Reverenza
Ukraine
Table of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT REVERANTZA (REVERANTZA)
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;
Excipients: microcrystalline cellulose, sodium croscarmellose, colloidal anhydrous silicon dioxide, magnesium stearate;
Film coating (20 mg/5 mg) contains: polyvinyl alcohol, partially hydrolyzed (E 1203), titanium dioxide (E 171), polyethylene glycol (E 1521), talc (E 553b).
Film coating (40 mg/5 mg) contains: polyvinyl alcohol, partially hydrolyzed (E 1203), titanium dioxide (E 171), polyethylene glycol (E 1521), talc (E 553b), iron oxide yellow (E 172).
Pharmaceutical form. Film-coated tablets.
Main physicochemical properties:
for dosage 20 mg/5 mg: white, round, biconvex, film-coated tablets, with "L" engraved on one side, smooth on the other, diameter 6.1 mm;
for dosage 40 mg/5 mg: yellow, round, biconvex, film-coated tablets, with "I" engraved on one side, smooth on the other, diameter 8.1 mm.
Pharmacotherapeutic group.
Cardiovascular system. Medicinal products affecting the renin-angiotensin system. Combinations of angiotensin II receptor blockers. Angiotensin II antagonists and calcium channel blockers. ATC code C09DB02.
Pharmacological properties.
Pharmacodynamics.
Revex 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 demonstrates a synergistic effect, resulting in greater reduction of arterial pressure than either component alone.
In an 8-week, double-blind, randomized, placebo-controlled factorial study involving 1940 patients (71% Caucasian and 29% other races), treatment with olmesartan medoxomil/amlodipine resulted in significantly greater reductions in diastolic and systolic blood pressure compared to monotherapy with either component alone. The mean reduction in systolic/diastolic blood pressure was dose-dependent: 24/14 mm Hg (20 mg/5 mg), 25/16 mm Hg (40 mg/5 mg).
Olmesartan medoxomil/amlodipine 40 mg/5 mg reduced seated systolic/diastolic blood pressure an additional 2.5/1.7 mm Hg compared to olmesartan medoxomil/amlodipine 20 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 diabetics) was 42.5%, 51%, and 0% for olmesartan medoxomil/amlodipine 20 mg/5 mg and 40 mg/5 mg, respectively.
The main antihypertensive effect of olmesartan medoxomil/amlodipine is typically 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 continuing to receive only olmesartan medoxomil 20 mg, systolic/diastolic blood pressure decreased by 10.6/7.8 mm Hg over the subsequent 8 weeks. Adding 5 mg amlodipine resulted in a reduction of systolic/diastolic blood pressure by 16.2/10.6 mm Hg 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 diabetics) was 44.5% for the combination 20 mg/5 mg compared to 28.5% for 20 mg olmesartan medoxomil alone.
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 continuing to receive 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 of systolic/diastolic blood pressure by 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 diabetics) was 29.9% in the amlodipine 5 mg monotherapy group, 53.5% for olmesartan medoxomil/amlodipine 20 mg/5 mg, and 50.5% for olmesartan medoxomil/amlodipine 40 mg/5 mg.
Randomized data comparing the outcomes of combination therapy with Revex at medium doses versus dose escalation of amlodipine or olmesartan medoxomil as monotherapy in patients with uncontrolled hypertension are lacking.
Results from three studies confirm that the antihypertensive effect of olmesartan medoxomil/amlodipine administered once daily is maintained over a 24-hour dosing interval, with the ratio of minimum to maximum systolic and diastolic blood pressure ranging from 71% to 82%. The 24-hour efficacy of the drug has been confirmed by ambulatory blood pressure monitoring.
The antihypertensive effect of olmesartan medoxomil/amlodipine is independent of age, sex, and the presence of diabetes mellitus.
In two open-label, non-randomized extension studies, sustained efficacy of olmesartan medoxomil/amlodipine 40 mg/5 mg was demonstrated in 49–67% of patients after one year of treatment.
Olmesartan medoxomil (active ingredient of Revex)
Olmesartan medoxomil, contained in Revex, 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 (RAAS) 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 causes a prolonged, dose-dependent 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 administered once daily to patients with arterial hypertension, olmesartan medoxomil provides effective and smooth blood pressure reduction over the 24-hour dosing interval.
The antihypertensive effect is similar whether the drug is administered once or twice daily at the same total daily dose. Maximum blood pressure reduction is achieved by 8 weeks after initiation of treatment, although a significant antihypertensive effect is observed as early as 2 weeks after starting therapy.
The effect of olmesartan medoxomil on morbidity and mortality has not been established.
A randomized study of olmesartan use for prevention of diabetic microalbuminuria (ROADMAP), involving 4447 patients with type 2 diabetes 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 median follow-up period of 3.2 years, patients received olmesartan or placebo in addition to other antihypertensive agents, except angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs).
The primary endpoint of the study demonstrated a significant reduction in the risk of time to onset of microalbuminuria in favor of olmesartan. After adjustment for differences in blood pressure, this risk reduction was no longer statistically significant. Microalbuminuria developed in 8.2% (178 of 2160) of patients in the olmesartan group and in 9.8% (210 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 trial (The Olmesartan Reducing Incidence of End-stage Renal Disease in Diabetic Nephropathy Trial), the effects of olmesartan on renal and cardiovascular outcomes were studied in 577 randomized patients in Japan and China with type 2 diabetes and overt nephropathy. During a median observation 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 was 8 (2.8%) and 11 (3.9%), and non-fatal myocardial infarction was 3 (1.1%) and 7 (2.5%), respectively.
Amlodipine (active ingredient of Revex)
Amlodipine, contained in Revex, is a calcium channel blocker that inhibits transmembrane influx of calcium ions 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 prolonged, dose-dependent 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 patients with arterial hypertension in supine, sitting, and standing positions. Long-term use of amlodipine is not associated with significant changes in heart rate or plasma catecholamine levels. In patients with arterial hypertension and normal renal function, amlodipine in therapeutic doses reduces renal vascular resistance and increases glomerular filtration rate (GFR) and effective renal plasma flow, without altering filtration fraction or causing proteinuria.
In hemodynamic studies in patients with heart failure and in clinical exercise testing studies in patients with heart failure (NYHA classes II–IV), 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 mortality or the combined risk of mortality and morbidity in patients with heart failure.
In a subsequent long-term, placebo-controlled study (PRAISE-2) involving patients with heart failure (NYHA classes 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 specifically. In this
group of patients, an increased incidence of pulmonary edema associated with amlodipine intake was observed, but there were no statistically significant differences in the frequency of worsening heart failure compared to placebo.
Preventive therapy of myocardial infarction (ALLHAT)
A double-blind, randomized study on morbidity and mortality called "Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial" (ALLHAT) was conducted to compare new antihypertensive therapies: amlodipine 2.5–10 mg daily (calcium channel blocker) or lisinopril 10–40 mg daily (ACE inhibitor) as first-line therapy versus the thiazide diuretic chlorthalidone 12.5–25 mg daily in mild to moderate arterial hypertension. All 33,357 patients with arterial hypertension aged 55 years or older were randomized and followed for a median of 4.9 years. Patients had at least one additional risk factor for ischemic heart disease (IHD), including prior myocardial infarction or stroke (more than 6 months before enrollment) or presence of other atherosclerotic cardiovascular diseases (CVD) (total 51.5%), type 2 diabetes (36.1%), high-density lipoprotein cholesterol (HDL-C) < 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 IHD or non-fatal myocardial infarction. No significant differences in the primary endpoint were observed between amlodipine and chlorthalidone therapy: 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 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 (OR 0.96, 95% CI [0.89–1.02], p = 0.20).
Other information
Combination therapy with ACE inhibitors and angiotensin receptor blockers (ARBs) was evaluated 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. The 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. Given the similarity of pharmacodynamic properties, these results are also applicable to other ACE inhibitors and ARBs.
Combination therapy with ACE inhibitors and ARBs 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 ARBs in patients with type 2 diabetes and chronic kidney disease, cardiovascular disease, or both. The study was prematurely terminated due to an increased risk of adverse outcomes. Cardiovascular mortality and incidence of
stroke were higher 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 Revex, maximum plasma concentrations (Cmax) 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 ingredients in Revex are consistent with their rate and extent of absorption when administered separately. The bioavailability of olmesartan medoxomil and amlodipine in Revex is not affected by food intake.
Olmesartan medoxomil (active ingredient of Revex)
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 group are not detected in plasma or excretory products. The mean absolute bioavailability of olmesartan as tablets is 25.6%.
The mean 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 independently of food intake.
No clinically significant differences in the pharmacokinetics of olmesartan based on sex have been observed.
Olmesartan is highly bound to plasma proteins (99.7%), but the risk of clinically significant competitive interactions with other highly protein-bound drugs is low, as evidenced by the lack of interaction between olmesartan medoxomil and warfarin. Olmesartan binds minimally to blood cells. The mean volume of distribution after intravenous administration is low (16–29 L).
Metabolism and elimination
The total plasma clearance of olmesartan is typically 1.3 L/hour (coefficient of variation 19%), which 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 excreted 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 dose.
Drug interactions
The drug 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 the area under the plasma concentration-time curve (AUC) for olmesartan. A smaller effect, with reductions in Cmax and AUC of 4% and 15%, 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 given 4 hours before colesevelam hydrochloride (see section "Interaction with other medicinal products and other types of interactions").
Amlodipine (active ingredient of Revex)
Absorption and distribution
After oral administration of therapeutic doses of amlodipine, it is well absorbed, with Cmax in blood reached within 6–12 hours. Absolute bioavailability 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 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 10% is unchanged.
Olmesartan medoxomil and amlodipine (active ingredients of Revex)
Special 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 arterial hypertension, the steady-state AUC of olmesartan in elderly patients (65–75 years) and very elderly patients (aged 75 years and older) is 35% and approximately 44% higher, respectively, compared to younger patients (see section "Method of administration and dosage"). This can be explained by the presence of moderate renal impairment in these patients. However, the same dosage regimen is recommended for elderly patients as for other patients, although dose escalation should be done with caution.
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 correspond to predictions for patients in this age group (see section "Special considerations").
Renal impairment
In patients with impaired renal function, 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 "Special considerations", "Method of administration and dosage").
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 patients with mild or moderate hepatic impairment was 0.26%, 0.34%, and 0.41%, respectively. With multiple dosing, 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 "Special considerations", "Method of administration and dosage").
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 by approximately 40–60% (see sections "Special considerations", "Method of administration and dosage").
Preclinical safety data
Based on the preclinical toxicity profile of each active ingredient, 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 dilation 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 supplement 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 ingredient of Revex)
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), histological signs of kidney damage (regenerative lesions of renal epithelium, thickening of the basal 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 intake 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 testing data suggest 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 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 did not exert fetotoxic effects.
Amlodipine (active ingredient of Revex)
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).
Impairment of fertility
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, calculated on a mg/m2 basis). In another study, in which male rats received amlodipine besylate for 30 days at doses comparable to the human dose on a mg/m2 basis, decreased plasma levels of follicle-stimulating hormone and testosterone, reduced sperm density, and decreased numbers of mature spermatids and Sertoli cells were observed.
Carcinogenesis, mutagenesis
Two-year carcinogenicity studies in rats and mice receiving amlodipine in the diet 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 in mice to the maximum recommended dose of 10 mg on a mg/m2 basis, and in rats twice the maximum recommended dose) was close to the maximum tolerated dose in mice but not in rats.
Mutagenicity studies did not reveal any drug-related effects at the gene or chromosome level.
*Assuming a patient body weight of 50 kg.
Clinical characteristics.
Indications.
Treatment of essential hypertension.
The medicinal product Revranza is indicated for patients in whom monotherapy with olmesartan medoxomil or amlodipine does not provide adequate blood pressure control (see sections "Pharmacodynamics", "Method of administration and dosage").
Contraindications.
Hypersensitivity to the active substances, dihydropyridine derivatives, or to any of the excipients of the medicinal product.
− Pregnancy and planned pregnancy (see sections "Special precautions", "Use during pregnancy or breastfeeding").
− Severe hepatic impairment and biliary obstruction (see section "Pharmacokinetics").
− Concomitant use of Revranza and medicinal products containing aliskiren is contraindicated in patients with diabetes mellitus or renal impairment (eGFR < 60 mL/min/1.73 m²) (see sections "Pharmacodynamics", "Interaction with other medicinal products and other forms of interaction").
Due to the presence of amlodipine, Revranza is also contraindicated in patients with:
− severe arterial hypotension;
− shock (including cardiogenic shock);
− obstructed 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 Revranza
Caution should be exercised when co-administering
Other antihypertensive agents
The antihypertensive effect of Revranza may be enhanced when used concomitantly with other antihypertensive medicinal products (e.g., alpha-blockers, diuretics).
Potential interactions related to the active substance olmesartan medoxomil in Revranza
Concomitant use is not recommended
ACE inhibitors, angiotensin II receptor blockers, or aliskiren
Clinical trial data show that dual blockade of the RAAS by combining ACE inhibitors with angiotensin II receptor blockers or aliskiren is associated with an increased incidence of adverse reactions 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 "Pharmacodynamics", "Contraindications", "Special precautions").
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 medicinal products affecting potassium levels in combination with Revranza, monitoring of serum potassium concentration is recommended.
Lithium preparations
Rare cases of reversible increases in serum lithium concentrations and lithium toxicity have been reported when lithium is used concomitantly with ACE inhibitors or angiotensin II receptor antagonists. Therefore, concomitant use of Revranza and lithium preparations is not recommended (see section "Special precautions"). If concomitant use of Revranza and lithium preparations is necessary, regular monitoring of serum lithium levels is recommended.
Co-administration 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 administered together with NSAIDs, the antihypertensive effect may be diminished. Furthermore, concomitant use of angiotensin II antagonists and NSAIDs may increase the risk of impaired renal function and lead to increased serum potassium concentration. Therefore, during such combination therapy, renal function should be regularly assessed and adequate hydration of the patient maintained.
Bile acid-binding medicinal product colesevelam
Concomitant use of the bile acid-binding agent colesevelam hydrochloride reduces systemic exposure and Cmax of olmesartan in plasma and shortens 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 reduction in bioavailability of olmesartan medoxomil has been observed after treatment with antacids (magnesium hydroxide and aluminium hydroxide).
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 was observed in vitro, and minimal or no induction of rat cytochrome P450 activity was recorded. 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 Revranza
Effect 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 arterial hypotension. Clinical manifestations of such pharmacokinetic changes may be more pronounced in elderly patients. There is an increased risk of arterial hypotension. Careful monitoring of patients is recommended. Clinical observation and dose adjustment may be required.
CYP3A4 inducers
Plasma concentrations of amlodipine may vary when used concomitantly with known CYP3A4 inducers. Therefore, blood pressure should be monitored and dosage adjusted both during and after concomitant therapy, especially when used with strong CYP3A4 inducers (such as rifampicin, St. John’s wort).
Consumption of amlodipine with grapefruit or grapefruit juice is not recommended, as it may increase the bioavailability of the drug in some patients, resulting in enhanced hypotensive effect.
Dantrolene (infusion)
In laboratory animal studies, ventricular fibrillation and cardiovascular collapse with fatal outcome were observed after administration of verapamil and intravenous dantrolene, associated with the development of hyperkalaemia. Due to the risk of hyperkalaemia in patients predisposed to malignant hyperthermia, as well as during treatment of malignant hyperthermia, concomitant use of calcium channel blockers such as amlodipine should be avoided.
Effect of amlodipine on other medicinal products
The antihypertensive effect of amlodipine is additive to the antihypertensive effects 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 simvastatin dose in patients taking amlodipine should not exceed 20 mg daily.
Tacrolimus
There is a risk of increased blood levels of tacrolimus when used concomitantly with amlodipine. To avoid tacrolimus toxicity, regular monitoring of tacrolimus blood levels is required when used concomitantly with amlodipine, and dose adjustment may be necessary.
Cyclosporine
In a prospective clinical study involving kidney transplant patients, co-administration of amlodipine with cyclosporine resulted in an average 40% increase in the minimum (trough) blood concentration of cyclosporine. Concomitant use of Revranza and cyclosporine may enhance the effect of cyclosporine. When used concomitantly with amlodipine, monitoring of the minimum (trough) blood concentration of cyclosporine should be considered, and the cyclosporine dose may need to be reduced if necessary.
Special precautions for use.
Patients with hypovolemia or sodium deficiency
In patients with hypovolemia and/or hyponatremia resulting from intensive diuretic therapy, dietary salt restriction, diarrhea, or vomiting, symptomatic hypotension may occur, especially after the first dose. It is recommended to correct this condition prior to initiating treatment with Revexanza or to ensure close medical supervision at the beginning of therapy.
Other conditions associated with activation of the RAAS
Patients in whom vascular tone and renal function are highly dependent on the activity of the renin-angiotensin-aldosterone system (RAAS) (e.g., patients with severe congestive heart failure or renal disease, including renal artery stenosis) may respond to other drugs affecting this system (such as angiotensin II receptor antagonists) with acute arterial hypotension, azotemia, oliguria, and rarely, acute renal failure.
Renovascular hypertension
There is an increased risk of severe arterial hypotension and renal failure in patients with bilateral renal artery stenosis or stenosis of the artery of a single functioning kidney when using drugs affecting the RAAS.
Renal function impairment and kidney transplantation
Periodic monitoring of serum potassium and creatinine levels is recommended in patients with renal impairment treated with Revexanza. Revexanza is not recommended in patients with severe renal impairment (creatinine clearance < 20 mL/min). There is no experience with the use of Revexanza in patients who have recently undergone kidney transplantation or in patients with end-stage renal disease (e.g., creatinine clearance < 12 mL/min) (see sections "Pharmacokinetics", "Dosage and administration").
Dual blockade of the RAAS
Concomitant use of ACE inhibitors, angiotensin II receptor blockers, or aliskiren has been reported to increase the risk of arterial hypotension, hyperkalemia, and impaired renal function (including acute renal failure). Therefore, dual blockade of the RAAS by combining ACE inhibitors with angiotensin II receptor blockers or aliskiren is not recommended (see section "Interaction with other medicinal products and other forms of interaction").
If dual blockade is considered absolutely necessary, it should be performed only under specialist supervision with close monitoring of renal function, electrolyte levels, and blood pressure.
ACE inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy.
Hepatic impairment
Exposure to amlodipine and olmesartan medoxomil is increased in patients with hepatic impairment (see section "Pharmacokinetics"). Revexanza 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. Revexanza is contraindicated in patients with severe hepatic impairment (see section "Contraindications").
Intestinal angioedema
Cases of intestinal angioedema have been reported in patients treated with angiotensin II receptor antagonists (see section "Adverse reactions"). These patients presented with abdominal pain, nausea, vomiting, and diarrhea. Symptoms resolved after discontinuation of angiotensin II receptor antagonists. If intestinal angioedema is diagnosed, Revexanza should be discontinued and appropriate monitoring initiated until symptoms completely resolve.
Hyperkalemia
As with other angiotensin II antagonists and ACE inhibitors, hyperkalemia may occur during treatment with Revexanza, 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.
Revexanza 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), and regular monitoring of serum potassium is recommended.
Lithium
As with other angiotensin II antagonists, concomitant use of Revexanza and lithium is not recommended (see section "Interaction with other medicinal products and other forms of interaction").
Aortic or mitral valve stenosis; obstructive hypertrophic cardiomyopathy
As with all vasodilators, particular caution is advised when prescribing Revexanza to patients with aortic or mitral valve stenosis or obstructive hypertrophic cardiomyopathy due to the presence of amlodipine in the formulation.
Primary hyperaldosteronism
Patients with primary hyperaldosteronism generally do not respond to antihypertensive drugs that suppress the renin-angiotensin system. Therefore, use of Revexanza is not recommended in these patients.
Heart failure
Due to suppression of the angiotensin-aldosterone system, renal function may be impaired in susceptible patients. In patients with severe heart failure, in whom renal function may depend on RAAS activity, treatment with ACE inhibitors and angiotensin II receptor antagonists may be associated with oliguria and/or progressive azotemia, rarely acute renal failure and/or death.
Patients with heart failure should be treated with caution. In a long-term placebo-controlled study of amlodipine in patients with severe heart failure (NYHA class 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 drugs may increase the risk of cardiovascular adverse reactions and mortality.
Sprue-like enteropathy
In very rare cases, 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 biopsies in such patients often show villous atrophy. If these symptoms occur in a patient during treatment with olmesartan 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, consultation with an appropriate specialist (e.g., a gastroenterologist) should be considered.
Ethnic differences
As with other angiotensin II receptor antagonists, the antihypertensive effect of Revexanza may be somewhat less in black patients compared to patients of other races, 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 antagonists are contraindicated during pregnancy. If treatment with angiotensin II antagonists must be continued and the patient plans pregnancy, alternative antihypertensive agents with a well-established safety profile during pregnancy should be used. If pregnancy is confirmed during treatment with angiotensin II antagonists, treatment should be discontinued immediately and, if necessary, replaced with another medicinal product (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.
Revexanza 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.
Pregnancy (see section "Contraindications").
There are no data on the use of Revexanza in pregnant women. Reproductive toxicity studies of Revexanza in animals have not been conducted.
Olmesartan medoxomil (active ingredient of Revexanza)
The use of angiotensin II 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 during the first trimester of pregnancy do not allow definitive conclusions, but such risks cannot be entirely excluded. A similar risk may be assumed for angiotensin II receptor antagonists, as controlled epidemiological studies have not been conducted. If treatment with angiotensin II antagonists must be continued and the patient plans pregnancy, alternative antihypertensive agents with a well-established safety profile during pregnancy should be used. If pregnancy is confirmed during treatment with angiotensin II antagonists, treatment should be discontinued immediately and, if necessary, replaced with another medicinal product.
During the second and third trimesters of pregnancy, angiotensin II receptor antagonists have toxic effects on the fetus (impaired renal function, oligohydramnios, delayed skull ossification) and the newborn (renal failure, arterial hypotension, hyperkalemia) (see section "Preclinical safety data").
If angiotensin II receptor antagonists are taken 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 Revexanza)
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 labor.
Given the above, Revexanza is not recommended during the first trimester of pregnancy and is contraindicated during the second and third trimesters (see sections "Contraindications", "Special precautions for use").
Lactation
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 to the maternal dose has been estimated at 3–7% (interquartile range), with a maximum of 15%. The effect of amlodipine on the infant is unknown.
Revexanza 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
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 "Preclinical safety data").
Ability to affect reaction speed when driving or operating machinery.
Revexanza may have a minor or moderate influence on the ability to drive and operate machinery.
Dizziness, headache, nausea, or fatigue may occasionally occur in patients receiving antihypertensive therapy, which may impair reaction ability. Caution is advised, especially at the beginning of treatment.
Method of Administration and Dosage
Adults
The recommended dose of Revanza is 1 tablet per day.
Revanza 20/5 may be prescribed to patients who have an inadequate response to monotherapy with olmesartan medoxomil 20 mg or amlodipine 5 mg.
Revanza 40/5 may be prescribed to patients who have an inadequate response to Revanza 20/5.
Prior to initiating fixed-dose combination therapy, stepwise titration of the individual components as monotherapies is recommended. 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 Revanza tablets containing equivalent doses of these components.
Revanza 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 "Pharmacokinetics", "Special Warnings and Precautions for Use").
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. Revanza is not recommended in patients with severe renal impairment (creatinine clearance < 20 mL/min) (see sections "Pharmacokinetics", "Special Warnings and Precautions for Use").
In patients with moderate renal impairment receiving Revanza, monitoring of serum potassium and creatinine concentrations is recommended.
Hepatic Impairment
Revanza should be used with caution in patients with mild to moderate hepatic impairment (see sections "Pharmacokinetics", "Special Warnings and Precautions for Use"). 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 concomitant therapy with diuretics and/or other antihypertensive agents is used, careful monitoring of blood pressure and renal function is recommended in patients with hepatic impairment. There is no experience with olmesartan medoxomil in patients with severe hepatic impairment.
As with all calcium antagonists, the elimination half-life of amlodipine is prolonged in patients with hepatic dysfunction; dosage recommendations have not been established. Therefore, Revanza should be administered with caution in such patients. The pharmacokinetics of amlodipine in patients with severe hepatic impairment have not been studied. Amlodipine therapy in patients with severe hepatic impairment should be initiated at the lowest dose with gradual dose escalation. Revanza is contraindicated in patients with severe hepatic impairment (see section "Contraindications").
Method of Administration
Tablets should be swallowed whole with sufficient fluid (e.g., a glass of water). Tablets should not be chewed. The medication should be taken daily at the same time.
Children
Safety and efficacy of Revanza in children and adolescents (under 18 years of age) have not been established. Data are lacking.
Overdose
Symptoms
There is no experience with overdose of the olmesartan medoxomil/amlodipine combination. The most likely consequences of olmesartan medoxomil overdose are arterial hypotension and tachycardia; bradycardia may occur if parasympathetic (vagal) stimulation takes place.
Overdose of amlodipine is expected to result in excessive peripheral vasodilation leading to marked hypotension and possibly reflex tachycardia. Marked and potentially prolonged systemic arterial hypotension, up to and including shock with fatal outcome, has been reported.
Rare cases of non-cardiogenic pulmonary edema following amlodipine overdose have been reported, which may present with delayed onset (24–48 hours after ingestion) and may require mechanical ventilation. Early resuscitative measures (including fluid loading) aimed at supporting perfusion and cardiac output may act as triggering 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 its absorption.
In the event of clinically significant arterial hypotension due to Revanza overdose, active cardiovascular support is required, including careful monitoring of cardiac and pulmonary function, elevation of the lower extremities, control of circulating blood volume, and diuresis. Vasopressor agents may be useful to restore vascular tone and blood pressure, provided there are no contraindications.
To reverse calcium channel blockade, intravenous calcium gluconate is recommended.
Since amlodipine is highly protein-bound, elimination by dialysis is unlikely. Information on the possibility of removing olmesartan by dialysis is lacking.
Adverse reactions
The most commonly reported adverse reactions during administration of Revolenta were peripheral edema (11.3%), headache (5.3%), and dizziness (4.5%).
Adverse reactions observed during clinical studies and post-marketing safety monitoring, as well as spontaneously reported adverse reactions, are listed in the table below. Additionally, the table includes adverse reactions reported with each of the active components of the medicinal product administered separately (olmesartan medoxomil and amlodipine), taking into account their established safety profiles.
Adverse reactions are listed by system organ class and frequency as follows: 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).
| MedDRA Organ Systems |
Adverse Reaction |
Frequency |
||
| Olmesartan/amlodipine combination |
Olmesartan |
Amlodipine |
||
| Blood and lymphatic system disorders |
leukopenia |
very rare |
||
| thrombocytopenia |
uncommon |
very rare |
||
| Immune system disorders |
allergic reaction/hypersensitivity to the drug |
uncommon |
very rare |
|
| anaphylactic reaction |
uncommon |
|||
| Metabolism and nutrition disorders |
hyperglycemia |
very rare |
||
| hyperkalemia |
uncommon |
rare |
||
| hypertriglyceridemia |
common |
|||
| hyperuricemia |
common |
|||
| Psychiatric disorders |
confusion |
uncommon |
||
| depression |
uncommon |
|||
| insomnia |
uncommon |
|||
| irritability |
uncommon |
|||
| decreased libido |
uncommon |
|||
| mood changes (including anxiety) |
uncommon |
|||
| Nervous system disorders |
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 disorder |
uncommon |
|||
| drowsiness |
rare |
common |
||
| loss of consciousness |
rare |
uncommon |
||
| tremor |
uncommon |
|||
| extrapyramidal disorders |
frequency unknown |
|||
| Eye disorders |
visual disturbances (including diplopia) |
common |
||
| Ear and labyrinth disorders |
tinnitus |
uncommon |
||
| dizziness |
uncommon |
uncommon |
||
| Cardiac disorders |
angina pectoris |
uncommon |
uncommon (including angina exacerbation) |
|
| arrhythmia (including bradycardia, ventricular tachycardia, atrial fibrillation) |
uncommon |
|||
| myocardial infarction |
very rare |
|||
| palpitations |
uncommon |
common |
||
| tachycardia |
uncommon |
|||
| Vascular disorders |
arterial hypotension |
uncommon |
rare |
uncommon |
| orthostatic hypotension |
uncommon |
|||
| flushing |
rare |
common |
||
| vasculitis |
very rare |
|||
| Respiratory system disorders |
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 |
|
| intestinal angioedema |
uncommon |
|||
| coeliac-like enteropathy (see section "Special warnings and precautions") |
very rare |
|||
| Hepatobiliary disorders |
elevated liver enzymes |
common |
very rare (mostly in the context of cholestasis) |
|
| hepatitis |
very rare |
|||
| jaundice |
very rare |
|||
| autoimmune hepatitis* |
frequency unknown |
|||
| Skin and subcutaneous tissue disorders |
alopecia |
uncommon |
||
| angioedema |
uncommon |
very rare |
||
| allergic dermatitis |
uncommon |
|||
| polymorphic erythema |
very rare |
|||
| exanthema |
uncommon |
uncommon |
||
| exfoliative dermatitis |
very rare |
|||
| increased sweating |
uncommon |
|||
| photosensitization |
very rare |
|||
| pruritus |
uncommon |
uncommon |
||
| hemorrhagic rash |
uncommon |
|||
| Quincke's edema |
very rare |
|||
| rash |
uncommon |
uncommon |
uncommon |
|
| skin discoloration |
uncommon |
|||
| Stevens-Johnson syndrome |
very rare |
|||
| toxic epidermal necrolysis |
frequency unknown |
|||
| urticaria |
rare |
uncommon |
uncommon |
|
| Musculoskeletal and connective tissue disorders |
calf swelling |
common |
||
| arthralgia |
uncommon |
|||
| arthritis |
common |
|||
| back pain |
uncommon |
common |
uncommon |
|
| muscle spasm |
uncommon |
rare |
common |
|
| myalgia |
uncommon |
uncommon |
||
| limb pain |
uncommon |
|||
| bone pain |
common |
|||
| Renal and urinary disorders |
acute renal failure |
uncommon |
||
| hematuria |
common |
|||
| increased urinary frequency |
uncommon |
|||
| urinary disorder |
uncommon |
|||
| nocturia |
uncommon |
|||
| polyuria |
uncommon |
|||
| renal failure |
uncommon |
|||
| urinary tract infections |
common |
|||
| Reproductive system and breast disorders |
erectile dysfunction/ impotence |
uncommon |
uncommon |
|
| gynecomastia |
uncommon |
|||
| General disorders and administration site conditions |
asthenia |
uncommon |
uncommon |
common |
| chest pain |
common |
uncommon |
||
| facial swelling |
rare |
uncommon |
||
| fatigue |
common |
common |
common |
|
| influenza-like illness |
common |
|||
| drowsiness |
rare |
|||
| malaise |
uncommon |
uncommon |
||
| edema |
common |
very common |
||
| pain |
common |
uncommon |
||
| peripheral edema |
common |
common |
||
| soft tissue swelling |
common |
|||
| Investigations |
increased blood creatinine |
uncommon |
rare |
|
| increased blood creatine phosphokinase |
common |
|||
| decreased blood potassium |
uncommon |
|||
| increased blood urea |
common |
|||
| increased blood uric acid |
uncommon |
|||
| increased blood gamma-glutamyltransferase |
uncommon |
|||
| decreased body weight |
uncommon |
|||
| increased body weight |
uncommon |
|||
*During the post-marketing period, cases of autoimmune hepatitis with a latent period ranging from several months to several years have been reported, which were reversible upon discontinuation of olmesartan.
There have been several reports of rhabdomyolysis occurring temporally in association with angiotensin II receptor blockers. In patients taking amlodipine, there have been several cases of extrapyramidal syndrome reported.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after medicine authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicine. Healthcare and pharmacy professionals, as well as patients or their legal representatives, are encouraged to 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.
Store at a temperature not exceeding 30 °C.
Keep out of reach and sight of children.
Packaging.
14 film-coated tablets in a blister; 2 blisters in a cardboard box.
Prescription status. Prescription only.
Manufacturer: JSC "Chaikapharma High-Quality Medicines".
Manufacturer's address and location of its business activity.
1172, Sofia, 1 G. M. Dimitrov Blvd., Bulgaria.