Olmesar 40
UkraineTable of Contents
INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT
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Olmesar 10 / Olmesar 10 Olmesar 20 / Olmesar 20 Olmesar 40 / Olmesar 40 Composition: Active substance: olmesartan medoxomil; 1 film-coated tablet contains olmesartan medoxomil 10 mg(mg)/ 20 mg(mg)/ 40 mg(mg); Excipients: microcrystalline cellulose; lactose monohydrate; hydroxypropylcellulose; magnesium stearate; colloidal anhydrous silicon dioxide; sodium starch glycolate (type B); coating «Instacoat Universal White A05G10022»: hypromellose, hydroxypropylcellulose, talc, titanium dioxide (E 171). Pharmaceutical form. Film-coated tablets. Main physicochemical properties: tablets 10 mg: white, round, biconvex film-coated tablets with an engraving "С 52" on one side and smooth on the other side; tablets 20 mg: white, round, biconvex film-coated tablets with an engraving "C 53" on one side and smooth on the other side; tablets 40 mg: white, oval, biconvex film-coated tablets with an engraving "С 54" on one side and smooth on the other side. Pharmacotherapeutic group. Angiotensin II antagonists. ATC code C09CA08. Pharmacological properties Pharmacodynamics. Olmesartan medoxomil is a selective blocker of angiotensin II receptors (type AT1), intended for oral administration. Angiotensin II is the main vasoactive hormone of the renin-angiotensin-aldosterone system, which plays an important role in the pathophysiology of arterial hypertension. It causes vasoconstriction, induces synthesis and secretion of aldosterone, stimulates cardiac activity and renal sodium reabsorption. Olmesartan inhibits the effects of angiotensin II directed at vasoconstriction and aldosterone secretion by blocking AT1-receptors in tissues, including vascular smooth muscle and adrenal glands. The action of olmesartan does not depend on the source or pathway of angiotensin II synthesis. Selective binding of olmesartan to angiotensin II AT1-receptors leads to an increase in plasma renin levels and concentrations of angiotensin I and angiotensin II, as well as to a certain decrease in plasma aldosterone concentration. In patients with arterial hypertension, olmesartan medoxomil provides a sustained reduction in blood pressure, the extent of which depends on the dose. No signs of arterial hypotension after the first dose (first-dose effect), tachyphylaxis during prolonged use, or rebound arterial hypertension after abrupt discontinuation of the drug were observed. Once-daily administration of olmesartan medoxomil provides effective and gentle reduction of blood pressure over 24 hours until the next dose. When administered once daily, its antihypertensive effect was approximately the same as when administered twice daily at the same daily dose. With continuous treatment, maximum reduction in blood pressure is achieved within 8 weeks after the start of therapy; while a significant antihypertensive effect is observed as early as 2 weeks after treatment initiation. The effect of olmesartan medoxomil on mortality and frequency of complications has not been established. The randomized trial of olmesartan use and prevention of diabetic microalbuminuria (ROADMAP), involving 4447 patients with type 2 diabetes with normal albuminuria levels and at least one additional cardiovascular risk factor, was conducted to determine whether olmesartan therapy could delay the onset of microalbuminuria. During a mean follow-up period of 3.2 years, patients received olmesartan or placebo in addition to other antihypertensive agents, except for ACE inhibitors or ARBs. In the primary endpoint of the study, a significant reduction in the risk of microalbuminuria development was demonstrated with olmesartan use. After adjusting for differences in blood pressure 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. The rate of cardiovascular mortality was higher in the olmesartan group than in 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 in the olmesartan group was numerically higher (26 patients (1.2%) vs. 15 patients (0.7%)), mainly due to higher cardiovascular mortality. In the ORIENT trial (The Olmesartan Reducing Incidence of End-stage Renal Disease in Diabetic Nephropathy Trial), the effect of olmesartan on renal and cardiovascular outcomes was studied in 577 randomized patients in Japan and China with type 2 diabetes and overt nephropathy. During a mean follow-up period of 3.1 years, patients received olmesartan or placebo in addition to other antihypertensive agents, including ACE inhibitors. The primary composite endpoint (time to first occurrence of doubling of serum creatinine, end-stage renal disease, or death from any cause) was reached in 116 patients in the olmesartan group (41.1%) and in 129 patients receiving placebo (45.4%) (HR 0.97 (95% CI 0.75–1.24); p = 0.791). The secondary composite cardiovascular endpoint was reached in 40 patients receiving olmesartan (14.2%) and in 53 patients receiving placebo (18.7%). This composite cardiovascular endpoint included cardiovascular mortality in 10 (3.5%) patients receiving olmesartan and 3 (1.1%) receiving placebo; overall mortality was 19 (6.7%) and 20 (7.0%), non-fatal stroke was 8 (2.8%) and 11 (3.9%), non-fatal myocardial infarction was 3 (1.1%) and 7 (2.5%), respectively. Pharmacokinetics. 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 in portal blood during absorption from the gastrointestinal tract. Unhydrolyzed olmesartan medoxomil or unchanged medoxomil side chain group were not detected in plasma or excretions. The mean absolute bioavailability of olmesartan in tablet form is 25.6%. The mean peak plasma concentration (Cmax) of olmesartan medoxomil is reached approximately 2 hours after oral administration, and its plasma concentration increases almost linearly with increasing single oral doses up to 80 mg. Food has practically no effect on olmesartan bioavailability; therefore, olmesartan medoxomil can be administered regardless of food intake. No clinically significant gender-related differences in olmesartan pharmacokinetics were observed. Protein binding of olmesartan medoxomil in plasma is 99.7%, but the potential for clinically significant displacement from protein binding due to interaction with other highly protein-bound drugs is low (this is confirmed by the absence of clinically significant interaction between olmesartan medoxomil and warfarin). Binding of olmesartan to blood cells is negligible. The mean volume of distribution after intravenous administration is small (16–29 L). Metabolism and elimination . Total plasma clearance was generally 1.3 L/h (coefficient of variation (CV) 19%) and was relatively slow compared to hepatic blood flow (approximately 90 L/h). After administration of a single oral dose of 14C-labeled olmesartan medoxomil, 10–16% of the administered radioactivity was excreted in urine (mostly within 24 hours after dosing), and the remainder of recovered radioactivity was excreted in feces. Based on systemic availability of 25.6%, it can be calculated that absorbed olmesartan is eliminated both by the kidneys (approximately 40%) and via the liver and biliary tract (approximately 60%). All recovered radioactivity was identified as olmesartan. No significant metabolites were detected. Enterohepatic recirculation of olmesartan is minimal. The terminal half-life of olmesartan ranged from 10 to 15 hours after multiple oral doses. Steady state was achieved after the first few doses. No accumulation was observed after 14 days of repeated administration. Renal clearance was approximately 0.5–0.7 L/h and was independent of dose. Pharmacokinetics in special populations Children . Pharmacokinetics of olmesartan were studied in children with hypertension aged 1 to 16 years. Olmesartan clearance in pediatric patients was similar to that in adults when adjusted for body weight. There is no pharmacokinetic information available for children with renal impairment. Elderly people (aged 65 years and older). In patients with arterial hypertension, the area under the concentration-time curve (AUC) at steady state increased by approximately 35% in patients aged 65–75 years and by approximately 44% in patients aged 75 years and older compared to younger patients. This may at least be related to reduced renal function in this patient group. Renal function impairment. In patients with mild, moderate, and severe renal impairment, steady-state AUC increased by 62%, 82%, and 179%, respectively, compared to healthy volunteers. Hepatic function impairment. After single oral administration, AUC values of olmesartan in patients with mild and moderate hepatic impairment were 6% and 65% higher, respectively, than in healthy volunteers. After repeated administration in patients with moderate hepatic impairment, olmesartan AUC was 65% higher than in healthy volunteers. Mean Cmax values of olmesartan were similar in patients with hepatic impairment and healthy volunteers. The effect of olmesartan medoxomil has not been evaluated in patients with severe hepatic impairment. Clinical characteristics. Indications. For treatment:
Contraindications.
Special precautions. Reduction in intravascular blood volume In patients with circulatory blood volume and/or sodium imbalance due to treatment with high-dose diuretics, dietary salt restriction, or diarrhea and/or vomiting, symptomatic hypotension may develop, mainly after the first dose of the drug. Possible hypovolemia should be corrected before starting olmesartan medoxomil therapy. Other conditions with stimulation of the renin-angiotensin-aldosterone system In patients whose vascular tone and renal function primarily depend on the activity of the renin-angiotensin-aldosterone system (e.g., patients with congestive heart failure or underlying kidney disease, including renal artery stenosis), treatment with other drugs affecting this system has led to acute arterial hypotension, azotemia, oliguria, and rarely acute renal failure. Such outcomes cannot be excluded with angiotensin II receptor antagonists. Renovascular hypertension There is an increased risk of severe arterial hypotension and renal failure when drugs affecting the renin-angiotensin-aldosterone system are administered to patients with bilateral renal artery stenosis or stenosis of the artery of a single functioning kidney. Renal function impairment and kidney transplantation When administering olmesartan medoxomil to patients with renal impairment, monitoring of serum potassium and creatinine levels is recommended. Olmesartan medoxomil is not recommended in patients with severe renal impairment (creatinine clearance < 20 mL/min). There is no experience with olmesartan medoxomil in patients who have recently undergone kidney transplantation or in patients with end-stage renal disease (creatinine clearance < 12 mL/min). Hepatic function impairment There is no experience with olmesartan medoxomil in patients with severe hepatic impairment; therefore, its use is not recommended in this patient group. Hyperkalemia Use of drugs affecting the renin-angiotensin-aldosterone system may cause hyperkalemia. The risk of hyperkalemia, which may be fatal, is increased in elderly individuals, patients with renal impairment, patients with diabetes mellitus, patients concurrently taking other drugs that may increase potassium levels, and patients with intercurrent conditions. Before deciding on concomitant use of drugs affecting the renin-angiotensin-aldosterone system, the benefit-risk ratio should be assessed, and alternative options considered. Main risk factors for hyperkalemia are:
Careful monitoring of serum potassium levels is recommended in patients at increased risk of hyperkalemia. Lithium Concomitant use of lithium with olmesartan medoxomil is not recommended, as with other angiotensin II receptor antagonists. Aortic or mitral valve stenosis / hypertrophic cardiomyopathyCaution should be exercised when prescribing olmesartan medoxomil, as with other vasodilators, 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 acting via inhibition of the renin-angiotensin system. Therefore, olmesartan medoxomil is not recommended for such patients. Sprue-like enteropathy In very rare cases, patients taking olmesartan medoxomil developed severe chronic diarrhea with significant weight loss within several months to a year after starting treatment, possibly due to a localized delayed-type hypersensitivity reaction. Intestinal biopsy in such patients often showed villous atrophy. If a patient develops corresponding symptoms during olmesartan medoxomil treatment, other etiologies should be ruled out. Discontinuation of olmesartan medoxomil should be considered if no other etiology is identified. If diarrhea symptoms do not resolve within one week after discontinuation, medical advice should be sought. Ethnic characteristics Like other angiotensin II receptor antagonists, olmesartan medoxomil may be less effective in reducing blood pressure in patients of black race compared to others, possibly due to higher prevalence of low-renin states in black patients. Other Excessive reduction in blood pressure with any antihypertensive agent in patients with ischemic heart disease or cerebrovascular disease may lead to myocardial infarction or stroke. Dual blockade of the renin-angiotensin-aldosterone system (RAAS) It has been proven that concomitant use of ACE inhibitors, angiotensin II receptor blockers, or aliskiren increases the risk of arterial hypotension, hyperkalemia, and reduced renal function (including acute renal failure). Therefore, dual blockade of RAAS, involving concomitant use of ACE inhibitors, angiotensin II receptor blockers, or aliskiren, is not recommended. If dual blockade therapy is considered absolutely necessary, it should be conducted only under specialist supervision with careful 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. Olmesar Macleods contains lactose. Patients with rare hereditary galactose intolerance, lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product. Interaction with other medicinal products and other types of interaction. Potassium supplements and potassium-sparing diuretics Based on experience with other drugs affecting the renin-angiotensin system, concomitant use of potassium-sparing diuretics, potassium supplements, potassium-containing salt substitutes, or other drugs that may increase serum potassium levels (e.g., heparin) may lead to increased serum potassium levels. Therefore, such concomitant use is not recommended. Other antihypertensive agents The antihypertensive effect of olmesartan medoxomil may be enhanced when used concomitantly with other antihypertensive agents. Nonsteroidal anti-inflammatory drugs Nonsteroidal anti-inflammatory drugs (including acetylsalicylic acid at doses > 3 g/day, and COX-2 inhibitors) and angiotensin II receptor antagonists may act synergistically by reducing glomerular filtration. Concomitant use of nonsteroidal anti-inflammatory drugs and angiotensin II antagonists carries a risk of acute renal failure. Monitoring of renal function at the start of treatment and ensuring adequate fluid intake in the patient are recommended. Additionally, concomitant use of nonsteroidal anti-inflammatory drugs may reduce the antihypertensive effect of angiotensin II receptor antagonists, leading to partial loss of efficacy. Other substances A moderate reduction in olmesartan bioavailability was observed after treatment with antacids (aluminum magnesium hydroxide). Concomitant use of warfarin and digoxin had no effect on olmesartan pharmacokinetics. Bile acid sequestrant colesevelam Concomitant use of the bile acid sequestrant colesevelam hydrochloride reduces systemic exposure to peak plasma concentrations of olmesartan and shortens its elimination half-life. Administration of olmesartan medoxomil at least 4 hours before colesevelam hydrochloride reduces their interaction. Therefore, olmesartan medoxomil should be administered at least 4 hours before colesevelam hydrochloride. Dual blockade of the renin-angiotensin-aldosterone system (RAAS) Clinically proven, dual blockade of the renin-angiotensin-aldosterone system (RAAS) by combined use of ACE inhibitors, angiotensin II receptor blockers, or aliskiren is associated with a higher incidence of adverse effects, such as arterial hypotension, hyperkalemia, and reduced renal function (including acute renal failure), compared to single use of RAAS-acting drugs. Effect of olmesartan medoxomil on other medicinal products Lithium Reversible increases in serum lithium concentration and toxicity have been observed during concomitant use of lithium with ACE inhibitors and angiotensin II receptor antagonists. Therefore, concomitant use of olmesartan medoxomil and lithium is not recommended. If such combination use is considered necessary, careful monitoring of serum lithium levels is recommended. Other substances No clinically significant interactions were observed with warfarin, digoxin, antacids (aluminum magnesium hydroxide), hydrochlorothiazide, and pravastatin; specifically, olmesartan medoxomil had no significant effect on the pharmacokinetics or pharmacodynamics of warfarin or the pharmacokinetics of digoxin. In vitro studies, olmesartan did not clinically significantly inhibit human cytochrome P450 enzymes 1A1/2, 2A6, 2C8/9, 2C19, 2D6, 2E1, and 3A4, and did not significantly induce cytochrome P450 activity in animals. Therefore, in vivo studies on interactions with known inhibitors and inducers of cytochrome P450 enzymes were not conducted. No clinically significant interactions between olmesartan and drugs metabolized by the aforementioned cytochrome P450 enzymes are expected. Children Interaction studies have been conducted only in adults. It is unknown whether interactions in children differ from those in adults. Special instructions. Use during pregnancy or breastfeeding. Pregnancy. Use of angiotensin II antagonists is not recommended during the first trimester of pregnancy. Use of angiotensin II antagonists is contraindicated during the second and third trimesters of pregnancy. Epidemiological evidence regarding teratogenic risk from ACE inhibitors during the first trimester of pregnancy was not convincing; however, some increased risk cannot be excluded. As there are no controlled epidemiological data on the teratogenicity of angiotensin II antagonists, similar risks cannot be excluded. Women planning pregnancy should switch from angiotensin receptor blockers to alternative antihypertensive therapies with established safety profiles during pregnancy unless continuation of such therapy is deemed necessary. If pregnancy is diagnosed, angiotensin II antagonists should be discontinued immediately and alternative therapy initiated if needed. It is known that angiotensin II antagonist therapy during the second and third trimesters causes human fetotoxicity (reduced renal function, oligohydramnios, delayed skull ossification) and neonatal toxicity (renal failure, hypotension, hyperkalemia). If exposure to angiotensin II antagonists occurred during the second trimester of pregnancy, ultrasound examination of renal and skull function is recommended. Newborns whose mothers took angiotensin II antagonists during pregnancy should be closely monitored for hypotension. Lactation. Olmesartan is excreted in rat milk, but it is unknown whether olmesartan is excreted in human milk. As there is no information on the use of olmesartan medoxomil during breastfeeding, the drug is not recommended for use during this period. Alternative therapies with established safety profiles during breastfeeding, especially when nursing a newborn or preterm infant, are preferred. Ability to affect reaction speed when driving or operating machinery. Olmesartan has a minor or moderate effect on the ability to drive or operate machinery. Dizziness or fatigue may occasionally occur in patients receiving antihypertensive therapy, which may impair reaction speed. Dosage and administration. It is recommended to take olmesartan medoxomil tablets approximately at the same time every day, with or without food, for example, during breakfast. The tablet should be swallowed with sufficient liquid (e.g., one glass of water). The tablet should not be chewed. Adults The recommended initial dose of olmesartan medoxomil is 10 mg once daily. For patients in whom blood pressure is not adequately controlled at this dose, the dose of olmesartan medoxomil may be increased to the optimal dose of 20 mg once daily. If additional blood pressure reduction is needed, the dose of olmesartan medoxomil may be increased up to a maximum of 40 mg daily or hydrochlorothiazide therapy may be added. The antihypertensive effect of olmesartan medoxomil is generally present within 2 weeks of starting therapy and is maximal approximately 8 weeks after initiation. This should be considered when evaluating dose adjustment schemes for any patient. Elderly people (over 65 years) Dose adjustment is generally not required for elderly patients. If increasing to the maximum dose of 40 mg daily is needed, blood pressure should be carefully monitored. Renal function impairment The maximum dose for patients with mild to moderate renal impairment (creatinine clearance 20–60 mL/min) is 20 mg of olmesartan medoxomil once daily due to limited experience with higher doses in this patient group. Use of olmesartan medoxomil in patients with severe renal impairment (creatinine clearance <20 mL/min) is not recommended due to limited experience in this patient group. Hepatic function impairment Dose adjustment is not required for patients with mild hepatic impairment. For patients with moderate hepatic impairment, the recommended initial dose is 10 mg of olmesartan medoxomil once daily, and the maximum dose should not exceed 20 mg once daily. Careful monitoring of blood pressure and renal function is recommended for patients with hepatitis who are already receiving diuretics and/or other antihypertensive agents. There is no experience with olmesartan medoxomil in patients with severe hepatic impairment; therefore, use in this patient group is not recommended. Olmesartan medoxomil should not be used in patients with biliary obstruction. Children Patients aged 6 to 18 years. The recommended initial dose of olmesartan medoxomil for children aged 6 years and older is 10 mg of olmesartan medoxomil once daily. In children whose blood pressure is not adequately controlled at this dose, the dose of olmesartan medoxomil may be increased to 20 mg once daily. If additional blood pressure reduction is needed, for children weighing ≥ 35 kg, the dose of olmesartan medoxomil may be increased up to a maximum of 40 mg. For children weighing <35 kg, the daily dose should not exceed 20 mg. Other pediatric patients. Olmesartan medoxomil should not be used in children under 6 years of age due to safety concerns and lack of data in this age group. Overdose. Limited information on human overdose is available. The most likely effect in overdose is arterial hypotension. In case of overdose, careful monitoring of the patient is required, and treatment should be symptomatic and supportive. There is no data on removal of olmesartan medoxomil by dialysis. Adverse reactions. The most commonly occurring adverse reactions during olmesartan medoxomil treatment are headache (7.7%), flu-like symptoms (4.0%), and dizziness (3.7%). In placebo-controlled monotherapy trials, the only treatment-related adverse reaction was dizziness (incidence 2.5% with olmesartan medoxomil vs. 0.9% in the placebo group). The frequency of laboratory parameter abnormalities was slightly higher with olmesartan medoxomil compared to placebo: hypertriglyceridemia — 2.0% with olmesartan medoxomil vs. 1.1% with placebo, elevated creatine phosphokinase levels — 1.3% with olmesartan medoxomil vs. 0.7% with placebo. Adverse effects from clinical trials of olmesartan medoxomil, post-marketing safety studies, and spontaneous reports are listed in the table. Adverse reactions are categorized by frequency of occurrence as follows: very common (≥1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1000, < 1/100); rare (≥ 1/10000, < 1/1000); very rare (< 1/10000); frequency not known (cannot be estimated from available data).
*Autoimmune hepatitis has been reported during the post-marketing period with a latency period of several months to years, which was reversible upon discontinuation of olmesartan. Isolated cases of rhabdomyolysis, temporally associated with the use of angiotensin II receptor blockers, have been reported. Special patient groups Paediatric population Safety monitoring of olmesartan medoxomil was conducted in two clinical studies involving children and adolescents (361 individuals) aged 1 to 17 years. While the nature and severity of adverse reactions were similar to those observed in adult patients, the frequency of the following adverse reactions was higher in children than in adults:
Overall, the safety profile of olmesartan medoxomil in paediatric patients did not differ substantially from that in adult patients. Elderly patients (aged 65 years and older) Hypotension may occur somewhat more frequently in elderly patients ("rarely" or "uncommonly"). Reporting of suspected adverse reactions Reporting of suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals should report any suspected adverse reactions. Shelf life. 3 years. Storage conditions. Store at a temperature not exceeding 25 °C in the original packaging. Keep out of the reach of children. Packaging. 10 tablets per blister, 3 or 9 blisters per cardboard pack. Prescription category. Prescription only. Manufacturer. Macleods Pharmaceuticals Limited. Manufacturer's name and address of the place of business. Village Thedda, P.O. Lodhiamaira, Tehsil Baddi, District Solan, Himachal Pradesh, 174101, India. |