasoconstriction, stimulates synthesis and release of aldosterone, has cardiostimulatory effects, and promotes renal sodium reabsorption. Olmesartan suppresses the vasoconstrictive and aldosterone-secreting actions of angiotensin II by blocking AT1 receptors in tissues, including vascular smooth muscles and adrenal glands. The action of olmesartan does not depend on the source or pathway of angiotensin II synthesis. Selective antagonism of olmesartan at angiotensin II AT1 receptors leads to increased plasma renin levels and concentrations of angiotensin I and angiotensin II, as well as some reduction in plasma aldosterone levels. In arterial hypertension, olmesartan medoxomil causes a prolonged dose-dependent reduction in arterial blood pressure. No cases of arterial hypotension after the first dose, signs of tachyphylaxis during long-term use, or rebound hypertension after discontinuation have been observed. When administered once daily to patients with arterial hypertension, olmesartan medoxomil effectively and smoothly reduces arterial blood pressure over the 24-hour dosing interval. The antihypertensive effect of the drug is similar whether administered once or twice daily at the same total daily dose. Maximum reduction in arterial blood pressure is achieved after 8 weeks of treatment, although a significant antihypertensive effect is observed as early as 2 weeks of therapy. The effect of olmesartan medoxomil on morbidity and mortality has not been established.

A randomized study of olmesartan use for prevention of diabetic microalbuminuria (ROADMAP), involving 4447 patients with type 2 diabetes with normal albuminuria levels and at least one additional cardiovascular risk factor, was conducted to determine whether olmesartan therapy could delay the onset of microalbuminuria. During a mean follow-up period of 3.2 years, patients received olmesartan or placebo in addition to other antihypertensive agents, except ACE inhibitors or ARBs.

The primary endpoint, time to onset of microalbuminuria, was prolonged by 23% with olmesartan (hazard ratio for onset of microalbuminuria 0.77; 95.1% confidence interval [CI], 0.63–0.94; P = 0.01). After adjusting for minor baseline differences in body mass index, blood pressure, and high-density lipoprotein levels, the hazard ratio for the primary endpoint was 0.75 (95.1% CI, 0.62–0.92; P = 0.006). Similar results were obtained in a pre-specified per-protocol analysis and in a post hoc analysis excluding patients who prematurely discontinued study treatment. The reduction in the primary endpoint with olmesartan remained significant after adjustment for blood pressure differences.

In the secondary endpoint, cardiovascular events occurred in 96 patients (4.3%) receiving olmesartan and in 94 patients (4.2%) receiving placebo. Cardiovascular mortality was higher in the olmesartan group compared to the placebo group (15 patients (0.7%) vs. 3 patients (0.1%)), despite similar rates of non-fatal stroke (14 patients (0.6%) vs. 8 patients (0.4%)), non-fatal myocardial infarction (17 patients (0.8%) vs. 26 patients (1.2%)), and non-cardiovascular mortality (11 patients (0.5%) vs. 12 patients (0.5%)). Overall mortality was higher in the olmesartan group (26 patients (1.2%) vs. 15 patients (0.7%)), primarily due to higher cardiovascular mortality.

In the ORIENT trial (The Olmesartan Reducing Incidence of End-stage Renal Disease in Diabetic Nephropathy Trial), the effect of olmesartan on renal and cardiovascular outcomes was studied in 577 randomized patients in Japan and China with type 2 diabetes and overt nephropathy. During a mean follow-up period of 3.1 years, patients received olmesartan or placebo in addition to other antihypertensive agents, including ACE inhibitors.

The primary composite endpoint (time to first occurrence of doubling of serum creatinine, end-stage renal disease, or death from any cause) was reached in 116 patients in the olmesartan group (41.1%) and in 129 patients receiving placebo (45.4%) (HR 0.97 (95% CI 0.75–1.24); p = 0.791). The secondary composite cardiovascular endpoint was reached in 40 patients receiving olmesartan (14.2%) and in 53 patients receiving placebo (18.7%). This composite cardiovascular endpoint included cardiovascular mortality in 10 (3.5%) patients receiving olmesartan and in 3 (1.1%) patients receiving placebo; overall mortality was 19 (6.7%) and 20 (7.0%), non-fatal stroke occurred in 8 (2.8%) and 11 (3.9%), and non-fatal myocardial infarction occurred in 3 (1.1%) and 7 (2.5%), respectively.

Amlodipine, included in ATTENTO® PLUS, is a calcium channel blocker that inhibits transmembrane calcium ion influx through voltage-dependent L-type channels in the heart and smooth muscles. Experimental data indicate that amlodipine interacts with both dihydropyridine binding sites and other sites. Amlodipine has relative vasoselectivity and affects vascular smooth muscle cells more than cardiomyocytes. The antihypertensive effect of amlodipine is due to direct relaxation of arterial smooth muscle cells, leading to reduced peripheral vascular resistance and, consequently, lower arterial blood pressure.

In arterial hypertension, amlodipine causes a prolonged, dose-dependent reduction in arterial blood pressure. No cases of arterial hypotension after the first dose, signs of tachyphylaxis during long-term treatment, or rebound hypertension after discontinuation have been observed.

After oral administration at therapeutic doses in patients with arterial hypertension, amlodipine effectively reduces arterial blood pressure in supine, sitting, and standing positions. Long-term use of amlodipine is not associated with significant changes in heart rate or plasma catecholamine levels. In patients with arterial hypertension and normal renal function, amlodipine at therapeutic doses reduces renal vascular resistance and increases glomerular filtration rate and effective renal plasma flow, without altering filtration fraction or causing proteinuria.

In hemodynamic studies in patients with heart failure and clinical studies with stress testing in heart failure (NYHA classes II–IV), amlodipine did not worsen patient status as assessed by exercise tolerance, left ventricular ejection fraction, or clinical signs and symptoms.

In a placebo-controlled study (PRAISE) involving patients with heart failure (NYHA classes III–IV) receiving digoxin, diuretics, and ACE inhibitors, amlodipine was shown not to increase the risk of mortality or morbidity in patients with heart failure.

In a subsequent long-term placebo-controlled study (PRAISE-2) of amlodipine in patients with heart failure (NYHA III and IV) without clinical symptoms or objective evidence of ischemic heart disease, receiving ACE inhibitors, digitalis agents, and diuretics at stable doses, amlodipine did not affect overall mortality or cardiovascular mortality specifically. In this patient group, an increased incidence of pulmonary edema associated with amlodipine use was observed, but no statistically significant differences in the frequency of worsening heart failure compared to placebo were noted.

To compare new antihypertensive and lipid-lowering therapies, a double-blind, randomized morbidity and mortality trial called "Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial" (ALLHAT) was conducted: amlodipine at 2.5–10 mg/day (calcium channel blocker) or lisinopril at 10–40 mg/day (ACE inhibitor) as first-line therapy versus the thiazide diuretic chlorthalidone at 12.5–25 mg/day in mild to moderate hypertension.

All 33,357 patients with arterial hypertension aged 55 years or older were randomized and followed for a mean of 4.9 years. Patients had at least one additional risk factor for ischemic heart disease (IHD), including prior myocardial infarction or stroke (more than 6 months before enrollment) or presence of other atherosclerotic cardiovascular diseases (51.5% total), type 2 diabetes (36.1%), HDL cholesterol level < 35 mg/dL (11.6%), left ventricular hypertrophy diagnosed by electrocardiography or echocardiography (20.9%), or current smoking (21.9%).

The primary endpoint of the study was fatal IHD or non-fatal myocardial infarction. No significant differences regarding the primary endpoint were observed between amlodipine and chlorthalidone therapy: HR 0.98 95% CI (0.90–1.07) p = 0.65. Regarding 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, no significant differences in all-cause mortality between amlodipine and chlorthalidone therapy were observed (HR 0.96 95% CI [0.89–1.02] p = 0.20).

Hydrochlorothiazide is a thiazide diuretic. The mechanism of antihypertensive action of thiazide diuretics is not fully understood. Thiazide diuretics affect electrolyte reabsorption in renal tubules, thereby enhancing excretion of sodium and chloride (approximately in equimolar amounts).

With its diuretic action, hydrochlorothiazide leads to reduced plasma volume, increased plasma renin activity, and enhanced aldosterone secretion, resulting in increased urinary excretion of potassium and bicarbonate and decreased serum potassium levels. Since the relationship between renin levels and aldosterone secretion is mediated by angiotensin II, potassium losses with thiazide diuretics may be reduced when hydrochlorothiazide is used in combination with an angiotensin II receptor blocker. After oral administration, diuresis begins approximately 2 hours after intake, maximum effect is reached about 4 hours later, and the effect lasts for 6–12 hours.

According to epidemiological data, long-term use of hydrochlorothiazide as monotherapy reduces the risk of cardiovascular complications and death from them.

Clinical study results

In a 12-week double-blind, randomized, parallel-group study involving 2492 patients (67% of patients were Caucasian), ATTENTO® PLUS 40/10/25 resulted in significantly greater reduction in diastolic and systolic arterial blood pressure compared to each of the following dual combinations: olmesartan medoxomil (40 mg) with amlodipine (10 mg), olmesartan medoxomil (40 mg) with hydrochlorothiazide (25 mg), and amlodipine (10 mg) with hydrochlorothiazide (25 mg).

The additional antihypertensive effect of ATTENTO® PLUS 40/10/25 compared to the respective dual combinations ranged from -3.8 to -6.7 mm Hg (diastolic blood pressure in sitting position) and from -7.1 to -9.6 mm Hg (systolic blood pressure in sitting position), and was evident within the first two weeks.

The proportion of patients achieving target blood pressure levels (< 140/90 mm Hg in non-diabetic patients and < 130/80 mm Hg in diabetic patients) after 12 weeks was 34.9–46.6% in the dual combination groups and 64.3% in the ATTENTO® PLUS 40/10/25 group.

In a second double-blind, randomized, parallel-group study involving 2690 patients (99.9% of patients were Caucasian), ATTENTO® PLUS (20 mg/5 mg/12.5 mg, 40 mg/5 mg/12.5 mg, 40 mg/5 mg/25 mg, 40 mg/10 mg/12.5 mg, 40 mg/10 mg/25 mg) resulted in significantly greater reduction in diastolic and systolic arterial blood pressure after 10 weeks compared to each of the following dual combinations: olmesartan medoxomil (20 mg) with amlodipine (5 mg), olmesartan medoxomil (40 mg) with amlodipine (5 mg), and olmesartan medoxomil (40 mg) with amlodipine (10 mg).

The additional antihypertensive effect of ATTENTO® PLUS compared to the respective dual combinations ranged from -1.3 to -1.9 mm Hg (diastolic blood pressure in sitting position) and from -2.7 to -4.9 mm Hg (systolic blood pressure in sitting position).

The proportion of patients achieving target blood pressure levels (< 140/90 mm Hg in non-diabetic patients and < 130/80 mm Hg in diabetic patients) after 10 weeks was 42.7–49.6% in the dual combination groups and 52.4–58.8% in the ATTENTO® PLUS group.

In a randomized, double-blind study involving 808 patients (99.9% of patients were Caucasian) whose blood pressure was not controlled after 8 weeks of treatment with the combination of olmesartan medoxomil (40 mg) and amlodipine (10 mg), use of ATTENTO® PLUS resulted in greater numerically expressed reduction in seated blood pressure (-1.8/-1.0 mm Hg with ATTENTO® PLUS 40/10/12.5) and statistically significant greater reduction in blood pressure of -3.6/-2.8 mm Hg with ATTENTO® PLUS 40/10/25 compared to the dual combination of olmesartan medoxomil (40 mg) and amlodipine (10 mg).

Treatment with ATTENTO® PLUS 40/10/25 using the triple combination of active substances led to a statistically significant increase in the percentage of patients achieving target blood pressure compared to dual combination treatment with olmesartan medoxomil (40 mg) and amlodipine (10 mg) (41.3% vs. 24.2%); conversely, use of the triple combination contained in ATTENTO® PLUS 40/10/12.5 led to a numerically greater increase in the percentage of patients achieving target blood pressure compared to dual combination treatment with olmesartan medoxomil (40 mg) and amlodipine (10 mg) in patients who did not achieve adequate blood pressure control (29.5% vs. 24.2%).

The antihypertensive effect of ATTENTO® PLUS does not depend on patient age or sex, or presence or absence of diabetes.

Other information

Concomitant use of ACE inhibitors and angiotensin II receptor blockers was studied in two large-scale randomized controlled trials (ONTARGET (ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial) and VA NEPHRON-D (The Veterans Affairs Nephropathy in Diabetes)).

ONTARGET was a study conducted in patients with prior 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 show significant beneficial effects 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. Due to 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 conducted to detect a positive effect of adding aliskiren to standard therapy with ACE inhibitors or angiotensin II receptor blockers in patients with type 2 diabetes and chronic kidney disease, cardiovascular disease, or both. This study was terminated early due to increased risk of adverse reactions. Cardiovascular mortality and incidence of stroke were higher in the aliskiren group than in the placebo group, and reports of adverse reactions and serious adverse reactions (hyperkalemia, arterial hypotension, and renal function impairment) were more frequent in the aliskiren group than in the placebo group.

Non-melanoma skin cancer (NMSC). Epidemiological data indicate an association between cumulative hydrochlorothiazide dose and development of NMSC. One study included a population of 71,533 patients with basal cell carcinoma (BCC) and 8,629 patients with squamous cell carcinoma (SCC), compared with 1,430,833 and 172,462 control group participants, respectively. High-dose hydrochlorothiazide use (cumulative ≥ 50,000 mg) was associated with an adjusted odds ratio (OR) of 1.29 (95% confidence interval (CI): 1.23–1.35) for BCC and 3.98 (95% CI: 3.68–4.31) for SCC. A clear dose-response relationship was observed for both BCC and SCC. Another study suggested a possible association between lip cancer (SCC) and hydrochlorothiazide: 633 patients with lip cancer were compared with 63,067 control group participants using a risk-set sampling strategy. A dose-response relationship was demonstrated: adjusted OR was 2.1 (95% CI: 1.7–2.6), increasing to OR 3.9 (3.0–4.9) with high doses (~25,000 mg) and OR 7.7 (5.7–10.5) with the highest cumulative dose (~100,000 mg) (see also section "Special precautions for use").

Pharmacokinetics.

In healthy volunteers, no clinically significant effect on the pharmacokinetics of each component was observed when olmesartan medoxomil, amlodipine, and hydrochlorothiazide were co-administered.

After oral administration of ATTENTO® PLUS to healthy adult volunteers, maximum plasma concentrations of olmesartan medoxomil, amlodipine, and hydrochlorothiazide are reached within 1.5–3 hours, 6–8 hours, and 1.5–2 hours, respectively. The rate and extent of absorption of olmesartan medoxomil, amlodipine, and hydrochlorothiazide in ATTENTO® PLUS are comparable to those when administered as dual combinations of olmesartan medoxomil with amlodipine and hydrochlorothiazide as monotherapy or olmesartan medoxomil with hydrochlorothiazide and amlodipine as monotherapy. The bioavailability of ATTENTO® PLUS is not affected by food intake.

Olmesartan medoxomil

Absorption and distribution

Olmesartan medoxomil is a prodrug. It is rapidly converted into the pharmacologically active metabolite olmesartan by esterases in the intestinal mucosa and portal blood during absorption in the gastrointestinal tract. Unconverted olmesartan medoxomil or the medoxomil side chain are not detected in plasma or excreta. The mean absolute bioavailability of olmesartan as tablets is 25.6%.

Mean maximum plasma concentration (Cmax) of olmesartan is reached approximately 2 hours after oral administration. Plasma olmesartan concentration increases approximately linearly with increasing single doses up to 80 mg.

Food has minimal effect on olmesartan bioavailability; therefore, olmesartan medoxomil can be administered independently of meals.

No clinically significant difference in olmesartan pharmacokinetics based on patient sex has been observed. Olmesartan is highly bound to plasma proteins (99.7%), but the risk of clinically significant competitive interactions with other highly protein-bound drugs is low, as evidenced by the lack of interaction between olmesartan medoxomil and warfarin. Binding of olmesartan to blood cells is negligible. The mean volume of distribution after intravenous administration is low (16–29 L).

Metabolism and elimination

Total plasma clearance of olmesartan is typically 1.3 L/hour (coefficient of variation 19%) and relatively small compared to hepatic blood flow (approximately 90 L/hour). After single oral administration of 14C-labeled olmesartan medoxomil,

10–16% of radioactivity was observed in urine (mostly within 24 hours after administration), and the remainder was excreted in feces. Based on systemic availability of 25.6%, it can be calculated that absorbed olmesartan is eliminated both renally (approximately 40%) and via the hepatobiliary system (approximately 60%). All detected radioactivity was identified as olmesartan. No other significant metabolites were found. Enterohepatic recirculation of olmesartan is minimal. Since most olmesartan is excreted in bile, its use is contraindicated in patients with biliary obstruction (see section "Contraindications").

Terminal elimination half-life of olmesartan after repeated oral administration ranges from 10 to 15 hours. Steady state is achieved within 2–5 days of dosing, and no further accumulation is observed after 14 days of repeated administration. Renal clearance is approximately 0.5–0.7 L/hour and does not depend on drug dose.

Drug interactions

Drug colesevelam, bile acid sequestrant

Concomitant administration of 40 mg olmesartan medoxomil and 3750 mg colesevelam hydrochloride in healthy volunteers resulted in a 28% reduction in Cmax and a 39% reduction in AUC for olmesartan. A smaller effect, with 4% and 15% reduction in Cmax and AUC respectively, was observed when olmesartan medoxomil was administered 4 hours before colesevelam hydrochloride. The elimination half-life of olmesartan was reduced by 50–52% regardless of whether the drugs were administered together or olmesartan was taken 4 hours before colesevelam hydrochloride (see section "Interaction with other medicinal products and other forms of interaction").

Amlodipine

Absorption and distribution

After oral administration at therapeutic doses, amlodipine is well absorbed, with peak blood concentration reached 6–12 hours after intake. Absolute bioavailability of the unchanged compound is approximately 64–80%. Volume of distribution is approximately 21 L/kg. In vitro studies showed that nearly 97.5% of circulating amlodipine is bound to plasma proteins. Food intake does not affect amlodipine absorption.

Metabolism and elimination

Elimination half-life from plasma ranges from 35 to 50 hours and remains unchanged with daily single administration. Amlodipine is extensively metabolized to inactive metabolites. Approximately 60% of the administered dose is excreted in urine, of which 10% is unchanged.

Hydrochlorothiazide.

After oral administration of hydrochlorothiazide in combination with olmesartan medoxomil, the mean time to reach maximum hydrochlorothiazide concentration was 1.5–2 hours after intake. Hydrochlorothiazide is 68% bound to plasma proteins, and its apparent volume of distribution is 0.83–1.14 L/kg.

Absorption and distribution

Hydrochlorothiazide is not metabolized in the human body and is almost entirely excreted unchanged in urine. After oral administration, approximately 60% of the dose is excreted unchanged within 48 hours. Renal clearance is approximately 250–300 mL/min. Terminal elimination half-life is about 10–15 hours.

Pharmacokinetics in specific patient populations

Pediatric population

The European Medicines Agency has deferred the requirement to submit results of ATTENTO® PLUS studies in pediatric patients with essential arterial hypertension across all pediatric subgroups.

Elderly patients (aged 65 years and older)

In elderly patients (65–75 years) with arterial hypertension, the steady-state area under the pharmacokinetic curve (AUC) of olmesartan was approximately 35% higher than in younger patients, and in patients aged ≥ 75 years, it was approximately 44% higher (see section "Dosage and administration"). This may be partly explained by the presence of moderate renal function impairment in this patient group. However, recommended doses for elderly patients are the same as for other patients, although caution should be exercised when increasing the dose. Time to maximum plasma concentration of amlodipine in elderly and younger individuals is comparable. In elderly patients, there is a tendency toward reduced amlodipine clearance, leading to increased AUC and prolonged elimination half-life. In this study, increases in AUC and prolonged elimination half-life in patients with congestive heart failure were within the range expected for this age group (see section "Special precautions for use"). Based on available data, systemic clearance of hydrochlorothiazide in elderly individuals (both healthy and hypertensive patients) is lower than in healthy volunteers.

Renal impairment

In patients with mild, moderate, and severe renal impairment, steady-state AUC of olmesartan was 62%, 82%, and 179% higher, respectively, than in healthy volunteers (see sections "Dosage and administration" and "Special precautions for use"). Pharmacokinetics of olmesartan medoxomil in patients undergoing hemodialysis has not been studied. Amlodipine is extensively metabolized to inactive metabolites. Ten percent of the substance is excreted unchanged in urine. Changes in plasma amlodipine concentration do not correlate with the degree of renal impairment. Amlodipine can be administered at usual doses to these patients. Amlodipine is not removed by hemodialysis. Elimination half-life of hydrochlorothiazide is prolonged in patients with renal impairment.

Hepatic impairment

After single oral administration, AUC values of olmesartan were 6% and 65% higher in patients with mild or moderate hepatic impairment, respectively, compared to healthy volunteers. Unbound fraction of olmesartan 2 hours after administration in healthy volunteers, patients with mild or moderate hepatic impairment was 0.26%, 0.34%, and 0.41%, respectively. With repeated administration, mean AUC of olmesartan in patients with moderate hepatic impairment was 65% higher than in healthy volunteers. Mean Cmax of olmesartan in patients with hepatic impairment and healthy volunteers were similar. Olmesartan medoxomil has not been evaluated in patients with severe hepatic impairment (see sections "Dosage and administration", "Special precautions for use").

Available clinical data on amlodipine use in patients with hepatic impairment are very limited. In patients with hepatic impairment, reduced amlodipine clearance and prolonged elimination half-life are observed, leading to approximately 40–60% increase in AUC (see sections "Dosage and administration", "Special precautions for use"). Hepatic impairment does not significantly affect hydrochlorothiazide pharmacokinetics.

Non-clinical safety data

Combination of olmesartan medoxomil/amlodipine/hydrochlorothiazide

Repeated-dose toxicity studies in rats showed that co-administration of olmesartan medoxomil, amlodipine, and hydrochlorothiazide did not result in increased known toxic effects of each component alone, appearance of new toxicity, or synergistic toxic effects. Since the safety profiles of the individual active substances are well characterized, no additional mutagenicity, carcinogenicity, or reproductive toxicity studies were conducted for ATTENTO® PLUS.

Olmesartan medoxomil

Chronic toxicity studies in rats and dogs showed effects of olmesartan medoxomil similar to other AT1 receptor antagonists and ACE inhibitors: increased blood urea nitrogen (BUN) and creatinine levels, reduced heart weight, reduced erythrocyte parameters (erythrocyte count and hemoglobin concentration, hematocrit), and histological signs of kidney damage (regenerative kidney epithelial lesions, thickening of the basement membrane, tubular dilation). These adverse reactions, caused by the pharmacological action of olmesartan medoxomil, were also observed in preclinical studies with other AT1 receptor antagonists and ACE inhibitors and can be reduced by oral sodium chloride intake. Similar to other AT1 receptor antagonists, olmesartan medoxomil increases the frequency of chromosomal breaks in in vitro cell cultures, but not in vivo. Overall results of comprehensive genotoxicity testing indicate that genotoxic effects of olmesartan in clinical use are unlikely.

Olmesartan medoxomil showed no carcinogenic effects in rats or transgenic mice.

Reproductive toxicity studies in rats showed that olmesartan medoxomil did not affect fertility or cause teratogenic effects. As with other angiotensin II receptor antagonists, offspring survival was reduced after exposure to olmesartan medoxomil, and female rats receiving the drug in late pregnancy and during lactation showed renal pelvis dilation. Fetotoxic effects were not observed in rabbits.

Amlodipine

Reproductive toxicity

Reproductive function studies in rats and mice revealed delayed onset of labor, prolonged labor duration, and reduced offspring survival at doses approximately 50 times higher than the maximum recommended human dose based on body surface area (mg/m²).

Fertility impairment

No effect on fertility was observed in rats receiving amlodipine (males for 64 days, females for 14 days before mating) at doses up to 10 mg/kg/day (8 times* the maximum recommended human dose of 10 mg, adjusted for mg/m²). In another study, male rats receiving amlodipine besylate for 30 days at doses comparable to human doses adjusted for mg/m² showed reduced plasma levels of follicle-stimulating hormone and testosterone, reduced sperm density, reduced number of mature spermatids, and reduced Sertoli cells.

Carcinogenesis, mutagenesis

Two-year studies in rats and mice receiving amlodipine in food at concentrations calculated to achieve doses of 0.5, 1.25, and 2.5 mg/kg/day showed no signs of carcinogenicity. The highest dose (equivalent to the maximum recommended dose of 10 mg in mice adjusted for mg/m², and twice the maximum recommended dose in rats) was close to the maximum tolerated dose in mice but not in rats.

Mutagenicity studies showed no drug-related effects at the gene or chromosome level.

*Assuming patient body weight of 50 kg.

Hydrochlorothiazide

In some experimental models, hydrochlorothiazide showed inconsistent results regarding genotoxic and carcinogenic effects. According to available epidemiological data, an increased risk of non-melanoma skin cancer has been observed in humans with increasing cumulative hydrochlorothiazide dose.

Clinical characteristics.

Indications.

Essential hypertension.

ATTEKTO® PLUS is indicated for adult patients whose blood pressure is not adequately controlled with a combination of olmesartan medoxomil and amlodipine.

ATTEKTO® PLUS is indicated for adult patients whose blood pressure is adequately controlled with a combination of olmesartan medoxomil, amlodipine, and hydrochlorothiazide administered as a two-component combination (olmesartan medoxomil and amlodipine or olmesartan medoxomil and hydrochlorothiazide) and as a single-component medicinal product (hydrochlorothiazide or amlodipine).

Contraindications.

• Hypersensitivity to the active substances, dihydropyridine derivatives, sulfonamide derivatives (since hydrochlorothiazide is a sulfonamide derivative), or to any of the excipients (see section "Composition").
• Severe renal impairment (see sections "Special precautions for use" and "Pharmacokinetics").
• Persistent hypokalemia, hypercalcemia, hyponatremia, and clinically evident hyperuricemia.
• Severe hepatic impairment, cholestasis, and biliary obstruction (see section "Pharmacokinetics").
• The medicinal product must not be used in pregnant women or in women planning pregnancy. If pregnancy is confirmed during treatment with this medicinal product, its use must be discontinued immediately and replaced with another medicinal product approved for use during pregnancy (see sections "Special precautions for use" and "Use during pregnancy or breastfeeding").
• Concomitant use of ATTEKTO® PLUS and medicinal products containing aliskiren is contraindicated in patients with diabetes mellitus or renal impairment (eGFR < 60 mL/min/1.73 m²) (see sections "Interaction with other medicinal products and other forms of interaction" and "Pharmacodynamics").
• Due to the presence of amlodipine, ATTEKTO® PLUS is also contraindicated in patients with:
  • Shock (including cardiogenic shock);
  • Severe arterial hypotension;
  • Impaired outflow from the left ventricle (e.g., in severe aortic stenosis);
  • Hemodynamically unstable heart failure following acute myocardial infarction.

Interaction with other medicinal products and other forms of interaction.

Potential interactions related to the combination of active substances in ATTEKTO® PLUS

Concomitant use not recommended

Lithium preparations

Concomitant use of lithium with angiotensin-converting enzyme inhibitors and, rarely, with angiotensin II receptor antagonists has been associated with reversible increases in serum lithium concentration and lithium toxicity. In addition, thiazides reduce renal clearance of lithium, thereby potentially increasing the risk of lithium toxicity. Therefore, concomitant use of ATTEKTO® PLUS and lithium preparations is not recommended (see section "Special precautions for use"). If concomitant use of ATTEKTO® PLUS and lithium preparations is necessary, regular monitoring of serum lithium levels is recommended.

Concomitant use requires caution

Baclofen

Possible potentiation of hypotensive effect.

Nonsteroidal anti-inflammatory drugs (NSAIDs)

NSAIDs, including selective COX-2 inhibitors, acetylsalicylic acid (> 3 g/day), and nonselective NSAIDs, may attenuate the antihypertensive effect 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 antagonists and cyclooxygenase inhibitors may lead to further deterioration of renal function, including the development of acute renal failure, which is usually reversible. This combination should be used with caution, especially in elderly patients. Therefore, renal function should be regularly assessed at the beginning of such concomitant therapy, and adequate hydration of the patient should be ensured.

Concomitant use requiring attention

Amifostine

Possible potentiation of hypotensive effect.

Other antihypertensive agents

The antihypertensive effect of ATTEKTO® PLUS may be enhanced when used concomitantly with other antihypertensive agents.

Alcohol, barbiturates, narcotic analgesics, and antidepressants

Possible potentiation of orthostatic hypotension.

Potential interactions related to olmesartan medoxomil

Concomitant use not recommended

ACE inhibitors, angiotensin II receptor blockers, or aliskiren

Clinical trial results show that dual blockade of the renin-angiotensin-aldosterone system (RAAS) associated with the concomitant use of ACE inhibitors and angiotensin II receptor blockers or aliskiren leads to an increased incidence of adverse events such as arterial hypotension, hyperkalemia, and decreased renal function (including acute renal failure), compared to the use of a single agent acting on the RAAS (see sections "Contraindications", "Special precautions for use", "Pharmacodynamics").

Medicinal products affecting potassium levels

Concomitant use with potassium-sparing diuretics, potassium supplements, potassium-containing salt substitutes, or other medicinal products that may increase potassium levels (e.g., heparin, ACE inhibitors) may lead to increased serum potassium concentration (see section "Special precautions for use"). When prescribing medicinal products affecting potassium levels in combination with ATTEKTO® PLUS, monitoring of serum potassium concentration is recommended.

Additional information

Bile acid-binding medicinal product colesevelam

Concomitant use of the bile acid-binding agent colesevelam hydrochloride reduces systemic exposure and peak plasma concentration of olmesartan, as well as decreases elimination half-life. Administration of olmesartan medoxomil at least 4 hours before colesevelam hydrochloride reduces the effect of this drug interaction. Consideration should be given to administering olmesartan medoxomil at least 4 hours before colesevelam hydrochloride (see section "Pharmacokinetics").

A moderate reduction in the bioavailability of olmesartan medoxomil has been observed after treatment with antacids (magnesium and aluminum hydroxides).

The effect of olmesartan medoxomil on the pharmacokinetics and pharmacodynamics of warfarin or the pharmacokinetics of digoxin is negligible. Concomitant use of olmesartan medoxomil with pravastatin does not lead to clinically significant changes in the pharmacokinetics of these drugs in healthy volunteers.

No clinically significant inhibitory effect of olmesartan on human cytochrome P450 enzymes 1A1/2, 2A6, 2C8/9, 2C19, 2D6, 2E1, and 3A4 has been observed in vitro, and minimal or no inductive effect on the activity of rat cytochrome P450 has been noted. Therefore, clinically significant interactions between olmesartan and medicinal products metabolized by the aforementioned cytochrome P450 enzymes are not expected.

Potential interactions related to amlodipine

Concomitant use requires caution

CYP3A4 inhibitors

The effect of amlodipine may be significantly enhanced when used concomitantly with strong or moderate CYP3A4 inhibitors (protease inhibitors, azole antifungals, macrolides such as erythromycin or clarithromycin, verapamil, or diltiazem). Clinical manifestations of these pharmacokinetic variations may be more pronounced in elderly patients. There is an increased risk of hypotension. Careful monitoring of patients is recommended. Therefore, clinical monitoring and dose adjustment may be necessary.

CYP3A4 inducers

Plasma concentrations of amlodipine may be altered when used concomitantly with known CYP3A4 inducers. Therefore, blood pressure should be monitored and dosage adjusted both during and after concomitant therapy, especially with strong CYP3A4 inducers (such as rifampicin, St. John's wort).

Consumption of amlodipine with grapefruit or grapefruit juice is not recommended, as it may increase the bioavailability of the drug in some patients, resulting in enhanced hypotensive effect.

Dantrolene (infusion): In laboratory animal studies, ventricular fibrillation and cardiovascular collapse with fatal outcome were observed after administration of verapamil and intravenous dantrolene, associated with the development of hyperkalemia. Due to the risk of hyperkalemia in patients predisposed to malignant hyperthermia or during treatment of malignant hyperthermia, concomitant use of calcium channel blockers such as amlodipine should be avoided.

Effect of amlodipine on the action of other medicinal products

The hypotensive effect of amlodipine is additive to the hypotensive effect of other agents that lower blood pressure.

In clinical drug interaction studies, amlodipine did not affect the pharmacokinetics of atorvastatin, digoxin, or warfarin.

Simvastatin. Concomitant use of multiple 10 mg doses of amlodipine and 80 mg simvastatin resulted in a 77% increase in simvastatin exposure compared to simvastatin alone. The dose of simvastatin in patients taking amlodipine should not exceed 20 mg per day.

Tacrolimus. There is a risk of increased blood levels of tacrolimus when used concomitantly with amlodipine. To avoid toxic effects of tacrolimus during concomitant use with amlodipine, regular monitoring of tacrolimus blood levels and, if necessary, dose adjustment are required.

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

Cyclosporine. In a prospective clinical study involving kidney transplant patients, coadministration of amlodipine with cyclosporine resulted in an average 40% increase in cyclosporine trough levels. Concomitant use of ATTEKTO® PLUS with cyclosporine may enhance the effect of cyclosporine. When used concomitantly with amlodipine, consideration should be given to monitoring cyclosporine trough levels and, if necessary, reducing the cyclosporine dose.

Potential interactions related to hydrochlorothiazide

Concomitant use not recommended

Medicinal products affecting potassium levels

The potassium-wasting effect of hydrochlorothiazide (see section "Special precautions for use") may be enhanced when used concomitantly with other medicinal products that cause potassium loss and hypokalemia (e.g., other potassium-wasting diuretics, laxatives, corticosteroids, ACTH, amphotericin, carbenoxolone, sodium penicillin G, or salicylate derivatives). Therefore, such concomitant use is not recommended.

Concomitant use requires caution

Calcium salts

Concomitant use with thiazide diuretics may lead to increased serum calcium levels due to reduced excretion. If calcium supplementation is required, monitoring of serum calcium levels and appropriate dose adjustment are necessary.

Cholestyramine and colestipol resins

Absorption of hydrochlorothiazide is impaired in the presence of anion-exchange resins.

Cardiac glycosides

Hypokalemia or hypomagnesemia due to the use of thiazide diuretics may predispose to cardiac arrhythmias induced by cardiac glycosides.

Medicinal products whose effects are influenced by disturbances in serum potassium levels

When ATTEKTO® PLUS is used concomitantly with medicinal products whose effects are influenced by disturbances in serum potassium levels (e.g., digitalis glycosides and antiarrhythmic agents), as well as with the following agents that may cause torsades de pointes (ventricular tachycardia), including certain antiarrhythmic agents (with hypokalemia being a contributing factor for the development of torsades de pointes), regular monitoring of serum potassium levels and ECG is recommended.

• Class Ia antiarrhythmic agents (e.g., quinidine, hydroquinidine, disopyramide).
• Class III antiarrhythmic agents (e.g., amiodarone, sotalol, dofetilide, ibutilide).
• Some antipsychotic agents (e.g., thioridazine, chlorpromazine, levomepromazine, trifluoperazine, zuclopenthixol, sulpiride, sulpiride, amisulpride, tiapride, pimozide, haloperidol, droperidol).
• Other agents (e.g., bepridil, cisapride, difemanil, intravenous erythromycin, halofantrine, mizolastine, pentamidine, sparfloxacin, terfenadine, intravenous vinca alkaloids).

Non-depolarizing muscle relaxants (e.g., tubocurarine)

Possible potentiation of response to muscle relaxants when used with hydrochlorothiazide.

Anticholinergic agents (e.g., atropine, biperiden)

Due to decreased gastrointestinal motility and delayed gastric emptying, bioavailability of thiazide diuretics may be increased.

Antidiabetic medicinal products (oral preparations and insulin)

Thiazide diuretics may affect glucose tolerance during treatment. Dose 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 caused by functional renal impairment that may occur with hydrochlorothiazide use.

Beta-adrenergic blockers and diazoxide

The hyperglycemic effect of beta-blockers and diazoxide may be enhanced by thiazide diuretics.

Vasoactive amines (e.g., norepinephrine)

The effect of vasoactive amines may be attenuated.

Medicinal products used for the treatment of gout (probenecid, sulfinpyrazone, allopurinol)

Dose adjustment of uricosuric medicinal products may be required, as hydrochlorothiazide may increase serum uric acid levels. Higher doses of probenecid or sulfinpyrazone may be needed. Concomitant use of thiazide diuretics may increase the frequency of hypersensitivity reactions to allopurinol.

Amantadine

Thiazide diuretics may increase the risk of adverse reactions caused by amantadine.

Cytotoxic agents (e.g., cyclophosphamide, methotrexate)

Thiazide diuretics may reduce renal excretion of cytotoxic agents and enhance their myelosuppressive effects.

Salicylates

When used with high doses of salicylates, hydrochlorothiazide may enhance their toxic effects on the central nervous system.

Methyldopa

Hemolytic anemia has been reported in isolated cases following concomitant use of hydrochlorothiazide and methyldopa.

Cyclosporine

Concomitant use of cyclosporine may increase the risk of hyperuricemia and gout-like complications.

Tetracyclines

The risk of increased urea levels caused by tetracyclines is increased when used concomitantly with thiazide diuretics. This interaction likely does not apply to doxycycline.

Special precautions for use.

Patients with hypovolemia or sodium depletion

In patients with hypovolemia and/or hyponatremia resulting from intensive diuretic therapy, dietary salt restriction, diarrhea, or vomiting, symptomatic hypotension may occur, especially after the first dose. It is recommended to correct these conditions prior to initiating treatment with ATTENTO® PLUS or to closely monitor the patient at the beginning of therapy.

Other conditions associated with activation of the renin-angiotensin-aldosterone system (RAAS)

Patients in whom vascular tone and renal function are highly dependent on RAAS activity (e.g., patients with severe congestive heart failure or renal disease, including renal artery stenosis) may experience acute hypotension, azotemia, oliguria, or rarely acute renal failure when treated with drugs affecting this system.

Renovascular hypertension

Use of drugs affecting the renin-angiotensin-aldosterone system in patients with bilateral renal artery stenosis or stenosis of the artery of a solitary functioning kidney is associated with an increased risk of severe hypotension and renal failure.

Renal impairment and kidney transplantation

Periodic monitoring of serum potassium and creatinine concentrations is recommended in patients with renal impairment receiving ATTENTO® PLUS. ATTENTO® PLUS is not recommended in patients with severe renal impairment (creatinine clearance < 30 mL/min) (see sections "Special precautions for use", "Dosage and administration", "Contraindications", and "Pharmacokinetics"). Azotemia associated with thiazide diuretics may occur in patients with renal impairment. If renal function deteriorates progressively, the treatment regimen should be carefully reviewed, including the possibility of discontinuing diuretic therapy.

There is no experience with the use of ATTENTO® PLUS in patients who have recently undergone kidney transplantation or in patients with end-stage renal disease (e.g., creatinine clearance < 12 mL/min).

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 renal dysfunction (including acute renal failure). Therefore, dual blockade of RAAS with concomitant use of ACE inhibitors, angiotensin II receptor blockers, or aliskiren is not recommended (see sections "Interaction with other medicinal products and other forms of interaction", "Pharmacokinetics").

If dual blockade therapy is absolutely necessary, it should be administered only under specialist supervision and with close monitoring of renal function, electrolyte levels, and blood pressure.

Concomitant use of ACE inhibitors and angiotensin II receptor blockers is contraindicated in patients with diabetic nephropathy.

Hepatic impairment

Exposure to amlodipine and olmesartan medoxomil is increased in patients with hepatic impairment (see section "Pharmacokinetics"). In addition, minor disturbances in fluid and electrolyte balance due to thiazide diuretic therapy may precipitate hepatic coma in patients with hepatic impairment or progressive liver disease. ATTENTO® PLUS should be used with caution in patients with mild to moderate hepatic impairment. In patients with moderate hepatic impairment, the dose of olmesartan medoxomil should not exceed 20 mg (see section "Dosage and administration"). Amlodipine therapy in patients with hepatic impairment should be initiated at the lowest dose, and caution should be exercised both at the beginning of treatment and when increasing the dose. ATTENTO® PLUS is contraindicated in patients with severe hepatic impairment (see section "Contraindications").

Aortic or mitral valve stenosis; obstructive hypertrophic cardiomyopathy

Due to the presence of amlodipine in ATTENTO® PLUS, as with other vasodilators, particular caution is recommended when prescribing to patients with aortic or mitral valve stenosis or obstructive hypertrophic cardiomyopathy.

Primary hyperaldosteronism

Patients with primary hyperaldosteronism generally do not respond to antihypertensive drugs that inhibit the renin-angiotensin system. Therefore, use of ATTENTO® PLUS is not recommended in such patients.

Metabolic and endocrine effects

Glucose tolerance may be impaired during treatment with thiazide diuretics. Patients with diabetes may require adjustment of insulin or oral antidiabetic drug dosage (see section "Interaction with other medicinal products and other forms of interaction"). Latent diabetes mellitus may manifest during thiazide diuretic therapy.

Elevated cholesterol and triglyceride levels are known adverse reactions associated with thiazide diuretic therapy.

Hyperuricemia or gout may occur in some patients during treatment with thiazide diuretics.

Electrolyte imbalance

All patients receiving diuretics should undergo periodic monitoring of serum electrolyte levels at appropriate intervals.

Thiazide diuretics, including hydrochlorothiazide, may cause disturbances in fluid and electrolyte balance (hypokalemia, hyponatremia, and hypochloremic alkalosis). Symptoms suggestive of fluid and electrolyte imbalance include dry mouth, thirst, weakness, lethargy, somnolence, restlessness, muscle pain or cramps, muscle weakness, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea and vomiting (see section "Adverse reactions").

The risk of hypokalemia is highest in patients with hepatic cirrhosis, those with a marked increase in diuresis, those with inadequate dietary electrolyte intake, and those receiving concomitant corticosteroids or ACTH (see section "Interaction with other medicinal products and other forms of interaction"). Conversely, due to the inhibitory effect of olmesartan medoxomil (a component of ATTENTO® PLUS) on angiotensin II receptors (AT1), hyperkalemia may occur, particularly in patients with renal impairment and/or heart failure, as well as in patients with diabetes mellitus. Close monitoring of serum potassium levels is recommended in patients at risk. Caution is advised and more frequent monitoring of serum potassium levels is required when potassium-sparing diuretics, potassium supplements, potassium-containing salt substitutes, or other medicinal products that may increase serum potassium levels (e.g., heparin) are used concomitantly with ATTENTO® PLUS (see section "Interaction with other medicinal products and other forms of interaction").

There is no evidence that olmesartan medoxomil may attenuate or prevent diuretic-induced hyponatremia. Chloride deficiency is usually mild and does not require treatment.

Thiazide diuretics may reduce calcium excretion in urine and cause transient mild increases in serum calcium levels in the absence of known disturbances in calcium metabolism.

Hypercalcemia may indicate occult hyperparathyroidism. Thiazide diuretics should be discontinued before assessing parathyroid function.

Thiazide diuretics have been shown to increase urinary magnesium excretion, which may lead to hypomagnesemia.

Hyponatremia of dilution may develop in patients with edema during hot weather.

Lithium preparations

As with other angiotensin II antagonists, concomitant use of ATTENTO® PLUS and lithium preparations is not recommended (see section "Interaction with other medicinal products and other forms of interaction").

Heart failure

Due to inhibition of the angiotensin-aldosterone system, renal function may be impaired in susceptible patients. In patients with severe heart failure, in whom renal function may depend on RAAS activity, treatment with angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor antagonists may be associated with oliguria and/or progressive azotemia and (rarely) acute renal failure and/or death.

Patients with heart failure should be treated with caution. In a long-term placebo-controlled study of amlodipine in patients with severe heart failure (NYHA III and IV), the number of reports of pulmonary edema was higher in the amlodipine group compared to the placebo group (see section "Pharmacodynamics"). Calcium channel blockers, including amlodipine, should be used with caution in patients with congestive heart failure, as these drugs may increase the future risk of cardiovascular events and mortality.

Sprue-like enteropathy

Very rarely, severe chronic diarrhea with significant weight loss has been reported, developing several months to years after initiation of treatment in patients taking olmesartan; the cause is likely a local delayed hypersensitivity reaction. Intestinal mucosal biopsy findings in such patients often show villous atrophy. If such symptoms occur in a patient during olmesartan treatment and no other obvious cause is identified, olmesartan should be discontinued immediately and not restarted. If diarrhea persists for more than one week after discontinuation of the drug, consultation with an appropriate specialist (e.g., gastroenterologist) should be considered.

Choroidal effusion, acute myopia, and angle-closure glaucoma

Hydrochlorothiazide, a sulfonamide, has been associated with idiosyncratic reactions leading to choroidal effusion with visual disturbances, acute transient myopia, and acute angle-closure glaucoma. Symptoms include acute decrease in visual acuity and eye pain. These typically occur within hours to one week after initiation of treatment. Untreated acute angle-closure glaucoma may lead to permanent vision loss.

The primary action is prompt discontinuation of hydrochlorothiazide. If intraocular pressure is not controlled, immediate therapeutic or surgical intervention may be required. A history of allergy to sulfonamides or penicillin may be a risk factor for the development of angle-closure glaucoma (see section "Adverse reactions").

Pregnancy

Angiotensin II receptor antagonists should not be initiated during pregnancy. Women planning pregnancy who are receiving angiotensin II receptor antagonist therapy should switch to an alternative antihypertensive with a proven safety profile in pregnancy. ATTENTO® PLUS should not be used in pregnant women or women planning pregnancy. If pregnancy is confirmed during treatment with this medicinal product, treatment must be discontinued immediately and replaced with another medicinal product approved for use in pregnancy (see sections "Contraindications" and "Use in pregnancy or lactation").

Paediatric population

ATTENTO® PLUS is not indicated for use in children and adolescents (under 18 years of age).

Elderly patients

Dose escalation in elderly patients should be performed with caution (see section "Pharmacokinetics").

Photosensitization

Cases of photosensitization reactions have been reported with thiazide diuretics (see section "Adverse reactions"). If photosensitization occurs during treatment with ATTENTO® PLUS, therapy should be discontinued. If reinitiation of diuretic therapy is necessary, protection of exposed skin areas from sunlight or artificial UV radiation is recommended.

Non-melanoma skin cancer (NMSC)

In two epidemiological studies based on data from the Danish National Cancer Registry, increasing cumulative doses of hydrochlorothiazide were associated with an increased risk of NMSC (basal cell carcinoma (BCC) and squamous cell carcinoma (SCC)). The photosensitizing effects of hydrochlorothiazide may play a role in the mechanism of NMSC development.

Patients taking hydrochlorothiazide should be informed about the risk of NMSC and advised to regularly check their skin for any new lesions and immediately report any suspicious skin changes. To minimize the risk of skin cancer, patients should be advised to limit exposure to sunlight and UV radiation and to use appropriate protection when such exposure occurs. Suspicious skin lesions should be promptly evaluated, including histological examination of biopsy specimens. In patients with a history of NMSC, reassessment of hydrochlorothiazide use may be necessary (see also section "Adverse reactions").

Acute respiratory toxicity

Very rarely, acute respiratory toxicity, including acute respiratory distress syndrome (ARDS), has been observed after hydrochlorothiazide administration. Pulmonary edema typically develops within minutes to hours after intake. Initial symptoms include dyspnea, fever, worsening lung function, and hypotension. In suspected cases of ARDS, ATTENTO® PLUS should be discontinued and appropriate treatment initiated. Hydrochlorothiazide should not be used in patients who have previously experienced ARDS after hydrochlorothiazide.

Other

As with any antihypertensive agent, excessive reduction of blood pressure in patients with ischemic heart disease or cerebrovascular disease may lead to myocardial infarction or stroke.

Hypersensitivity reactions to hydrochlorothiazide may occur both in patients with or without a history of allergy or bronchial asthma, but are more frequent in patients with such conditions in their history.

Exacerbation or activation of systemic lupus erythematosus has been reported during treatment with thiazide diuretics.

As with other angiotensin II receptor antagonists, the antihypertensive effect of olmesartan may be somewhat less pronounced in black patients than in other racial groups. However, this effect was not observed in one of the three clinical trials of ATTENTO® PLUS that included black patients (30%) (see section "Pharmacodynamics").

This medicinal product contains less than 1 mmol of sodium (23 mg) per film-coated tablet and is therefore considered practically sodium-free.

Use during pregnancy or breastfeeding

Pregnancy

ATTENTO® PLUS should not be used in pregnant women or women planning pregnancy. If pregnancy is confirmed during treatment with this medicinal product, treatment must be discontinued immediately and replaced with another medicinal product approved for use in pregnancy (see sections "Contraindications", "Special precautions for use").

Olmesartan medoxomil

Use of angiotensin II antagonists is not recommended in women during the first trimester of pregnancy (see section "Special precautions for use"). Use of angiotensin II antagonists is contraindicated during the second and third trimesters of pregnancy (see sections "Contraindications", "Special precautions for use").

Epidemiological data on the teratogenic risk of ACE inhibitors during the first trimester of pregnancy do not allow definitive conclusions, but a small risk of such effects cannot be entirely excluded. A similar risk for angiotensin II receptor antagonists may be assumed, although controlled epidemiological studies on these drugs have not been conducted. Women planning pregnancy should switch to other antihypertensive agents with a proven safety profile in pregnancy unless there is an urgent need for angiotensin II receptor antagonists. Angiotensin II receptor antagonists should be discontinued immediately upon detection of pregnancy and alternative treatment initiated if necessary.

During the second and third trimesters, angiotensin II receptor antagonists have toxic effects on the fetus (impaired renal function, oligohydramnios, delayed skull ossification) and newborn (renal failure, hypotension, hyperkalemia) (see section "Preclinical safety data").

If angiotensin II receptor antagonists are taken from the second trimester of pregnancy, monitoring of fetal renal function and skull ossification by ultrasound is required. Newborns of mothers who have taken angiotensin II receptor antagonists should be monitored for possible hypotension (see sections "Contraindications" and "Special precautions for use").

Hydrochlorothiazide

Experience with hydrochlorothiazide use during pregnancy, especially in the first trimester, is limited. Animal experimental data are insufficient. Hydrochlorothiazide crosses the placenta. Due to its mechanism of action, use of hydrochlorothiazide during the second and third trimesters of pregnancy may impair fetoplacental circulation and adversely affect the fetus and newborn, causing jaundice, electrolyte disturbances, and thrombocytopenia.

Hydrochlorothiazide is not indicated for the treatment of edema in pregnancy, gestational hypertension, or preeclampsia, as it may reduce plasma volume and cause placental hypoperfusion without providing adequate therapeutic benefit.

Hydrochlorothiazide is also not recommended for the treatment of essential hypertension in pregnancy, except in exceptional cases when other drugs cannot be used.

Amlodipine

Data from limited observations in pregnant women do not indicate that amlodipine or other calcium channel antagonists have harmful effects on fetal health. However, there is a risk of prolonged labor.

In view of the above, ATTENTO® PLUS is contraindicated in pregnant women and women planning pregnancy (see sections "Contraindications" and "Special precautions for use").

Breastfeeding

ATTENTO® PLUS is not recommended during breastfeeding. During lactation, especially when nursing newborns or preterm infants, alternative drugs with proven safety in pregnancy are preferred.

Olmesartan is excreted in the milk of lactating rats. However, it is unknown whether olmesartan is excreted in human breast milk. Amlodipine is excreted in human breast milk. The infant's exposure to the maternal dose has been estimated at 3–7% (maximum 15%) based on interquartile range.

The effect of amlodipine on the infant is unknown.

Hydrochlorothiazide is excreted in human breast milk in small amounts. Thiazide diuretics in high doses, causing intense diuresis, may suppress milk production.

Use of ATTENTO® PLUS during breastfeeding is not recommended. If ATTENTO® PLUS is used during breastfeeding, the dose should be as low as possible.

Fertility

Cases of reversible biochemical changes in the sperm head have been reported in some patients taking calcium channel blockers. Clinical data on the potential effect of amlodipine on fertility are limited. Unfavorable effects on male fertility were observed in rat studies (see section "Preclinical safety data").

Ability to affect reaction speed when driving or operating machinery

No studies on the effect of ATTENTO® PLUS on reaction speed during driving or operating machinery have been conducted. However, it should be considered that dizziness, headache, nausea, or fatigue may occasionally occur in patients taking antihypertensive drugs, which may impair their reaction ability. Caution should be exercised, especially at the beginning of treatment.

Method of Administration and Dosage.

Adults.

The recommended dose of ATTENTO® PLUS is 1 tablet per day.

ATTENTO® PLUS 20/5/12.5 may be prescribed to patients in whom olmesartan medoxomil 20 mg and amlodipine 5 mg as a combined medicinal product do not provide adequate blood pressure control.

ATTENTO® PLUS 40/10/12.5 may be prescribed to patients in whom olmesartan medoxomil 40 mg and amlodipine 10 mg as a combined medicinal product do not provide adequate blood pressure control.

ATTENTO® PLUS 40/10/25 may be prescribed to patients in whom ATTENTO® PLUS 40/10/12.5 does not provide adequate blood pressure control.

Before prescribing a fixed-dose combination product containing three active substances, it is recommended to titrate the doses of these components individually. If clinically appropriate, direct substitution of a dual-combination product with a triple-combination product may be considered.

Patients whose blood pressure control can be achieved with concomitant administration of olmesartan medoxomil, amlodipine, and hydrochlorothiazide at fixed doses as a dual combination (olmesartan medoxomil and amlodipine or olmesartan medoxomil and hydrochlorothiazide) and as a single agent (hydrochlorothiazide or amlodipine) may be switched to treatment with ATTENTO® PLUS containing the same components in corresponding doses.

The maximum recommended dose of ATTENTO® PLUS is 40 mg/10 mg/25 mg once daily.

Elderly Patients (aged 65 years and older)

Elderly patients should be treated with caution, including more frequent monitoring of blood pressure, especially when receiving the maximum possible dose (ATTENTO® PLUS 40/10/25).

Dose escalation in elderly patients should be performed cautiously (see sections "Special Warnings and Precautions for Use", "Pharmacokinetics").

Data on the use of ATTENTO® PLUS in patients aged 75 years and older are limited. Special caution, including more frequent blood pressure monitoring, is recommended.

Renal Impairment

The maximum dose of ATTENTO® PLUS in patients with mild to moderate renal impairment (creatinine clearance 30–60 mL/min) is 20 mg/5 mg/12.5 mg due to limited experience with olmesartan medoxomil 40 mg in this patient group.

When administering ATTENTO® PLUS to patients with moderate renal impairment, monitoring of potassium and creatinine levels is recommended.

ATTENTO® PLUS is contraindicated in patients with severe renal impairment (creatinine clearance < 30 mL/min) (see sections "Contraindications", "Special Warnings and Precautions for Use", "Pharmacokinetics").

Hepatic Impairment

ATTENTO® PLUS should be used with caution in patients with mild hepatic impairment (see sections "Special Warnings and Precautions for Use", "Pharmacokinetics").

For patients with moderate hepatic impairment, the maximum dose should not exceed 20 mg/5 mg/12.5 mg once daily. Careful monitoring of blood pressure and renal function is recommended in such patients. As with all calcium channel antagonists, the elimination half-life of amlodipine is prolonged in patients with hepatic dysfunction; dosage recommendations have not been established. Therefore, ATTENTO® PLUS should be used with caution in these patients. The pharmacokinetics of amlodipine in patients with severe hepatic impairment have not been studied. Amlodipine therapy in patients with hepatic impairment should be initiated at the lowest dose and gradually titrated upward. ATTENTO® PLUS is contraindicated in patients with severe hepatic impairment (see sections "Contraindications", "Pharmacokinetics"), cholestasis, or biliary obstruction (see section "Contraindications").

Pediatric Patients

ATTENTO® PLUS is not recommended for patients under 18 years of age due to lack of data on safety and efficacy in this age group.

Method of Administration

Tablets should be swallowed whole with sufficient liquid (e.g., a glass of water). Tablets must not be chewed. The medication should be taken daily at the same time.

ATTENTO® PLUS can be taken independently of food intake.

Children.

Data on the safety and efficacy of ATTENTO® PLUS in children and adolescents (under 18 years of age) are lacking.

Overdose.

Symptoms

The maximum recommended dose of ATTENTO® PLUS is 40 mg/10 mg/25 mg once daily. Information on human overdose with ATTENTO® PLUS is lacking. The most likely effect of ATTENTO® PLUS overdose is hypotension. The most likely effects of olmesartan medoxomil overdose are hypotension and tachycardia; bradycardia may also occur in the case of parasympathetic stimulation (vagus nerve). Overdose of amlodipine may lead to excessive peripheral vasodilation, resulting in hypotension and possibly reflex tachycardia. Prolonged, severe generalized hypotension, up to shock with fatal outcome, has been reported.

Hydrochlorothiazide overdose is associated with electrolyte disturbances (hypokalemia, hypochloremia) and dehydration due to excessive diuresis. The most common signs and symptoms of overdose include nausea and drowsiness. Hypokalemia may lead to muscle cramps and/or exacerbation of cardiac arrhythmias caused by concomitant use of digitalis glycosides or certain antiarrhythmic agents.

Treatment

In case of ATTENTO® PLUS overdose, symptomatic and supportive therapy should be administered. Therapeutic measures depend on the time elapsed since ingestion and the severity of symptoms. In cases of recent ingestion, gastric lavage may be performed. In healthy volunteers, administration of activated charcoal immediately or within 2 hours after oral intake of amlodipine significantly reduced its absorption.

In the event of clinically significant hypotension due to ATTENTO® PLUS overdose, active cardiovascular support is required, including careful monitoring of cardiac and pulmonary function, elevation of the lower extremities, monitoring of circulating blood volume and diuresis. Vasopressor agents may be useful to restore vascular tone and blood pressure, provided there are no contraindications. Intravenous calcium gluconate is recommended to reverse calcium channel blockade. Frequent monitoring of serum electrolytes and creatinine is necessary. If the patient's blood pressure drops, the patient should be placed in shock position and rapid replacement of electrolytes and circulating blood volume should be ensured. Since amlodipine is highly protein-bound, elimination by dialysis is unlikely. Information on the possibility of removing olmesartan and hydrochlorothiazide by dialysis is lacking. The extent of removal of olmesartan and hydrochlorothiazide during hemodialysis is not established.

Adverse Reactions

The safety of the ATTENTO® PLUS medication was evaluated in clinical studies involving 7,826 patients who received olmesartan medoxomil in combination with amlodipine and hydrochlorothiazide.

Table 1 presents both adverse reactions to ATTENTO® PLUS identified during clinical and post-marketing safety studies, as well as those reported spontaneously, along with adverse reactions observed during treatment with each of the individual active components—olmesartan medoxomil, amlodipine, and hydrochlorothiazide—based on their known safety profiles.

The most commonly reported adverse reactions during treatment with ATTENTO® PLUS were peripheral edema, headache, and dizziness.

The following classification was used to categorize the frequency of adverse reactions:

very common (≥ 1/10);
common (≥ 1/100 to < 1/10);
uncommon (≥ 1/1,000 to < 1/100);
rare (≥ 1/10,000 to < 1/1,000);
very rare (< 1/10,000);
not known (frequency cannot be estimated from the available data).

Table 1

Overview of adverse reactions associated with the use of ATTENTO® PLUS and with each of its individual active substances separately

MedDRA System Organ Class	Adverse Reactions	Frequency
		ATTENTO® PLUS	Olmesartan	Amlodipine	Hydrochlorothiazide
Infections and infestations	Upper respiratory tract infections	Common
	Nasopharyngitis	Common
	Urinary tract infections	Common	Common
	Sialadenitis				Uncommon
Benign, malignant and unspecified neoplasms (including cysts and polyps)	Non-melanoma skin cancer (NMSC) (basal cell carcinoma and squamous cell carcinoma)				Unknown
Blood and lymphatic system disorders	Leukopenia			Very rare	Uncommon
	Thrombocytopenia		Uncommon	Very rare	Uncommon
	Bone marrow function depression				Uncommon
	Neutropenia/agranulocytosis				Uncommon
	Hemolytic anemia				Uncommon
	Aplastic anemia				Uncommon
Immune system disorders	Anaphylactic reaction		Uncommon
	Drug hypersensitivity			Very rare
Metabolism and nutrition disorders	Hyperkalemia	Uncommon	Uncommon
	Hypokalemia	Uncommon			Common
	Anorexia				Uncommon
	Glucosuria				Common
	Hypercalcemia				Common
	Hyperglycemia			Very rare	Common
	Hypomagnesemia				Common
	Hypnatremia				Common
	Hypochloremia				Common
	Hypertriglyceridemia		Common		Very common
	Hypercholesterolemia				Very common
	Hyperuricemia		Common		Very common
	Hypochloremic alkalosis				Very rare
	Hyperamylasemia				Common
Psychiatric disorders	Confusion			Uncommon	Common
	Depression			Uncommon	Uncommon
	Apathy				Uncommon
	Irritability			Uncommon
	Anxiety				Uncommon
	Mood changes (including anxiety)			Uncommon
	Sleep disorders (including insomnia)			Uncommon	Uncommon
Nervous system disorders	Dizziness	Common	Common	Common	Common
	Headache	Common	Common	Common	Uncommon
	Postural dizziness	Uncommon
	Presyncope	Uncommon
	Dysgeusia			Uncommon
	Hypertension			Very rare
	Hypoesthesia			Uncommon
	Paresthesia			Uncommon	Uncommon
	Peripheral neuropathy			Very rare
	Somnolence			Common
	Syncope			Uncommon
	Convulsions				Uncommon
	Loss of appetite				Uncommon
	Tremor			Uncommon
	Extrapyramidal disorders			Unknown
Eye disorders	Visual disturbances (including diplopia, blurred vision)			Common	Uncommon
	Decreased lacrimation				Uncommon
	Myopia exacerbation				Uncommon
	Xanthopsia				Uncommon
	Acute myopia, acute angle-closure glaucoma (see section "Special warnings and precautions for use")				Unknown
	Choroidal effusion				Unknown
Ear and labyrinth disorders	Vertigo	Uncommon	Uncommon		Uncommon
	Tinnitus			Uncommon
Cardiac disorders	Palpitations	Common		Common
	Tachycardia	Uncommon
	Myocardial infarction			Very rare
	Arrhythmia (including bradycardia, ventricular tachycardia, atrial fibrillation)			Uncommon	Uncommon
	Angina pectoris		Uncommon	Uncommon (including exacerbation)
Vascular disorders	Arterial hypotension	Common	Uncommon	Uncommon
	Flushing	Uncommon		Common
	Orthostatic hypotension				Uncommon
	Angioedema (including necrotizing angiitis)			Very rare	Uncommon
	Thrombosis				Uncommon
	Embolism				Uncommon
Respiratory, thoracic and mediastinal disorders	Cough	Uncommon	Common	Uncommon
	Bronchitis		Common
	Dyspnea			Common	Uncommon
	Pharyngitis		Common
	Rhinitis		Common	Uncommon
	Acute interstitial pneumonia				Uncommon
	Respiratory distress syndrome				Uncommon
	Lung edema				Uncommon
	Acute respiratory distress syndrome (ARDS) (see section “Special warnings and precautions for use”)				Very rare
Gastrointestinal disorders	Diarrhea	Common	Common		Common
	Nausea	Common	Common	Common	Common
	Constipation	Common			Common
	Dry mouth	Uncommon		Uncommon
	Abdominal pain		Common	Common	Common
	Intestinal dysfunction (including constipation and diarrhea)			Common
	Flatulence				Common
	Dyspepsia		Common	Common
	Gastritis			Very rare
	Gastric mucosa irritation				Common
	Gastroenteritis		Common
	Gingival hyperplasia			Very rare
	Paralytic ileus				Very rare
	Pancreatitis			Very rare	Uncommon
	Vomiting		Uncommon	Uncommon	Common
	Coeliac-like enteropathy (see section "Special warnings and precautions for use")		Very rare
Hepatobiliary disorders	Hepatitis			Very rare
	Jaundice (intrahepatic cholestatic jaundice)			Very rare	Uncommon
	Acute cholecystitis				Uncommon
	Autoimmune hepatitis*		Unknown
Skin and subcutaneous tissue disorders	Alopecia			Uncommon
	Angioedema		Uncommon	Very rare
	Allergic dermatitis		Uncommon
	Polymorphic erythema			Very rare
	Erythema				Uncommon
	Cutaneous form of systemic lupus erythematosus				Uncommon
	Exanthema		Uncommon	Uncommon
	Exfoliative dermatitis			Very rare
	Hyperhidrosis			Uncommon
	Photosensitization			Very rare	Uncommon
	Pruritus		Uncommon	Uncommon	Uncommon
	Purpura			Uncommon	Uncommon
	Quincke's edema			Very rare
	Rash		Uncommon	Uncommon	Uncommon
	Reactivation of cutaneous form of lupus erythematosus				Uncommon
	Toxic epidermal necrolysis			Unknown	Uncommon
	Skin color changes			Uncommon
	Stevens-Johnson syndrome			Very rare
	Urticaria		Uncommon	Uncommon	Uncommon
Musculoskeletal and connective tissue disorders	Muscle cramps	Common	Uncommon	Common
	Joint swelling	Common
	Muscle weakness	Uncommon			Uncommon
	Ankle edema			Common
	Arthralgia			Uncommon
	Arthritis		Common
	Back pain		Common	Uncommon
	Paralysis				Uncommon
	Myalgia		Uncommon	Uncommon
	Bone pain		Common
Renal and urinary disorders	Frequency of urination	Common
	Increased frequency of urination			Uncommon
	Acute renal failure		Uncommon
	Hematuria		Common
	Urination disorders			Uncommon
	Nocturia			Uncommon
	Interstitial nephritis				Uncommon
	Renal failure		Uncommon		Uncommon
Reproductive system and breast disorders	Erectile dysfunction	Uncommon		Uncommon	Uncommon
	Gynecomastia			Uncommon
General disorders and administration site conditions	Asthenia	Common	Uncommon	Common
	Peripheral edema	Common	Common
	Fatigue	Common	Common	Common
	Chest pain		Common	Uncommon
	Fever				Uncommon
	Influenza-like symptoms		Common
	Lethargy		Uncommon
	Malaise		Uncommon	Uncommon
	Edema			Very common
	Pain		Common	Uncommon
	Facial edema		Uncommon
Investigations	Increase in blood creatinine level	Common	Uncommon		Common
	Increase in blood urea level	Common	Common		Common
	Increase in blood uric acid level	Common
	Decrease in blood potassium level	Uncommon
	Increase in blood gamma-glutamyltransferase level	Uncommon
	Increase in alanine aminotransferase level	Uncommon
	Increase in aspartate aminotransferase level	Uncommon
	Increase in liver enzymes		Common	Very rare (most often associated with cholestasis)
	Increase in blood creatine phosphokinase level		Common
	Decrease in body weight			Uncommon
	Increase in body weight			Uncommon

* During the post-marketing period, cases of autoimmune hepatitis with a latency period ranging from several months to years have been reported, which resolved upon discontinuation of olmesartan.

Isolated cases of rhabdomyolysis, temporally associated with the use of angiotensin II receptor blockers, have been reported. In patients taking amlodipine, isolated cases of extrapyramidal syndrome have been reported.

Non-melanoma skin cancer (NMSC): based on available epidemiological study data, a cumulative dose-dependent association has been established between hydrochlorothiazide use and the risk of developing NMSC (see sections "Special precautions", "Pharmacodynamics").

The adverse reactions listed below have been identified during clinical trials or post-marketing use of the fixed-dose combination of olmesartan medoxomil and amlodipine, and have not yet been reported during the use of ATTENTO® PLUS, olmesartan medoxomil, or amlodipine alone, or have been reported more frequently with the use of the dual combination (Table 2).

Table 2

Combination of olmesartan medoxomil and amlodipine

Organ system class	Frequency	Adverse reactions
Immune system disorders	Rare	Hypersensitivity to the medicinal product
Gastrointestinal disorders	Uncommon	Upper abdominal pain
Reproductive system and breast disorders	Uncommon	Decreased libido
General disorders and administration site conditions	Common	Soft tissue edema
	Uncommon	Lethargy
Skeletal and connective tissue disorders	Uncommon	Limb pain

The adverse reactions listed below were identified during clinical studies or post-marketing use of the fixed-dose combination of olmesartan medoxomil and hydrochlorothiazide, and have not previously been reported during the use of ATTENTO® PLUS, olmesartan medoxomil, or hydrochlorothiazide alone, or have been reported more frequently with the use of the dual combination (Table 3).

Table 3

Combination of olmesartan medoxomil and hydrochlorothiazide

Organ system class	Frequency	Adverse reactions
Nervous system disorders	Rare	Consciousness disturbances (e.g., loss of consciousness)
Skin and subcutaneous tissue disorders	Uncommon	Ecchymosis
Musculoskeletal and connective tissue disorders	Uncommon	Limb pain
Investigations	Rare	Slight decrease in mean hemoglobin and hematocrit values

Reporting of suspected adverse reactions

Reporting of adverse reactions following the marketing authorization of a medicinal product is of significant importance. It enables continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, as well as their legal representatives, are encouraged to report all suspected adverse reactions and lack of efficacy of the medicinal product via the Automated Information System for Pharmacovigilance at the following link: https://aisf.dec.gov.ua.

Shelf life.

3 years.

Storage conditions.

No special storage conditions required. Keep out of reach and sight of children.

Packaging.

14 tablets per blister; 2 blisters per cardboard box.

Prescription status.

Prescription-only.

Manufacturers.

Daiichi Sankyo Europe GmbH.

Berlin-Chemie AG.

Menarini von Heyden GmbH.

Manufacturers' addresses and locations of their business operations.

Ludwigstraße 1, 85276 Pfaffenhofen, Germany.

Glienicker Weg 125, 12489 Berlin, Germany.

Leipziger Straße 7-13, 01097 Dresden, Germany.

Marketing Authorization Holder.

Menarini International Operations Luxembourg S.A.

Address of the Marketing Authorization Holder.

1, Avenue de la Gare, L-1611 Luxembourg, Luxembourg.