Sevikar

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT SEVIKAR (SEVIKAR)

Composition:

Active substances: olmesartan medoxomil; amlodipine besylate;

One film-coated tablet contains olmesartan medoxomil 20 mg, amlodipine besylate 6.944 mg, equivalent to amlodipine 5 mg;

or olmesartan medoxomil 40 mg, amlodipine besylate 6.944 mg, equivalent to amlodipine 5 mg;

or olmesartan medoxomil 40 mg, amlodipine besylate 13.888 mg, equivalent to amlodipine 10 mg;

Excipients: pregelatinized corn starch, microcrystalline cellulose silicified (containing 98% microcrystalline cellulose (Ph. Eur.) and 2% colloidal anhydrous silicon dioxide (Ph. Eur.)), sodium croscarmellose, magnesium stearate (of plant origin);

film coating contains: Opadry II 85F18422 white or Opadry II 85F22093 yellow or Opadry II 85F25467 red (polyvinyl alcohol, titanium dioxide (E 171), polyethylene glycol, talc, yellow iron oxide (E 172), red iron oxide (E 172)).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

for the 20 mg/5 mg dosage: white, round, film-coated tablets, 6 mm in size, with "C73" embossed on one side;

for the 40 mg/5 mg dosage: cream-colored, round, film-coated tablets, 8 mm in size, with "C75" embossed on one side;

for the 40 mg/10 mg dosage: brownish-red, round, film-coated tablets, 8 mm in size, with "C77" embossed on one side.

Pharmacotherapeutic group.

Cardiovascular system. Drugs affecting the renin-angiotensin system. Combinations of angiotensin II receptor blockers. Angiotensin II antagonists and calcium channel blockers. Olmesartan medoxomil and amlodipine. ATC code C09DB02.

Pharmacological properties.

Pharmacodynamics.

Sevikar is a combination medicinal product containing olmesartan medoxomil – an angiotensin II receptor antagonist – and amlodipine besylate – a calcium channel blocker. The combination of these two active substances exhibits a synergistic effect and provides greater reduction in arterial pressure than either 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 Sevikar demonstrated significantly greater reductions in diastolic and systolic blood pressure compared to monotherapy with the respective components. The mean reduction in systolic/diastolic blood pressure showed a dose-dependent relationship: -24/-14 mm Hg (for the fixed combination 20 mg/5 mg), -25/-16 mm Hg (for the fixed combination 40 mg/5 mg), and -30/-19 mm Hg (for the fixed combination 40 mg/10 mg).

Sevikar 40 mg/5 mg reduced seated systolic/diastolic blood pressure an additional 2.5/1.7 mm Hg compared to Sevikar 20 mg/5 mg. Similarly, Sevikar 40 mg/10 mg reduced seated systolic/diastolic blood pressure an additional 4.7/3.5 mm Hg compared to Sevikar 40 mg/5 mg.

The proportion of patients achieving 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 Sevikar at doses of 20 mg/5 mg, 40 mg/5 mg, and 40 mg/10 mg, respectively.

The main antihypertensive effect of Sevikar is 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 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 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 achieving target blood pressure values (< 140/90 mm Hg in non-diabetic patients and < 130/80 mm Hg in diabetic patients) was 44.5% for the combination 20 mg/5 mg compared to 28.5% for 20 mg olmesartan medoxomil.

Further studies evaluated the efficacy of adding various doses of olmesartan medoxomil to the treatment regimen in Caucasian patients with inadequate response to monotherapy with amlodipine 5 mg over 8 weeks.

In patients who continued receiving only amlodipine 5 mg, systolic/diastolic blood pressure decreased by 9.9/5.7 mm Hg over the subsequent 8 weeks. Adding 20 mg olmesartan medoxomil resulted in a reduction in systolic/diastolic blood pressure of -15.3/-9.3 mm Hg, and adding 40 mg olmesartan medoxomil resulted in a reduction of -16.7/-9.5 mm Hg (p < 0.0001).

The proportion of patients achieving 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 monotherapy group at 5 mg, 53.5% in the Sevikar 20 mg/5 mg group, and 50.5% in the Sevikar 40 mg/5 mg group.

Randomized data comparing the outcomes of combined therapy with Sevikar at medium doses versus increasing the doses of amlodipine and olmesartan in monotherapy in patients with uncontrolled arterial hypertension are lacking.

Results from three studies confirm that the antihypertensive effect of Sevikar administered once daily persisted over a 24-hour dosing interval, with the ratio between minimum and maximum systolic and diastolic blood pressure values ranging from 71% to 82%. The 24-hour efficacy of the drug was confirmed by ambulatory blood pressure monitoring.

The antihypertensive effect of Sevikar was independent of patient age and sex, as well as the presence of diabetes mellitus.

In two open-label, non-randomized, extended studies, sustained efficacy of Sevikar 40 mg/5 mg was demonstrated in 49–67% of patients after one year of treatment.

Olmesartan medoxomil (active substance of Sevikar)

Olmesartan medoxomil, contained in Sevikar, is a selective antagonist of angiotensin II type 1 (AT1) receptors. In the body, olmesartan medoxomil is rapidly converted into its 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 synthesis and release of aldosterone, promotes cardiac stimulation, and enhances 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 is independent of the source and pathway of angiotensin II synthesis. Selective antagonism of angiotensin II AT1 receptors leads to increased 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 induces a dose-dependent, prolonged reduction in blood 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.

When olmesartan medoxomil is administered once daily to patients with arterial hypertension, effective and smooth blood pressure reduction is achieved over the 24-hour dosing interval.

The antihypertensive effect was similar whether the drug was administered once or twice daily at the same total daily dose. Maximum blood pressure reduction is achieved after 8 weeks of treatment, although a significant antihypertensive effect is observed as early as 2 weeks after initiation of therapy.

The effect of olmesartan medoxomil on morbidity and mortality has not been established.

The Randomized Olmesartan for the Prevention of Diabetic Microalbuminuria (ROADMAP) trial, 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 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.

In the primary endpoint, the study demonstrated a significant reduction in the risk of time to onset of microalbuminuria in favor of olmesartan. After adjusting for differences in blood pressure (BP) values, this risk reduction was no longer statistically significant. Microalbuminuria developed in 8.2% (178 out of 2160) of patients in the olmesartan group and in 9.8% (210 out of 2139) 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 effects of olmesartan on renal and cardiovascular outcomes were evaluated in 577 randomized patients in Japan and China with type 2 diabetes and overt diabetic 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 in the placebo group (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 was 8 (2.8%) and 11 (3.9%), and non-fatal myocardial infarction was 3 (1.1%) and 7 (2.5%), respectively.

Amlodipine (active substance of Sevikar)

Amlodipine, contained in Sevikar, 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 arterial smooth muscle cells, leading to reduced peripheral vascular resistance and, consequently, reduced arterial pressure.

In arterial hypertension, amlodipine induces a dose-dependent, prolonged reduction in blood 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 administration in therapeutic doses, amlodipine effectively reduces blood pressure in supine, seated, 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 in therapeutic doses reduces renal vascular resistance and increases glomerular filtration rate and effective renal plasma flow without altering filtration fraction or causing proteinuria.

Hemodynamic studies in patients with heart failure and clinical studies with stress testing in patients with heart failure (NYHA classes II–IV) showed that amlodipine did not worsen the condition of study participants, as assessed by exercise tolerance, left ventricular ejection fraction, and 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 fatal outcomes or mortality and morbidity in patients with heart failure.

In a subsequent long-term placebo-controlled study (PRAISE-2) involving patients with heart failure (NYHA III and IV) without clinical 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 were no statistically significant differences in the frequency of worsening heart failure compared to placebo.

Preventive therapy of myocardial infarction (ALLHAT)

To compare modern therapeutic approaches, 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: amlodipine 2.5–10 mg/day (calcium channel blocker) or lisinopril 10–40 mg/day (ACE inhibitor) as first-line therapy versus the thiazide diuretic chlorthalidone 12.5–25 mg/day in mild to moderate hypertension. A total of 33,357 hypertensive patients aged 55 years and 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 other atherosclerotic cardiovascular diseases (51.5% total), type 2 diabetes (36.1%), LDL-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 was a composite of fatal CHD or non-fatal myocardial infarction. No significant differences in the primary endpoint between amlodipine and chlorthalidone therapy were observed: RR (RR 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 disease endpoint) was significantly higher in the amlodipine group compared to the chlorthalidone group (10.2% vs. 7.7%, RR 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 (RR 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 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 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 any significant beneficial effect on renal and/or cardiovascular outcomes or mortality, while an increased risk of hyperkalemia, acute kidney injury, and/or hypotension was observed compared to monotherapy. Given the similarity in 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 designed 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 prematurely due to an increased risk of adverse outcomes. Cardiovascular mortality and stroke events were more frequent in the aliskiren group than in the placebo group, and reports of adverse events and serious adverse events (hyperkalemia, arterial hypotension, and renal function impairment) were more frequent in the aliskiren group than in the placebo group.

Pharmacokinetics.

After oral administration of Sevikar, maximum plasma concentrations of olmesartan medoxomil and amlodipine are reached within 1.5–2 hours and 6–8 hours, respectively. The rate and extent of absorption of the two active substances in Sevikar correspond to their rate and extent of absorption when administered separately. The bioavailability of olmesartan medoxomil and amlodipine in the Sevikar formulation is independent of food intake.

Olmesartan medoxomil (active substance of Sevikar)

Absorption and distribution

Olmesartan medoxomil is a prodrug. It is rapidly converted into its 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 group are not detected in plasma or excreted products. The mean absolute bioavailability of olmesartan in tablet form is 25.6%.

The 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 the bioavailability of olmesartan; therefore, olmesartan medoxomil can be administered independently of food intake.

No clinically significant differences in the pharmacokinetics of olmesartan based on patient sex have been identified.

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 binds minimally 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 14C-labeled olmesartan medoxomil, 10–16% of the radioactive substance 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 the majority of olmesartan is excreted via 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 achieved after the first few doses, and no further accumulation occurs after 14 days of multiple dosing. Renal clearance is approximately 0.5–0.7 L/hour and is independent of drug dose.

Drug interactions

Bile acid-binding drug colesevelam

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 of 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 forms of interaction").

Amlodipine (active substance of Sevikar)

Absorption and distribution

After oral administration in therapeutic doses, amlodipine is well absorbed, with peak blood concentrations reached 6–12 hours after administration. Absolute bioavailability is approximately 64–80%. The volume of distribution is approximately 21 L/kg. In vitro studies have shown that nearly 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 after a single daily dose ranges from 35 to 50 hours. Amlodipine is extensively metabolized in the liver to inactive metabolites. Approximately 60% of the administered dose is excreted in urine, of which about 10% is unchanged amlodipine.

Olmesartan medoxomil and amlodipine (active substances of Sevikar)

Specific patient groups

Children (under 18 years of age)

Pharmacokinetic data in children are lacking.

Elderly patients (aged 65 years and older)

It has been demonstrated that in patients with arterial hypertension, the steady-state AUC (area under the concentration-time curve) of olmesartan increases by approximately 35% in elderly patients (aged 65–75 years) compared to younger patients and by approximately 44% in very elderly patients (≥ 75 years) (see section "Dosage and administration"). This can be explained by a moderate age-related decline in renal function in this patient group. 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 similar in older and younger patients. In elderly patients, there is a tendency toward reduced clearance of amlodipine, 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 expectations for this age group (see section "Special precautions").

Renal impairment

In patients with mild, moderate, and severe renal impairment, the steady-state AUC of olmesartan is 62%, 82%, and 179% higher, respectively, compared to healthy volunteers (see sections "Dosage and administration", "Special precautions").

Amlodipine is extensively metabolized to inactive metabolites. 10% 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 such patients. Amlodipine is not removed by hemodialysis.

Hepatic impairment

After a single oral dose, AUC values of 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 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").

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 is observed, leading to an increase in AUC of approximately 40–60% (see sections "Dosage and administration", "Special precautions").

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 after 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 dilation and diffuse thickening of the mucosa of the ileum and colon), adrenal gland changes (hypertrophy of glomerular zone cells and vacuolization of fascicular 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 Sevikar)

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, decreased heart weight, decreased erythrocyte parameters (erythrocyte count and hemoglobin, 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 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, results from comprehensive genotoxicity studies suggest that genotoxic effects of olmesartan are unlikely during clinical use.

No carcinogenic properties of olmesartan medoxomil were detected in a 2-year study in rats or a 6-month transgenic mouse carcinogenicity study.

In reproductive organ toxicity studies in rats, olmesartan medoxomil did not affect fertility and had no teratogenic effects. As with other angiotensin II receptor antagonists, offspring survival was reduced after exposure to olmesartan medoxomil, and female rats treated during late pregnancy and 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 effects.

Amlodipine (active substance of Sevikar)

Reproductive toxicity

Reproductive function studies in rats and mice revealed delayed delivery, prolonged labor, 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 (males for 64 days, females for 14 days before mating) receiving amlodipine at doses up to 10 mg/kg/day (8 times the maximum recommended human dose of 10 mg on a mg/m² basis assuming a 50 kg patient weight). In another study, male rats receiving amlodipine besylate for 30 days at doses comparable to the human dose on a mg/m² basis showed decreased plasma levels of follicle-stimulating hormone and testosterone, as well as reduced sperm density, decreased number of mature spermatids, and Sertoli cell changes.

Carcinogenesis, mutagenesis

Two-year carcinogenicity studies in rats and mice receiving amlodipine in the diet at concentrations calculated to provide doses of 0.5, 1.25, and 2.5 mg/kg/day did not reveal signs of carcinogenicity. The highest dose (equivalent in mice to the maximum recommended dose of 10 mg on a mg/m² basis 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.

Clinical characteristics.

Indications.

Treatment of essential hypertension.

Sevikar 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 any of the excipients (see section “Composition”).

− Pregnancy and planned pregnancy (see sections “Special precautions”, “Use in pregnancy or lactation”).

− Severe hepatic impairment and biliary obstruction (see section “Pharmacokinetics”).

− Concomitant use of Sevikar and medicinal products containing aliskiren is contraindicated in patients with diabetes or renal impairment (GFR < 60 mL/min/1.73 m²) (see sections “Interaction with other medicinal products and other forms of interaction”, “Pharmacodynamics”).

Due to the presence of amlodipine, Sevikar is also contraindicated in patients with:

− severe arterial hypotension;

− shock (including cardiogenic shock);

− left ventricular outflow tract obstruction (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 Sevikar

Caution is advised when co-administering

Other antihypertensive agents

The antihypertensive effect of Sevikar may be enhanced when used concomitantly with other antihypertensive drugs (e.g., alpha-blockers, diuretics).

Potential interactions related to the active substance olmesartan medoxomil in Sevikar

Concomitant use not recommended

ACE inhibitors, angiotensin II receptor blockers, or aliskiren

Clinical trial data show that dual blockade of the renin-angiotensin-aldosterone system (RAAS) by combining ACE inhibitors with angiotensin II receptor blockers or aliskiren increases the incidence of adverse events such as arterial hypotension, hyperkalemia, and impaired renal function (including acute renal failure), compared to using a single agent acting on the RAAS (see sections “Contraindications”, “Special precautions”, “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”). When prescribing such agents in combination with Sevikar, monitoring of serum potassium levels is recommended.

Lithium-containing preparations

Reversible increases in serum lithium concentration and lithium toxicity have been observed when lithium is used concomitantly with ACE inhibitors and, rarely, with angiotensin II receptor antagonists. Therefore, concomitant use of Sevikar and lithium preparations is not recommended (see section “Special precautions”). If concomitant use is necessary, regular monitoring of serum lithium levels is advised.

Co-administration requires caution

Nonsteroidal anti-inflammatory drugs (NSAIDs), including selective COX-2 inhibitors, acetylsalicylic acid (> 3 g/day), and non-selective NSAIDs

When angiotensin II antagonists are administered with NSAIDs, the antihypertensive effect may be attenuated. Additionally, concomitant use of angiotensin II antagonists and NSAIDs may increase the risk of worsening renal function and lead to increased serum potassium concentration. Therefore, regular assessment of renal function and adequate hydration of the patient are recommended during such combination therapy.

Cholestyramine, a bile acid-binding medicinal product

Concomitant administration of the bile acid-binding agent cholestyramine 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 cholestyramine hydrochloride reduces the interaction effect. Administration of olmesartan medoxomil at least 4 hours before cholestyramine hydrochloride should be considered (see section “Pharmacokinetics”).

Additional information

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

Olmesartan medoxomil has no significant effect on the pharmacokinetics and pharmacodynamics of warfarin or on the pharmacokinetics of digoxin. Concomitant administration of olmesartan medoxomil with pravastatin does not result in clinically significant changes in the pharmacokinetics of either drug 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 induction of cytochrome P450 activity has been observed in rats. Therefore, clinically significant interactions between olmesartan and medicinal products metabolized by the above-mentioned cytochrome P450 enzymes are not expected.

Potential interactions related to the active substance amlodipine in Sevikar

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 such pharmacokinetic changes may be more pronounced in elderly patients. There is an increased risk of hypotension. Careful monitoring of patients is recommended. Clinical observation and dose adjustment may be required.

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 when strong CYP3A4 inducers (such as rifampicin, St. John’s wort) are used.

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 leading to death were observed after administration of verapamil and intravenous dantrolene, due to the development of hyperkalemia. Given the risk of hyperkalemia in patients prone 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 that of other antihypertensive 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 increased the exposure to simvastatin by 77% compared to simvastatin alone. The daily dose of simvastatin should not exceed 20 mg in patients taking amlodipine.

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 is required, and dose adjustment may be necessary.

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. Concomitant use of amlodipine with mTOR inhibitors may increase the effects of mTOR inhibitors.

Cyclosporine

In a prospective clinical study in kidney transplant patients, co-administration of amlodipine with cyclosporine resulted in an average increase of 40% in the minimum blood concentration of cyclosporine. Concomitant use of Sevikar and cyclosporine may enhance the effect of cyclosporine. When used concomitantly with amlodipine, monitoring of the minimum cyclosporine blood concentration should be considered, and cyclosporine dosage may need to be 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 Sevikar 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 largely 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 levels is recommended in patients with renal impairment receiving Sevikar. Sevikar is not recommended in patients with severe renal impairment (creatinine clearance < 20 mL/min). Experience with Sevikar 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", "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 renal function deterioration (including acute renal failure). Therefore, dual RAAS blockade with concomitant use of ACE inhibitors, 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"). Sevikar 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 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. Sevikar 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 Sevikar, 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.

Sevikar should be used with caution when combined with potassium supplements, potassium-sparing diuretics, potassium-containing salt substitutes, or other medicinal products that may increase potassium levels (e.g., heparin); regular monitoring of serum potassium is recommended.

Lithium preparations

As with other angiotensin II receptor antagonists, concomitant use of Sevikar 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 Sevikar, as with all 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 inhibit the renin-angiotensin system. Therefore, use of Sevikar 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 ACE inhibitors and angiotensin II receptor antagonists may be associated with oliguria and/or progressive azotemia and (rarely) acute renal failure and/or death.

Treatment in patients with heart failure should be performed with caution. In a long-term placebo-controlled study of amlodipine in patients with severe heart failure (NYHA III and IV), the incidence of pulmonary edema was higher in the amlodipine group compared to placebo (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 future 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, likely due to 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 Sevikar 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

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

Pregnancy

Angiotensin II receptor antagonists are contraindicated during pregnancy.

If antihypertensive therapy is considered necessary, patients planning pregnancy should switch from angiotensin II receptor antagonists to alternative antihypertensive therapy with a proven safety profile during pregnancy. If pregnancy is diagnosed, treatment with angiotensin II receptor antagonists should be discontinued immediately and alternative therapy initiated if needed (see sections "Contraindications", "Use during pregnancy or breastfeeding").

Other

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

Sevikar contains less than 1 mmol of sodium (23 mg) per film-coated tablet and is therefore considered essentially sodium-free.

Use during pregnancy or breastfeeding.

Sevikar is contraindicated in pregnant women or women planning pregnancy (see sections "Contraindications", "Special precautions for use").

Pregnancy

Data on the use of Sevikar in pregnant women are lacking. Reproductive toxicity studies of Sevikar in animals have not been conducted.

Olmesartan medoxomil (active ingredient of Sevikar)

The use of angiotensin II receptor antagonists is contraindicated in pregnant women and women planning pregnancy (see sections "Contraindications", "Special precautions for use").

Epidemiological data on the teratogenic risk of ACE inhibitors in the first trimester of pregnancy do not allow definitive conclusions, but such risks cannot be entirely excluded. A similar risk for angiotensin II receptor antagonists is plausible, as controlled epidemiological studies on these drugs have not been conducted. Women planning pregnancy should switch to antihypertensive agents with a proven safety profile during pregnancy. If pregnancy is confirmed during treatment with angiotensin II receptor antagonists, such therapy should be discontinued immediately and alternative treatment initiated if needed.

During the second and third trimesters, angiotensin II receptor antagonists exert toxic effects on the fetus (impaired renal function, oligohydramnios, delayed skull ossification) and on the newborn (renal failure, arterial hypotension, hyperkalemia) (see section "Non-clinical 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", "Special precautions for use").

Amlodipine (active ingredient of Sevikar)

Data from limited observations in pregnant women do not indicate that amlodipine or other calcium channel blockers cause harmful effects on the fetus. However, there is a risk of prolonged duration of labor.

Breastfeeding

Olmesartan is excreted in 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 has been estimated at an interquartile range of 3–7% of the maternal dose, with a maximum of 15%. The effect of amlodipine on the infant is unknown.

Sevikar is not recommended during breastfeeding. Alternative therapies with a better-established safety profile during breastfeeding should be preferred, especially when breastfeeding newborns or preterm infants.

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 insufficient. Adverse effects on male fertility were observed in rat studies (see section "Non-clinical safety data").

Ability to affect reaction speed when driving or operating machinery.

Sevikar may have a slight or moderate influence on the ability to drive 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 Sevikar is 1 tablet daily.

Sevikar 20 mg/5 mg may be prescribed to patients who have shown an inadequate response to monotherapy with olmesartan medoxomil 20 mg or amlodipine 5 mg.

Sevikar 40 mg/5 mg may be prescribed to patients who have shown an inadequate response to treatment with Sevikar 20 mg/5 mg.

Sevikar 40 mg/10 mg may be prescribed to patients who have shown an inadequate response to treatment with Sevikar 40 mg/5 mg.

Prior to initiating fixed-dose combination therapy, stepwise dose titration of the individual components as monotherapies is recommended. If necessary, direct substitution of monotherapies with the fixed-dose combination product is possible.

For convenience, patients receiving olmesartan medoxomil and amlodipine as separate tablets may be switched to Sevikar tablets containing equivalent doses of these components.

Sevikar 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 daily), careful monitoring of arterial 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. Sevikar is not recommended in patients with severe renal impairment (creatinine clearance < 20 mL/min) (see sections "Special Warnings", "Pharmacokinetics").

In patients with moderate renal impairment receiving Sevikar, monitoring of serum potassium and creatinine concentrations is recommended.

Hepatic Impairment

Sevikar should be administered with caution in patients with mild to moderate hepatic impairment (see sections "Special Warnings", "Pharmacokinetics"). In patients with moderate hepatic impairment, the initial dose of olmesartan medoxomil should be 10 mg once daily. The maximum dose in such patients should not exceed 20 mg once daily. When co-administered with diuretics and/or other antihypertensive agents, careful monitoring of blood pressure and renal function is recommended in patients with hepatic impairment. 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, Sevikar should be used with caution in such patients. The pharmacokinetics of amlodipine have not been studied in patients with severe hepatic impairment. Amlodipine administration in patients with severe hepatic impairment should begin at the lowest dose with gradual dose escalation. Sevikar 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 must not be chewed. The medication should be taken daily at the same time.

Children

Safety and efficacy of Sevikar in children (under 18 years of age) have not been established. Data are lacking.

Overdose

Symptoms

No cases of Sevikar 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 hypotension and possibly reflex tachycardia. There have been reports of prolonged, severe generalized hypotension progressing 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 loading) to maintain perfusion and cardiac output may act as precipitating factors.

Treatment

If ingestion was recent, gastric lavage is indicated. In healthy volunteers, administration of activated charcoal immediately or within 2 hours after oral intake of amlodipine significantly reduces its absorption.

In case of clinically significant hypotension due to Sevikar overdose, active cardiovascular support is required, including careful monitoring of cardiac and respiratory function, elevation of the lower limbs, control 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 counteract calcium channel blockade.

Since amlodipine is highly protein-bound, elimination by dialysis is unlikely. There is no information available on the possibility of removing olmesartan by dialysis.

Adverse reactions.

The most commonly reported adverse reactions during administration of the medicinal product Sevikar were peripheral edema (11.3%), headache (5.3%), and dizziness (4.5%).

Adverse reactions observed during clinical trials and post-marketing safety studies, as well as spontaneously reported adverse reactions, are listed in the table below. Additionally, 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); frequency not known (cannot be estimated from the available data).

*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, temporally associated with the use of angiotensin II receptor blockers, have been reported. In patients receiving amlodipine, several cases of extrapyramidal syndrome have been reported.

Reporting of adverse reactions

Reporting of adverse reactions after marketing authorization is important. It allows ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, as well as 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.

Keep out of the reach of children.

Packaging.

14 film-coated tablets in a blister; 2 blisters in a cardboard pack.

Prescription status. Prescription only.

Manufacturer.

Daiichi Sankyo Europe GmbH.

Address of the manufacturer and location of its operations.

Luitpoldstraße 1, Pfaffenhofen a.d. Ilm, Bavaria, 85276, Germany.