Attento® 40/5
UkraineTable of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ATTENTOâ20/5, ATTENTOâ40/5, ATTENTOâ40/10 (ATTENTOâ20/5, ATTENTOâ40/5, ATTENTOâ40/10)
Composition:
Active substances: olmesartan medoxomil; amlodipine besylate;
Attentoâ20/5:
One film-coated tablet contains olmesartan medoxomil 20 mg and amlodipine besylate 6.944 mg (equivalent to amlodipine 5 mg);
Attentoâ40/5:
One film-coated tablet contains olmesartan medoxomil 40 mg and amlodipine besylate 6.944 mg (equivalent to amlodipine 5 mg);
Attentoâ40/10:
One film-coated tablet contains olmesartan medoxomil 40 mg and amlodipine besylate 13.888 mg (equivalent to amlodipine 10 mg);
Excipients:
pregelatinized starch (corn), microcrystalline cellulose silicified (containing 98% microcrystalline cellulose (Ph.Eur.) and 2% colloidal anhydrous silicon dioxide (Ph.Eur.)), sodium croscarmellose, magnesium stearate;
Film coating:
Attentoâ20/5:
Opadry II 85F18422 white (polyvinyl alcohol, titanium dioxide (E 171), polyethylene glycol, talc);
Attentoâ40/5:
Opadry II 85F22093 yellow (polyvinyl alcohol, titanium dioxide (E 171), iron oxide yellow (E 172), polyethylene glycol, talc);
Attentoâ40/10:
Opadry II 85F25467 red (polyvinyl alcohol, titanium dioxide (E 171), iron oxide yellow (E 172), iron oxide red (E 172), polyethylene glycol, talc).
Pharmaceutical form. Film-coated tablets.
Main physicochemical properties.
Attentoâ20/5:
White, round, film-coated tablets, with "C73" embossed on one side;
Attentoâ40/5:
Cream-colored, round, film-coated tablets, with "C75" embossed on one side;
Attentoâ40/10:
Brownish-red, round, film-coated tablets, with "C77" embossed on one side.
Pharmacotherapeutic group. Angiotensin II antagonists and calcium channel blockers.
ATC code: C09D B02.
Pharmacological properties.
Pharmacodynamics.
Attento® is a combination medicinal product containing olmesartan medoxomil – an angiotensin II receptor antagonist – and amlodipine besilate – a calcium channel blocker. The combination of these two active substances produces a synergistic effect, resulting in a greater reduction in arterial pressure than each active substance alone.
In an 8-week, double-blind, randomized, placebo-controlled factorial study involving 1940 patients (71% of patients were Caucasian and 29% belonged to other races), treatment with Attento® resulted in a significantly greater reduction in diastolic and systolic blood pressure compared to monotherapy with the respective components. The mean reduction in systolic/diastolic pressure was dose-dependent: -24/-14 mm Hg (20 mg/5 mg), -25/-16 mm Hg (40 mg/5 mg), and -30/-19 mm Hg (40 mg/10 mg).
Attento® 40/5 reduced seated systolic/diastolic blood pressure by an additional 2.5/1.7 mm Hg compared to Attento® 20/5. Similarly, Attento® 40/10 reduced seated systolic/diastolic blood pressure by an additional 4.7/3.5 mm Hg compared to Attento® 40/5.
The proportion of patients who achieved target blood pressure values (< 140/90 mm Hg in non-diabetic patients and < 130/80 mm Hg in diabetic patients) was 42.5%, 51.0%, and 49.1% with Attento® 20/5, Attento® 40/5, and Attento® 40/10, respectively.
The main antihypertensive effect of Attento® was generally achieved within the first 2 weeks of therapy.
In a second double-blind, randomized, placebo-controlled study, the efficacy of adding amlodipine to the treatment regimen was evaluated in Caucasian patients with an inadequate response to monotherapy with olmesartan medoxomil 20 mg over 8 weeks.
In patients who continued receiving only olmesartan medoxomil 20 mg, systolic/diastolic blood pressure decreased by 10.6/7.8 mm Hg over the subsequent 8 weeks. When 5 mg of amlodipine was added, a reduction in systolic/diastolic blood pressure of -16.2/-10.6 mm Hg was achieved over 8 weeks (p = 0.0006).
The proportion of patients who achieved target blood pressure values (< 140/90 mm Hg in non-diabetic patients and < 130/80 mm Hg in diabetic patients) was 44.5% with Attento® 20/5 compared to 28.5% with olmesartan medoxomil 20 mg.
Further studies evaluated the efficacy of adding different doses of olmesartan medoxomil to the treatment regimen in Caucasian patients with an inadequate response to monotherapy with amlodipine 5 mg over 8 weeks.
In patients who continued receiving only 5 mg of amlodipine, systolic/diastolic blood pressure decreased by 9.9/5.7 mm Hg over the subsequent 8 weeks. Adding 20 mg of olmesartan medoxomil resulted in a reduction in systolic/diastolic blood pressure of -15.3/-9.3 mm Hg, and adding 40 mg of olmesartan medoxomil resulted in a reduction of -16.7/-9.5 mm Hg (p < 0.0001).
The proportion of patients who achieved target blood pressure values (< 140/90 mm Hg in non-diabetic patients and < 130/80 mm Hg in diabetic patients) was 29.9% in the amlodipine 5 mg monotherapy group, 53.5% in the Attento® 20/5 group, and 50.5% in the Attento® 40/5 group.
There are no randomized data in patients with uncontrolled arterial hypertension allowing comparison of the outcomes of combined therapy with Attento® at medium doses versus dose escalation of amlodipine and olmesartan medoxomil in monotherapy.
Results from three studies confirm that the antihypertensive effect of Attento® administered once daily was maintained over a 24-hour dosing interval, with the ratio between minimum and maximum values of systolic and diastolic pressure ranging from 71% to 82%. The efficacy of the medicinal product over 24 hours was confirmed by ambulatory blood pressure monitoring.
The antihypertensive effect of Attento® was independent of age and sex, as well as the presence of diabetes mellitus in patients.
In two open, non-randomized, extended studies, sustained efficacy of Attento® 40/5 was demonstrated in 49–67% of patients after one year of treatment.
Olmesartan medoxomil (active substance of Attento®)
Olmesartan medoxomil, included in Attento®, is a selective antagonist of angiotensin II type 1 (AT1) receptors. In the body, olmesartan medoxomil is rapidly converted into the pharmacologically active metabolite olmesartan. Angiotensin II is the primary vasoactive hormone of the renin-angiotensin-aldosterone system and plays a key role in the pathophysiology of arterial hypertension. Angiotensin II causes vasoconstriction, stimulates the synthesis and release of aldosterone, has cardiostimulatory effects, and promotes renal sodium reabsorption. Olmesartan inhibits the vasoconstrictive and aldosterone-secreting effects of angiotensin II by blocking AT1 receptors in tissues, including vascular smooth muscle and adrenal glands. The action of olmesartan does not depend on the source or pathway of angiotensin II synthesis. Selective antagonism of angiotensin II AT1 receptors leads to an increase in plasma renin levels and concentrations of angiotensin I and angiotensin II, as well as a slight decrease in plasma aldosterone levels. In arterial hypertension, olmesartan medoxomil causes a dose-dependent, prolonged reduction in arterial pressure.
No episodes of arterial hypotension after the first dose, signs of tachyphylaxis during long-term use, or rebound hypertension after discontinuation have been observed with its use.
When olmesartan medoxomil is administered once daily to patients with arterial hypertension, effective and smooth reduction in arterial pressure occurs over the 24-hour interval between doses.
The antihypertensive effect of the medicinal product was similar when administered once or twice daily at the same total daily dose. Maximum reduction in arterial pressure is achieved 8 weeks after the start of treatment, although a significant antihypertensive effect is observed as early as 2 weeks after treatment initiation.
The effect of olmesartan medoxomil on morbidity and mortality has not been established.
A randomized study of olmesartan use for the prevention of diabetic microalbuminuria (ROADMAP), involving 4447 patients with type 2 diabetes and normal albuminuria levels and at least one additional cardiovascular risk factor, was conducted to determine whether olmesartan therapy could delay the time to first onset of microalbuminuria. During a mean follow-up period of 3.2 years, patients received olmesartan or placebo in addition to other antihypertensive agents, excluding 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 a post hoc analysis excluding patients who prematurely discontinued the study treatment. The reduction in the primary endpoint with olmesartan remained significant after adjustment for blood pressure differences. Microalbuminuria developed in 8.2% (178 of 2160) of patients in the olmesartan group and in 9.8% (210 of 2139) of patients in the placebo group.
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 (Olmesartan Reducing Incidence of End-stage Renal Disease in Diabetic Nephropathy Trial) study, the effect of olmesartan on renal and cardiovascular outcomes was evaluated 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 (active substance of Attento®)
Amlodipine, included in Attento®, is a calcium channel blocker that inhibits transmembrane calcium ion influx through voltage-dependent L-type channels in the heart and smooth muscle. 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 vascular smooth muscle cells, leading to reduced peripheral vascular resistance and, consequently, reduced arterial pressure.
In arterial hypertension, amlodipine causes a dose-dependent, prolonged reduction in arterial pressure. No episodes 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, amlodipine effectively reduces arterial pressure in supine, sitting, and standing positions in patients with arterial hypertension. 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, as well as in clinical exercise testing studies 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 and mortality 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, and diuretics at stable doses, amlodipine did not affect overall mortality or cardiovascular mortality. In this patient group, an increased incidence of pulmonary edema was observed with amlodipine, but there was no statistically significant difference in the frequency of heart failure exacerbation compared to placebo.
Preventive therapy of myocardial infarction (ALLHAT)
A double-blind, randomized study on the impact on morbidity and mortality, titled "Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial" (ALLHAT), was conducted to compare new types of drug therapy: 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 coronary heart disease (CHD), including prior myocardial infarction or stroke (more than 6 months before enrollment) or presence of other atherosclerotic cardiovascular diseases (total 51.5%), 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 a composite of fatal CHD or non-fatal myocardial infarction. No significant differences in the primary endpoint were observed between amlodipine and chlorthalidone therapy: OR 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%, OR 1.38, 95% CI [1.25–1.52], p < 0.001). However, no significant differences in all-cause mortality were observed between amlodipine and chlorthalidone therapy (OR 0.96, 95% CI [0.89–1.02], p = 0.20).
Other information
The combined use of ACE inhibitors and angiotensin II receptor blockers was investigated in two large-scale, randomized, controlled studies (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 a history of cardiovascular or cerebrovascular disease or type 2 diabetes with evidence of target organ damage. VA NEPHRON-D was a study conducted in patients with type 2 diabetes and diabetic nephropathy. These studies did not demonstrate a significant beneficial effect on renal and/or cardiovascular outcomes or mortality, but showed an increased risk of hyperkalemia, acute kidney injury, and/or hypotension compared to monotherapy. Due to the similarity of pharmacodynamic properties, these results are also applicable to other ACE inhibitors and angiotensin II receptor blockers.
The combined 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 evaluate the 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 an increased risk of adverse outcomes. Cardiovascular mortality and stroke were more frequent in the group receiving aliskiren than in the placebo group, and adverse events and serious adverse events (hyperkalemia, arterial hypotension, and renal function impairment) were more frequently reported in the aliskiren group than in the placebo group.
Pharmacokinetics.
After oral administration of Attento®, maximum plasma concentrations of olmesartan medoxomil and amlodipine are reached at 1.5–2 hours and 6–8 hours, respectively. The rate and extent of absorption of the two active substances in Attento® correspond to the rate and extent of absorption when administered separately. The bioavailability of olmesartan and amlodipine in the medicinal product Attento® is independent of food intake.
Olmesartan medoxomil (active substance of Attento®)
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 excretory products. The mean absolute bioavailability of olmesartan as tablets is 25.6%.
The mean maximum concentration (Cmax) of olmesartan in plasma 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 the bioavailability of olmesartan; therefore, olmesartan medoxomil can be administered regardless of food intake.
No clinically significant differences in the pharmacokinetics of olmesartan based on patient sex have been observed. Olmesartan is highly bound to plasma proteins (99.7%), but the risk of clinically significant competitive interactions with other drugs highly bound to plasma proteins is low. This is supported by the absence of interaction between olmesartan medoxomil and warfarin. Olmesartan is extensively bound to blood cells. 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 is relatively low compared to hepatic blood flow (approximately 90 L/hour). After a single oral dose of radiolabeled (14C) 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. Intestinal-hepatic recirculation of olmesartan is minimal. Since most of olmesartan is excreted in bile, its use is contraindicated in patients with biliary obstruction (see section "Contraindications").
The terminal elimination half-life of olmesartan after multiple oral doses ranges from 10 to 15 hours. Steady state is reached after the first few doses, and no further accumulation occurs after 14 days of repeated administration. Renal clearance is approximately 0.5–0.7 L/hour and is independent of the dose.
Drug interactions
The medicinal product colesevelam, a 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% reductions 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 administered 4 hours before colesevelam hydrochloride (see section "Interaction with other medicinal products and other types of interactions").
Amlodipine (active substance of Attento®)
Absorption and distribution
After oral administration at therapeutic doses, amlodipine is well absorbed, reaching peak blood concentration 6–12 hours after administration. The absolute bioavailability of unchanged compound is approximately 64–80%. The volume of distribution is approximately 21 L/kg. In vitro studies have shown that approximately 97.5% of circulating amlodipine is bound to plasma proteins. Food intake does not affect the absorption process of amlodipine.
Metabolism and elimination
The elimination half-life from plasma ranges from 35 to 50 hours and remains unchanged with daily single administration. Amlodipine is extensively metabolized, forming inactive metabolites. Approximately 60% of the administered dose is excreted in urine, of which 10% is unchanged.
Olmesartan medoxomil and amlodipine (active substances of Attento®)
Special patient groups
Children (under 18 years of age)
There are no data on pharmacokinetics in children.
Elderly patients (65 years of age and older)
It has been demonstrated that in patients with arterial hypertension, the steady-state AUC (area under the concentration-time curve) of olmesartan is 35% higher in elderly patients (65–75 years) and approximately 44% higher in very elderly patients (75 years and older) compared to younger patients (see section "Dosage and administration"). This can be explained by the presence of moderate renal impairment in these patients. However, the same dosing regimen is recommended for elderly patients as for other patients, although dose escalation should be done cautiously.
The time to reach maximum plasma concentration of amlodipine is the same in elderly and younger patients. In elderly patients, there is a tendency toward reduced amlodipine clearance, leading to increased AUC and prolonged elimination half-life. The increase in AUC and prolonged elimination half-life in patients with congestive heart failure are consistent with predictions for patients in this age group (see section "Special precautions for use").
Renal impairment
In patients with renal impairment, steady-state AUC was approximately 62%, 82%, and 179% higher in cases of mild, moderate, and severe impairment, respectively, compared to healthy volunteers (see sections "Dosage and administration", "Special precautions for use").
Amlodipine is extensively metabolized to inactive metabolites. 10% of the substance is excreted unchanged in urine. Changes in amlodipine plasma concentration do not correlate with the degree of renal impairment. Amlodipine can be administered at usual doses to such patients. Amlodipine is not removed by hemodialysis.
Hepatic impairment
After a single oral dose, AUC values for olmesartan were 6% and 65% higher in patients with mild or moderate hepatic impairment, respectively, compared to healthy volunteers. The unbound fraction of olmesartan 2 hours after administration in healthy volunteers and in patients with mild or moderate hepatic impairment was 0.26%, 0.34%, and 0.41%, respectively. With repeated administration, the mean AUC of olmesartan in patients with moderate hepatic impairment was 65% higher than in healthy volunteers. Mean Cmax values 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").
Only very limited clinical data are available on the use of amlodipine in patients with severe hepatic impairment. In patients with hepatic impairment, a reduction in amlodipine clearance and prolonged elimination half-life are observed, leading to an increase in AUC of approximately 40–60% (see sections "Dosage and administration", "Special precautions for use").
Preclinical safety data
Based on the preclinical toxicity profile of each active substance, increased toxicity for the combination product is not expected, as these substances affect different organs: olmesartan medoxomil acts on the kidneys, and amlodipine acts on the heart.
In a 3-month toxicity study of the combination product olmesartan medoxomil/amlodipine in rats with repeated oral administration, the following changes were observed: decreased erythrocyte parameters and kidney changes (both effects may be caused by olmesartan medoxomil), intestinal changes (lumen enlargement and diffuse thickening of the mucosa of the ileum and colon), adrenal gland changes (hypertrophy of glomerular zone cells and vacuolization of fasciculate zone cells), and mammary duct hypertrophy, which may be caused by amlodipine. These changes do not complement previously obtained data on the toxicity of individual components and do not indicate the emergence of new toxic effects or synergistic toxicity.
Olmesartan medoxomil (active substance of Attento®)
In chronic toxicity studies in rats and dogs, the effects of olmesartan medoxomil were similar to those of other AT1 receptor antagonists and ACE inhibitors: increased blood urea nitrogen (BUN) and creatinine levels, reduced heart weight, decreased erythrocyte parameters (erythrocyte count, hemoglobin, hematocrit), and histological signs of kidney damage (regenerative lesions of renal epithelium, 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 may be reduced by oral administration of sodium chloride. In both animal species, increased plasma renin activity and hypertrophy/hyperplasia of renal juxtaglomerular cells were observed. These changes, typical of the class of ACE inhibitors and other AT1 receptor antagonists, are likely not clinically significant.
Similar to other AT1 receptor antagonists, olmesartan medoxomil increases the frequency of chromosomal breaks in in vitro cell cultures. However, similar effects were reproduced in several in vivo studies where olmesartan medoxomil was administered at very high oral doses up to 2000 mg/kg. Overall, comprehensive genotoxicity studies indicate that genotoxic effects of olmesartan are unlikely at clinical use.
In a 2-year study in rats or a 6-month carcinogenicity study in transgenic mice, no carcinogenic properties of olmesartan medoxomil were detected.
In reproductive organ toxicity studies in rats, olmesartan medoxomil did not affect fertility and had no teratogenic effect. 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. Like other antihypertensive drugs, olmesartan medoxomil was more toxic to pregnant rabbits than to pregnant rats, but had no fetotoxic effect.
Amlodipine (active substance of Attento®)
Reproductive toxicity
Reproductive function studies in rats and mice showed 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 weight (mg/kg).
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 to mg/m²). In another study, male rats receiving amlodipine besilate for 30 days at doses comparable to the human dose adjusted to mg/m² showed decreased plasma levels of follicle-stimulating hormone and testosterone, as well as reduced sperm density, decreased number of mature spermatids, and Sertoli cells.
Carcinogenesis, mutagenesis
Two-year carcinogenicity studies in rats and mice receiving amlodipine in feed at concentrations calculated to achieve doses of 0.5, 1.25, and 2.5 mg/kg/day did not show signs of carcinogenicity. The highest dose (equivalent to the maximum recommended dose of 10 mg in mice adjusted to 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 did not reveal drug-related effects at the gene or chromosome level.
*Assuming patient body weight of 50 kg.
Clinical Characteristics.
Indications.
Treatment of essential hypertension.
Attento® is indicated in adult patients whose blood pressure is not adequately controlled with monotherapy with either olmesartan medoxomil or amlodipine (see sections “Dosage and Administration”, “Pharmacodynamics”).
Contraindications.
- Hypersensitivity to the active substances, dihydropyridine derivatives, or to any of the excipients (see section “Composition”).
- Pregnancy and planned pregnancy (see sections “Contraindications” and “Use in Pregnancy or Breastfeeding”).
- Severe hepatic impairment and biliary obstruction (see section “Pharmacokinetics”).
- Concomitant use of Attento® 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, Attento® is also contraindicated in patients with:
- severe arterial hypotension;
- shock (including cardiogenic shock);
- obstruction of left ventricular outflow (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 caused by combination with Attento®
Caution is advised when co-administering
Other antihypertensive agents
The antihypertensive effect of Attento® may be enhanced when used concomitantly with other antihypertensive medicinal products (e.g., alpha-blockers, diuretics).
Potential interactions related to the olmesartan medoxomil component of Attento®
Concomitant use is not recommended
ACE inhibitors, angiotensin II receptor blockers, or aliskiren
Clinical trial data 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 frequency of adverse events such as arterial hypotension, hyperkalaemia, and impaired renal function (including acute renal failure), compared to using a single agent acting on the RAAS (see sections “Contraindications”, “Special Warnings and 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 Warnings and Precautions for Use”). When prescribing medicinal products affecting potassium levels in combination with Attento®, monitoring of serum potassium concentration is recommended.
Lithium-containing medicinal products
When lithium is used concomitantly with ACE inhibitors and rarely with angiotensin II receptor antagonists, reversible increases in serum lithium concentration and lithium toxicity have been observed. Therefore, concomitant use of Attento® and lithium-containing medicinal products is not recommended (see section “Special Warnings and Precautions for Use”). If concomitant use of Attento® and lithium is necessary, regular monitoring of serum lithium levels is recommended.
Concomitant use requires caution
Non-steroidal anti-inflammatory drugs (NSAIDs), including selective COX-2 inhibitors, acetylsalicylic acid (> 3 g/day), and non-selective NSAIDs
When angiotensin II antagonists are co-administered with NSAIDs, the antihypertensive effect may be attenuated. In addition, concomitant use of angiotensin II antagonists and NSAIDs may increase the risk of worsening renal function and lead to increased serum potassium concentration. Therefore, when such combination therapy is used, initial regular assessment of renal function and adequate hydration of the patient are recommended.
Bile acid sequestrant medicinal product colesevelam
Concomitant use of the bile acid sequestrant colesevelam hydrochloride reduces systemic exposure and peak plasma concentration of olmesartan, as well as its elimination half-life. Administration of olmesartan medoxomil at least 4 hours before colesevelam hydrochloride reduces the effect of this drug interaction. Administration of olmesartan medoxomil at least 4 hours before colesevelam hydrochloride should be considered (see section “Pharmacokinetics”).
Additional information
A moderate decrease in bioavailability of olmesartan medoxomil has been observed after treatment with antacids (magnesium and aluminium hydroxides).
Olmesartan medoxomil has no significant effect on the pharmacokinetics and pharmacodynamics of warfarin or the pharmacokinetics of digoxin. Concomitant administration of olmesartan medoxomil with pravastatin does not result in 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 cytochrome P450 activity has been observed in rats. Therefore, clinically significant interactions between olmesartan and medicinal products metabolized by the aforementioned cytochrome P450 enzymes are not expected.
Potential interactions related to the amlodipine component of Attento®
Effects of other medicinal products on amlodipine
CYP3A4 inhibitors
When amlodipine is used concomitantly with strong or moderate CYP3A4 inhibitors (protease inhibitors, azole antifungals, macrolides such as erythromycin or clarithromycin, verapamil, or diltiazem), the effect of amlodipine may be significantly enhanced, which may also increase the risk of hypotension. 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. Clinical monitoring and dose adjustment may therefore be necessary.
CYP3A4 inducers
When known CYP3A4 inducers are used concomitantly, plasma concentrations of amlodipine may vary. Therefore, blood pressure should be monitored and dosage adjusted both during and after concomitant therapy, especially with strong CYP3A4 inducers (e.g., 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 effects.
Dantrolene (infusion): In animal studies, ventricular fibrillation and cardiovascular collapse with fatal outcome were observed after administration of verapamil and intravenous dantrolene, due to the development of hyperkalaemia. Due to the risk of hyperkalaemia in patients predisposed to malignant hyperthermia or during treatment of malignant hyperthermia, concomitant use of calcium channel blockers such as amlodipine should be avoided.
Effects of amlodipine on other medicinal products
The antihypertensive effect of amlodipine is additive to the antihypertensive effects of other blood pressure-lowering agents.
In clinical drug interaction studies, amlodipine did not affect the pharmacokinetics of atorvastatin, digoxin, or warfarin.
Simvastatin. Concomitant administration of multiple doses of amlodipine 10 mg and simvastatin 80 mg resulted in a 77% increase in the exposure to simvastatin 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 tacrolimus toxicity 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, co-administration of amlodipine with cyclosporine resulted in an average 40% increase in cyclosporine trough levels. Concomitant use of Attento® with cyclosporine may enhance the effects of cyclosporine. When used concomitantly with amlodipine, monitoring of cyclosporine trough levels should be considered, and cyclosporine dosage reduced if necessary.
Special precautions for use.
Patients with hypovolemia or sodium deficiency
Symptomatic hypotension may occur in patients with hypovolemia and/or hyponatremia resulting from intensive diuretic therapy, dietary salt restriction, diarrhea, or vomiting, particularly after the first dose. It is recommended to correct these conditions prior to initiating treatment with AttenTo® or to ensure close monitoring of 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 (such as angiotensin II receptor antagonists).
Renovascular hypertension
The use of drugs affecting the renin-angiotensin-aldosterone system in patients with bilateral renal artery stenosis or stenosis of the artery of a single 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 when AttenTo® is administered to patients with renal impairment. Use of AttenTo® is not recommended in patients with severe renal impairment (creatinine clearance < 20 mL/min). Experience with AttenTo® in patients who have recently undergone kidney transplantation or in patients with end-stage renal disease (e.g., creatinine clearance < 12 mL/min) is lacking (see sections "Dosage and administration" and "Pharmacokinetics").
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 decreased renal function (including acute renal failure). Therefore, dual blockade of RAAS with concomitant use of ACE inhibitors and angiotensin II receptor blockers or aliskiren is not recommended (see section "Interaction with other medicinal products and other forms of interaction").
If dual RAAS blockade is considered absolutely necessary, it should be performed only under specialist supervision and with careful 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"). AttenTo® should be used with caution in patients with mild to moderate hepatic impairment. For patients with moderate hepatic impairment, the dose of olmesartan medoxomil should not exceed 20 mg (see section "Dosage and administration"). Amlodipine should be initiated at the lowest dose in patients with hepatic impairment, and caution should be exercised both at the beginning of treatment and when increasing the dose. AttenTo® is contraindicated in patients with severe hepatic impairment (see section "Contraindications").
Hyperkalemia
As with other angiotensin II antagonists and ACE inhibitors, hyperkalemia may occur during treatment with AttenTo®, particularly in patients with renal impairment and/or heart failure (see section "Interaction with other medicinal products and other forms of interaction"). Frequent monitoring of serum potassium levels is recommended in these high-risk patients.
The concomitant use of AttenTo® with potassium supplements, potassium-sparing diuretics, potassium-containing salt substitutes, or other medicinal products that may increase potassium levels (e.g., heparin) should be done with caution; regular monitoring of serum potassium levels is recommended.
Lithium preparations
As with other angiotensin II antagonists, concomitant use of AttenTo® and lithium preparations is not recommended (see section "Interaction with other medicinal products and other forms of interaction").
Aortic or mitral valve stenosis; obstructive hypertrophic cardiomyopathy
Due to the presence of amlodipine in AttenTo®, as with other vasodilating agents, 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 suppress the renin-angiotensin system. Therefore, use of AttenTo® is not recommended in such patients.
Heart failure
Due to suppression of the angiotensin-aldosterone system, renal function may deteriorate 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 II receptor antagonists may be associated with oliguria and/or progressive azotemia and (rarely) acute renal failure and/or death.
Therapy in patients with heart failure should be administered with caution. In a long-term placebo-controlled study of amlodipine in patients with severe heart failure (NYHA III and IV), reports of pulmonary edema were more frequent 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 agents may increase the risk of cardiovascular events and mortality.
Sprue-like enteropathy
Very rarely, severe chronic diarrhea with substantial weight loss has been reported, developing several months to years after initiation of treatment in patients taking olmesartan; the cause is likely a localized delayed hypersensitivity reaction. Intestinal mucosal biopsies 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., a gastroenterologist) should be considered.
Intestinal angioedema
Cases of intestinal angioedema have been reported in patients taking angiotensin II receptor blockers, [including olmesartan] (see section "Adverse reactions"). These patients experienced abdominal pain, nausea, vomiting, and diarrhea. Symptoms resolved after discontinuation of angiotensin II receptor blockers. If intestinal angioedema is diagnosed, olmesartan should be discontinued and appropriate monitoring initiated until complete resolution of symptoms.
Ethnic differences
As with other angiotensin II receptor antagonists, the antihypertensive effect of AttenTo® may be somewhat less in Black patients compared to other patients, possibly due to a higher prevalence of low renin levels in this population.
Elderly patients
Dosage increases in elderly patients should be performed cautiously (see section "Pharmacokinetics").
Pregnancy
Angiotensin II receptor antagonists should not be initiated during pregnancy. Women planning pregnancy should switch to an alternative antihypertensive therapy with a proven safety profile in pregnancy. If pregnancy is detected, treatment with angiotensin II receptor antagonists should be discontinued immediately and alternative therapy initiated if needed (see sections "Contraindications" and "Use during pregnancy or lactation").
Other
As with any antihypertensive agents, excessive reduction of blood pressure in patients with ischemic heart disease or cerebrovascular disease may lead to myocardial infarction or stroke.
This medicinal product contains less than 1 mmol sodium (23 mg) per film-coated tablet and is therefore considered essentially "sodium-free."
Use during pregnancy or breastfeeding
Pregnancy (see section "Contraindications")
Data on the use of AttenTo® in pregnant women are lacking. Reproductive toxicity studies of AttenTo® in animals have not been conducted.
Olmesartan medoxomil (active ingredient of AttenTo®)
The use of angiotensin II antagonists is contraindicated in pregnant women and women planning pregnancy (see sections "Contraindications" and "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 such risk cannot be entirely excluded. A similar risk may be assumed for angiotensin II receptor antagonists, as controlled epidemiological studies on these drugs have not been conducted. Women planning pregnancy should be switched to antihypertensive drugs with proven safety in pregnancy unless there is an urgent need for angiotensin II receptor antagonists. If pregnancy is detected, angiotensin II receptor antagonists should be discontinued immediately and alternative therapy initiated if needed.
During the second and third trimesters, angiotensin II receptor antagonists have toxic effects on the fetus (impaired renal function, oligohydramnios, delayed skull ossification) and on the newborn (renal failure, arterial hypotension, hyperkalemia) (see section "Preclinical safety data").
If angiotensin II receptor antagonists are used during the second or third trimester, renal function and skull ossification in the fetus should be monitored by ultrasound. Newborns whose mothers received angiotensin II receptor antagonists should be monitored for possible arterial hypotension (see sections "Contraindications" and "Special precautions for use").
Amlodipine (active ingredient of AttenTo®)
Data from limited observations in pregnant women do not indicate harmful effects of amlodipine or other calcium channel antagonists on the fetus. However, there is a risk of prolonged labor.
Given the above, AttenTo® is contraindicated in pregnant women or women planning pregnancy (see sections "Contraindications" and "Special precautions for use").
Lactation
Olmesartan crosses into the milk of lactating rats. It is unknown whether olmesartan passes into human breast milk. Amlodipine is excreted in human breast milk. The infant's exposure was estimated to be in the interquartile range of 3–7% of the maternal dose, with a maximum of 15%. The effect of amlodipine on the infant is unknown. Use of AttenTo® during breastfeeding is not recommended, and alternative therapies with a better-established safety profile during breastfeeding should be preferred, especially when breastfeeding newborns or preterm infants.
Fertility
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. Adverse effects on male fertility were observed in rat studies (see section "Preclinical safety data").
Ability to influence reaction speed when driving or operating machinery
AttenTo® may have a slight or moderate influence on the ability to drive vehicles or operate machinery.
Occasionally, patients receiving antihypertensive agents may experience headache, dizziness, nausea, and increased fatigue, which may impair reaction time. Caution should be exercised, especially at the beginning of treatment.
Method of Administration and Dosage.
Adults
The recommended dose of the medicine Atento® is 1 tablet per day.
Atento®20/5 may be prescribed to patients with inadequate response to monotherapy with olmesartan medoxomil at a dose of 20 mg or amlodipine at a dose of 5 mg.
Atento®40/5 may be prescribed to patients with inadequate response to therapy with Atento®20/5.
Atento®40/10 may be prescribed to patients with inadequate response to therapy with Atento®40/5.
Prior to prescribing a fixed-dose combination product, it is recommended to titrate the doses of the individual components as monotherapies. If necessary, direct substitution of monotherapies with the combination product is possible.
For convenience, patients receiving olmesartan medoxomil and amlodipine as separate tablets may be switched to Atento® tablets containing these components in equivalent doses.
Atento® may be taken independently of food intake.
Elderly patients (aged 65 years and older)
Generally, dose adjustment is not required in elderly patients; however, dose escalation should be performed cautiously (see sections "Special Warnings", "Pharmacokinetics").
When increasing the dose of olmesartan medoxomil to the maximum (40 mg per day), careful monitoring of blood pressure is required.
Renal impairment
The maximum dose of olmesartan medoxomil in patients with mild to moderate renal impairment (creatinine clearance 20−60 mL/min) is 20 mg once daily, as experience with higher doses in this patient group is limited. Atento® is not recommended in patients with severe renal impairment (creatinine clearance < 20 mL/min) (see sections "Special Warnings", "Pharmacokinetics").
When administering Atento® to patients with moderate renal impairment, monitoring of potassium and creatinine levels is recommended.
Hepatic impairment
Atento® should be prescribed with caution to patients with mild to moderate hepatic impairment (see sections "Special Warnings", "Pharmacokinetics").
In patients with moderate hepatic impairment, olmesartan medoxomil should be initiated at a dose of 10 mg once daily. The maximum dose in such patients should not exceed 20 mg once daily. In patients with hepatic impairment receiving concomitant therapy with diuretics and/or other antihypertensive agents, careful monitoring of blood pressure and renal function is recommended. Experience with olmesartan medoxomil in patients with severe hepatic impairment is lacking.
As with other calcium antagonists, the elimination half-life of amlodipine is prolonged in patients with hepatic dysfunction; dosage recommendations have not been established. Therefore, Atento® should be prescribed with caution in such patients. The pharmacokinetics of amlodipine in patients with severe hepatic impairment have not been studied. Amlodipine administration in patients with severe hepatic impairment should begin at the lowest dose with gradual dose escalation. Atento® is contraindicated in patients with severe hepatic impairment (see section "Contraindications").
Method of administration
Tablets should be swallowed whole with sufficient liquid (e.g., a glass of water). Tablets should not be chewed. The medicine should be taken daily at the same time.
Children
Safety and efficacy of Atento® in children and adolescents (under 18 years of age) have not been established. Data are lacking.
Overdose.
Symptoms
No cases of Atento® overdose have been reported. The most likely effects of olmesartan medoxomil overdose are hypotension and tachycardia; bradycardia may also occur in case of parasympathetic stimulation (vagus nerve). Amlodipine overdose may lead to excessive peripheral vasodilation, resulting in marked reduction in arterial pressure and possibly reflex tachycardia. There have been reports of prolonged severe generalized hypotension, up to shock with fatal outcome.
Rarely, non-cardiogenic pulmonary edema has been reported as a consequence of amlodipine overdose, which may present with delayed onset (24–48 hours after ingestion) and may require mechanical ventilation.
Early resuscitative measures (including fluid overload) to support perfusion and cardiac output may be provocative factors.
Treatment
If the drug has been recently ingested, gastric lavage is indicated. In healthy volunteers, administration of activated charcoal immediately or within 2 hours after oral intake of amlodipine significantly reduces absorption of the substance.
In case of clinically significant hypotension due to Atento® overdose, active cardiovascular support is required, including careful monitoring of cardiac and pulmonary function, elevation of lower limbs, monitoring of circulating blood volume and diuresis. Vasopressor agents may be useful to restore vascular tone and arterial pressure, provided there are no contraindications. Intravenous calcium gluconate is recommended to reverse calcium channel blockade.
Since amlodipine is highly protein-bound, elimination by dialysis is unlikely. Information on the possibility of removing olmesartan by dialysis is lacking.
Adverse Reactions
Attento®
The most common adverse reactions observed during treatment with Attento® were peripheral edema (11.3%), headache (5.3%), and dizziness (4.5%).
Adverse reactions observed during clinical trials and post-marketing safety studies with Attento®, as well as spontaneously reported adverse reactions, are listed in the table below. In addition, the table includes adverse reactions observed with each of the active components of the medicinal product administered separately (olmesartan medoxomil and amlodipine), taking into account their established safety profiles.
The following terminology was used to classify 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).
| Organ or System (by MedDRA) |
Adverse Reactions |
Frequency |
||
| Olmesartan/amlodipine combination |
Olmesartan |
Amlodipine |
||
| Blood and lymphatic system |
Leukopenia |
Very rare |
||
| Thrombocytopenia |
Uncommon |
Very rare |
||
| Immune system |
Allergic reactions/hypersensitivity reactions |
Uncommon |
Very rare |
|
| Anaphylactic reaction |
Uncommon |
|||
| Metabolism and nutrition disorders |
Hypoglycemia |
Very rare |
||
| Hyperkalemia |
Uncommon |
Uncommon |
||
| Hypertriglyceridemia |
Common |
|||
| Hyperuricemia |
Common |
|||
| Psychiatric |
Confusion |
Uncommon |
||
| Depression |
Uncommon |
|||
| Insomnia |
Uncommon |
|||
| Irritability |
Uncommon |
|||
| Decreased libido |
Uncommon |
|||
| Mood changes, including anxiety |
Uncommon |
|||
| Nervous system |
Dizziness |
Common |
Common |
Common |
| Dysgeusia |
Uncommon |
|||
| Headache |
Common |
Common |
Common (especially at the beginning of treatment) |
|
| Hypertonia |
Very rare |
|||
| Hypoesthesia |
Uncommon |
Uncommon |
||
| Drowsiness |
Uncommon |
|||
| Paraesthesia |
Uncommon |
Uncommon |
||
| Peripheral neuropathy |
Very rare |
|||
| Postural dizziness |
Uncommon |
|||
| Sleep disturbance |
Uncommon |
|||
| Somnolence |
Common |
|||
| Syncope |
Uncommon |
Uncommon |
||
| Tremor |
Uncommon |
|||
| Extrapyramidal disorders |
Unknown |
|||
| Eye disorders |
Visual disturbances (including diplopia) |
Common |
||
| Ear and labyrinth disorders |
Tinnitus |
Uncommon |
||
| Dizziness |
Uncommon |
Uncommon |
||
| Cardiac disorders |
Angina pectoris |
Uncommon |
Uncommon (including exacerbation) |
|
| Arrhythmias (including bradycardia, ventricular tachycardia, atrial fibrillation) |
Uncommon |
|||
| Myocardial infarction |
Very rare |
|||
| Pounding heartbeat |
Uncommon |
Common |
||
| Tachycardia |
Uncommon |
|||
| Vascular disorders |
Arterial hypotension |
Uncommon |
Uncommon |
Uncommon |
| Orthostatic hypotension |
Uncommon |
|||
| Flushing |
Uncommon |
Common |
||
| Vasculitis |
Very rare |
|||
| Respiratory system |
Bronchitis |
Common |
||
| Cough |
Uncommon |
Common |
Uncommon |
|
| Dyspnea |
Uncommon |
Common |
||
| Pharyngitis |
Common |
|||
| Rhinitis |
Common |
Uncommon |
||
| Gastrointestinal disorders |
Abdominal pain |
Common |
Common |
|
| Intestinal dysfunction (including constipation and diarrhea) |
Common |
|||
| Constipation |
Uncommon |
|||
| Diarrhea |
Uncommon |
Common |
||
| Dry mouth |
Uncommon |
Uncommon |
||
| Dyspepsia |
Uncommon |
Common |
Common |
|
| Gastritis |
Very rare |
|||
| Gastroenteritis |
Common |
|||
| Gingival hyperplasia |
Very rare |
|||
| Nausea |
Uncommon |
Common |
Common |
|
| Pancreatitis |
Very rare |
|||
| Upper abdominal pain |
Uncommon |
|||
| Vomiting |
Uncommon |
Uncommon |
Uncommon |
|
| Angioneurotic intestinal edema |
Uncommon |
|||
| Coeliac-like enteropathy (see section "Special warnings and precautions for use") |
Very rare |
|||
| On the part of the liver and biliary tract |
Elevation of liver enzymes |
Common |
Very rare (mostly against a background of cholestasis) |
|
| Hepatitis |
Very rare |
|||
| Jaundice |
Very rare |
|||
| Autoimmune hepatitis* |
Unknown |
|||
| On the part of the skin and its appendages |
Alopecia |
Uncommon |
||
| Angioneurotic edema |
Uncommon |
Very rare |
||
| Allergic dermatitis |
Uncommon |
|||
| Polymorphic erythema |
Very rare |
|||
| Exanthem |
Uncommon |
Uncommon |
||
| Exfoliative dermatitis |
Very rare |
|||
| Increased sweating |
Uncommon |
|||
| Photosensitization |
Very rare |
|||
| Itching |
Uncommon |
Uncommon |
||
| Hemorrhagic rash |
Uncommon |
|||
| Quincke's edema |
Very rare |
|||
| Rash |
Uncommon |
Uncommon |
Uncommon |
|
| Skin color change |
Uncommon |
|||
| Stevens-Johnson syndrome |
Very rare |
|||
| Toxic epidermal necrolysis |
Unknown |
|||
| Urticaria |
Uncommon |
Uncommon |
Uncommon |
|
| On the part of the musculoskeletal system and connective tissue |
Lower leg swelling |
Common |
||
| Arthralgia |
Uncommon |
|||
| Arthritis |
Common |
|||
| Back pain |
Uncommon |
Common |
Uncommon |
|
| Muscle spasm |
Uncommon |
Uncommon |
Common |
|
| Myalgia |
Uncommon |
Uncommon |
||
| Limb pain |
Uncommon |
|||
| Bone pain |
Common |
|||
| On the part of the kidneys and urinary tract |
Acute renal failure |
Uncommon |
||
| Hematuria |
Common |
|||
| Increased frequency of urination |
Uncommon |
|||
| Urinary disorders |
Uncommon |
|||
| Nocturia |
Uncommon |
|||
| Frequency of urination |
Uncommon |
|||
| Renal failure |
Uncommon |
|||
| Urinary tract infections |
Common |
|||
| On the part of the reproductive system and mammary glands |
Erectile dysfunction/impotence |
Uncommon |
Uncommon |
|
| Gynecomastia |
Uncommon |
|||
| General disorders |
Asthenia |
Uncommon |
Uncommon |
Common |
| Chest pain |
Common |
Uncommon |
||
| Facial swelling |
Uncommon |
Uncommon |
||
| Weakness |
Common |
Common |
Common |
|
| Influenza-like conditions |
Common |
|||
| Somnolence |
Uncommon |
|||
| Malaise |
Uncommon |
Uncommon |
||
| Edema |
Common |
Very common |
||
| Pain |
Common |
Uncommon |
||
| Peripheral edema |
Common |
Common |
||
| Soft tissue swelling |
Common |
|||
| Results of additional investigations |
Elevated blood creatinine levels |
Uncommon |
Uncommon |
|
| Elevated blood creatine phosphokinase levels |
Common |
|||
| Decreased blood potassium levels |
Uncommon |
|||
| Elevated blood urea levels |
Common |
|||
| Elevated blood uric acid levels |
Uncommon |
|||
| Elevated blood gamma-glutamyl transferase levels |
Uncommon |
|||
| Decreased body weight |
Uncommon |
|||
| Increased 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 were reversible upon discontinuation of olmesartan.
Several cases of rhabdomyolysis occurring temporally in association with angiotensin II receptor blockers have been reported. In patients taking amlodipine, several cases of extrapyramidal syndrome have been reported.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after medicine authorization is important. It allows ongoing monitoring of the benefit-risk balance of the medicine. Healthcare and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.
Shelf life.
5 years.
Storage conditions.
No special storage conditions required.
Packaging.
14 tablets per blister; 1 or 2 blisters per cardboard box.
Prescription status.
Prescription only.
Manufacturers.
Daiichi Sankyo Europe GmbH.
BERLIN-CHEMIE AG.
Laboratorios Menarini S.A.
Addresses of manufacturers and locations of their business operations.
Luitpoldstraße 1, 85276 Pfaffenhofen, Germany.
Glienicker Weg 125, 12489 Berlin, Germany.
Alfons XII, 587, Badalona, Barcelona, 08918, Spain.
Marketing Authorization Holder.
Menarini International Operations Luxembourg S.A.
Address of the Marketing Authorization Holder.
1, Avenue de la Gare, L-1611 Luxembourg, Luxembourg.
Under license from Daiichi Sankyo Europe GmbH.