Each film-coated tablet contains: Olmesartan medoxomil 20 mg.
Excipients/Inactive Ingredients: Lactose monohydrate, Microcrystalline cellulose (Avicel PH 112), Pregelatinized corn starch, Croscarmellose sodium, Butylated hydroxytoluene, Edetate disodium, Poloxamer (Poloxamer 407), Sodium lauryl sulfate, Copovidone, Colloidal silicon dioxide, Sodium stearyl fumarate, Hypromellose (Methocel E 15LV/HPMC 2910), Propylene glycol, Kollicoat protect/PVA PEG PVA Copolymer, Titanium dioxide (C.I. No. 77891), Talc, and Polyethylene glycol (PEG 6000).
Pharmacology: Mechanism of action: Olmesartan medoxomil is a potent, orally active, selective angiotensin II receptor (type AT1) antagonist. It is expected to block all actions of angiotensin II mediated by the AT1 receptor, regardless of the source or route of synthesis of angiotensin II. The selective antagonism of the angiotensin II (AT1) receptors results in increases in plasma renin levels and angiotensin I and II concentrations, and some decrease in plasma aldosterone concentrations.
Angiotensin II is the primary vasoactive hormone of the renin-angiotensin-aldosterone system and plays a significant role in the pathophysiology of hypertension via the type 1 (AT1) receptor.
Pharmacokinetics: Absorption and distribution: Olmesartan medoxomil is a prodrug. It is rapidly converted to the pharmacologically active metabolite, Olmesartan, by esterases in the gut mucosa and in portal blood during absorption from the gastrointestinal tract.
No intact Olmesartan medoxomil or intact side chain medoxomil moiety have been detected in plasma or excreta. The mean absolute bioavailability of Olmesartan from a tablet formulation was 25.6%.
The mean peak plasma concentration (Cmax) of Olmesartan is reached within about 2 hours after oral dosing with Olmesartan medoxomil, and Olmesartan plasma concentrations increase approximately linearly with increasing single oral doses up to about 80 mg.
Food had minimal effect on the bioavailability of Olmesartan and therefore Olmesartan medoxomil may be administered with or without food.
No clinically relevant gender-related differences in the pharmacokinetics of Olmesartan have been observed.
Olmesartan is highly bound to plasma protein (99.7%), but the potential for clinically significant protein binding displacement interactions between Olmesartan and other highly bound co-administered drugs is low (as confirmed by the lack of a clinically significant interaction between Olmesartan medoxomil and Warfarin). The binding of Olmesartan to blood cells is negligible. The mean volume of distribution after intravenous dosing is low (16-29 L).
Biotransformation and elimination: Total plasma clearance was typically 1.3 L/h (CV, 19%) and was relatively slow compared to hepatic blood flow (ca 90 L/h). Following a single oral dose of 14C-labelled Olmesartan medoxomil, 10-16% of the administered radioactivity was excreted in the urine (the vast majority within 24 hours of dose administration) and the remainder of the recovered radioactivity was excreted in the feces. Based on the systemic availability of 25.6%, it can be calculated that absorbed Olmesartan is cleared by both renal excretion (ca 40%) and hepato-biliary excretion (ca 60%). All recovered radioactivity was identified as Olmesartan. No other significant metabolite was detected. Enterohepatic recycling of Olmesartan is minimal. Since a large proportion of Olmesartan is excreted via the biliary route, use in patients with biliary obstruction is contraindicated.
The terminal elimination half-life of Olmesartan varied between 10 and 15 hours after multiple oral dosing. Steady state was reached after the first few doses and no further accumulation was evident after 14 days of repeated dosing. Renal clearance was approximately 0.5-0.7 L/h and was independent of dose.
Pharmacokinetics in special populations: Pediatric population: The pharmacokinetics of Olmesartan was studied in pediatric hypertensive patients aged 1 to 16 years. The clearance of Olmesartan in pediatric patients was similar to that in adult patients when adjusted by the body weight.
There is no pharmacokinetic information available in renally impaired pediatric subjects.
Elderly (age 65 years or over): In hypertensive patients, the AUC at steady state was increased by ca 35% in elderly people (65-75 years old) and by ca 44% in very elderly people (≥75 years old) compared with the younger age group. This may be at least in part related to a mean decrease in renal function in this group of patients.
Renal impairment: In renally impaired patients, the AUC at steady state increased by 62%, 82% and 179% in patients with mild, moderate and severe renal impairment, respectively, compared to healthy controls.
Hepatic impairment: After single oral administration, Olmesartan AUC values were 6% and 65% higher in mildly and moderately hepatically impaired patients, respectively, than in their corresponding matched healthy controls. The unbound fraction of Olmesartan at 2 hours post-dose in healthy subjects, in patients with mild hepatic impairment and in patients with moderate hepatic impairment was 0.26%, 0.34% and 0.41%, respectively. Following repeated dosing in patients with moderate hepatic impairment, Olmesartan mean AUC was again about 65% higher than in matched healthy controls. Olmesartan mean Cmax values were similar in hepatically-impaired and healthy subjects. Olmesartan medoxomil has not been evaluated in patients with severe hepatic impairment.
Treatment of essential hypertension in adults.
Oral.
In order to assist compliance, it is recommended that Olmesartan medoxomil tablets be taken at about the same time each day, with or without food, for example at breakfast time. The tablet should be swallowed with a sufficient amount of fluid (e.g. one glass of water). The tablet should not be chewed.
Posology: Adults: The recommended starting dose of Olmesartan medoxomil is 10 mg once daily. In patients whose blood pressure is not adequately controlled at this dose, the dose of Olmesartan medoxomil may be increased to 20 mg once daily as the optimal dose. If additional blood pressure reduction is required, Olmesartan medoxomil dose may be increased to a maximum of 40 mg daily or Hydrochlorothiazide therapy may be added. Consider other sources for 10 mg dosing.
The antihypertensive effect of Olmesartan medoxomil is substantially present within 2 weeks of initiating therapy and is maximal by about 8 weeks after initiating therapy. This should be borne in mind when considering changing the dose regimen for any patient.
Elderly (65 years or over): No adjustment of dosage is generally required in elderly people. If up-titration to the maximum dose of 40 mg daily is required, blood pressure should be closely monitored.
Renal impairment: The maximum dose in patients with mild to moderate renal impairment (creatinine clearance of 20-60 mL/min) is 20 mg Olmesartan medoxomil once daily, owing to limited experience of higher dosages in this patient group. The use of Olmesartan medoxomil in patients with severe renal impairment (creatinine clearance <20 mL/min) is not recommended, since there is only limited experience in this patient group.
Hepatic impairment: No adjustment of dosage recommendations is required for patients with mild hepatic impairment. In patients with moderate hepatic impairment, an initial dose of 10 mg Olmesartan medoxomil once daily is recommended and the maximum dose should not exceed 20 mg once daily. Close monitoring of blood pressure and renal function is advised in hepatically-impaired patients who are already receiving diuretics and/or other antihypertensive agents. There is no experience of Olmesartan medoxomil in patients with severe hepatic impairment, therefore use is not recommended in this patient group. Olmesartan medoxomil should not be used in patients with biliary obstruction. Consider other sources for 10 mg dosing.
Pediatric population: The safety and efficacy of Olmesartan medoxomil in children and adolescents below 18 years has not been established.
Only limited information is available regarding overdosage in humans. The most likely effect of overdosage is hypotension. In the event of overdosage, the patient should be carefully monitored and treatment should be symptomatic and supportive. No information is available regarding the dialysability of Olmesartan.
Hypersensitivity to the active substance or to any of the excipients.
Second and third trimester of pregnancy.
Biliary obstruction.
The concomitant use of Olmesartan medoxomil with Aliskiren-containing products is contraindicated in patients with diabetes mellitus or renal impairment (GFR <60 mL/min/1.73 m2).
Intravascular volume depletion: Symptomatic hypotension, especially after the first dose, may occur in patients who are volume and/or sodium depleted by vigorous diuretic therapy, dietary salt restriction, diarrhea or vomiting. Such conditions should be corrected before the administration of Olmesartan medoxomil.
Other conditions with stimulation of the renin-angiotensin-aldosterone system: In patients whose vascular tone and renal function depend predominantly on the activity of the renin-angiotensin-aldosterone system (e.g. patients with severe congestive heart failure or underlying renal disease, including renal artery stenosis), treatment with other drugs that affect this system has been associated with acute hypotension, azotemia, oliguria or, rarely, acute renal failure. The possibility of similar effects cannot be excluded with angiotensin II receptor antagonists.
Renovascular hypertension: There is an increased risk of severe hypotension and renal insufficiency when patients with bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney are treated with medicinal products that affect the renin-angiotensin-aldosterone system.
Renal impairment and kidney transplantation: When Olmesartan medoxomil is used in patients with impaired renal function, periodic monitoring of serum potassium and creatinine levels is recommended. Use of Olmesartan medoxomil is not recommended in patients with severe renal impairment (creatinine clearance <20 mL/min). There is no experience of the administration of Olmesartan medoxomil in patients with a recent kidney transplant or in patients with end-stage renal impairment (i.e. creatinine clearance <12 mL/min).
Hepatic impairment: There is no experience in patients with severe hepatic impairment and therefore use of Olmesartan medoxomil in this patient group is not recommended.
Hyperkalemia: The use of medicinal products that affect the renin-angiotensin-aldosterone system may cause hyperkalemia. The risk, that may be fatal, is increased in elderly people, in patients with renal insufficiency and in diabetic patients, in patients concomitantly treated with other medicinal products that may increase potassium levels, and/or in patients with intercurrent events. Before considering the concomitant use of medicinal products that affect the renin-angiotensin-aldosterone system, the benefit risk ratio should be evaluated and other alternatives considered.
The main risk factors for hyperkalemia to be considered are as follows.
Diabetes, renal impairment, age (>70 years).
Combination with one or more other medicinal products that affect the renin-angiotensin-aldosterone system and/or potassium supplements. Some medicinal products or therapeutic class of medicinal products may provoke a hyperkalemia: salt substitutes containing potassium, potassium-sparing diuretics, ACE inhibitors, angiotensin II receptors antagonists, non-steroidal anti-inflammatory drugs (including selective COX-2 inhibitors), heparin, immunosuppressor such as Ciclosporin or Tacrolimus, Trimethoprim.
Intercurrent events, in particular dehydration, acute cardiac decompensation, metabolic acidosis, worsening of renal function, sudden worsening of the renal condition (e.g. infectious diseases), cellular lysis (e.g. acute limb ischemia, rhabdomyolysis, extended trauma). Close monitoring of serum potassium in at risk patients is recommended.
Dual blockade of the renin-angiotensin-aldosterone system (RAAS): There is evidence that the concomitant use of ACE inhibitors, angiotensin II receptor blockers or Aliskiren increases the risk of hypotension, hyperkalemia and decreased renal function (including acute renal failure). Dual blockade of RAAS through the combined use of ACE inhibitors, angiotensin II receptor blockers or Aliskiren is therefore not recommended. If dual blockade therapy is considered absolutely necessary, this should only occur under specialist supervision and subject to frequent close monitoring of renal function, electrolytes and blood pressure. ACE inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy.
Lithium: As with other angiotensin II receptor antagonists, the combination of Lithium and Olmesartan medoxomil is not recommended.
Aortic or mitral valve stenosis/obstructive hypertrophic cardiomyopathy: As with other vasodilators, special caution is indicated in patients suffering from aortic or mitral valve stenosis, or obstructive hypertrophic cardiomyopathy.
Primary aldosteronism: Patients with primary aldosteronism generally will not respond to antihypertensive drugs acting through inhibition of the renin-angiotensin system. Therefore, the use of Olmesartan medoxomil is not recommended in such patients.
Sprue-like enteropathy: In very rare cases severe, chronic diarrhea with substantial weight loss has been reported in patients taking Olmesartan few months to years after drug initiation, possibly caused by a localized delayed hypersensitivity reaction. Intestinal biopsies of patients often demonstrated villous atrophy. If a patient develops these symptoms during treatment with Olmesartan, and in the absence of other apparent etiologies, Olmesartan treatment should be immediately discontinued and should not be restarted. If diarrhea does not improve during the week after the discontinuation, further specialist (e.g. a gastro-enterologist) advice should be considered.
Ethnic differences: As with all other angiotensin II antagonists, the blood pressure lowering effect of Olmesartan medoxomil is somewhat less in Black patients than in non-Black patients, possibly because of a higher prevalence of low-renin status in the Black hypertensive population.
Other: As with any antihypertensive agent, excessive blood pressure decrease in patients with ischemic heart disease or ischemic cerebrovascular disease could result in a myocardial infarction or stroke. This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
Use in Pregnancy: Angiotensin II antagonists should not be initiated during pregnancy. Unless continued angiotensin II antagonists therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with angiotensin II antagonists should be stopped immediately, and, if appropriate, alternative therapy should be started.
Pregnancy: The use of angiotensin II antagonists is not recommended during the first trimester of pregnancy. The use of angiotensin II antagonists is contraindicated during the 2nd and 3rd trimester of pregnancy.
Epidemiological evidence regarding the risk of teratogenicity following exposure to ACE inhibitors during the first trimester of pregnancy has not been conclusive; however a small increase in risk cannot be excluded. Whilst there is no controlled epidemiological data on the risk with angiotensin II antagonists, similar risks may exist for this class of drugs. Unless continued angiotensin receptor blocker therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with angiotensin II antagonists should be stopped immediately, and, if appropriate, alternative therapy should be started.
Angiotensin II antagonists therapy exposure during the second and third trimesters is known to induce human fetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalemia).
Should exposure to angiotensin II antagonists have occurred from the second trimester of pregnancy, ultrasound check of renal function and skull is recommended. Infants whose mothers have taken angiotensin II antagonists should be closely observed for hypotension.
Breastfeeding: Olmesartan is excreted in the milk of lactating rats but it is not known whether Olmesartan is excreted in human milk. Because no information is available regarding the use of Olmesartan medoxomil during breastfeeding, Olmesartan medoxomil is not recommended and alternative treatments with better established safety profiles during breastfeeding are preferable, especially while nursing a newborn or preterm infant.
Summary of the safety profile: The most commonly reported adverse reactions during treatment with Olmesartan are headache (7.7%), influenza-like symptoms (4.0%) and dizziness (3.7%).
In placebo-controlled monotherapy studies, the only adverse drug reaction that was unequivocally related to treatment was dizziness (2.5% incidence on Olmesartan medoxomil and 0.9% on placebo).
The incidence was also somewhat higher on Olmesartan medoxomil compared with placebo for hypertriglyceridemia (2.0% versus 1.1%) and for raised creatine phosphokinase (1.3% versus 0.7%).
Tabulated list of adverse reactions: Adverse reactions from Olmesartan in clinical trials, post-authorization safety studies and spontaneous reporting are summarized in the following table.
The following terminologies have been used in order to classify the occurrence 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). (See table.)
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Single cases of rhabdomyolysis have been reported in temporal association with the intake of angiotensin II receptor blockers.
Additional information on special populations: Elderly (age 65 years or over): In elderly people the frequency of hypotension is slightly increased from rare to uncommon.
Interaction studies have only been performed in adults.
Effects of other medicinal products on Olmesartan medoxomil: Other antihypertensive medications: The blood pressure lowering effect of Olmesartan medoxomil can be increased by concomitant use of other antihypertensive medications.
ACE inhibitors, angiotensin II receptor blockers or Aliskiren: Clinical trial data has shown that dual blockade of the renin-angiotensin-aldosterone system (RAAS) through the combined use of ACE inhibitors, angiotensin II receptor blockers or Aliskiren is associated with a higher frequency of adverse events such as hypotension, hyperkalemia and decreased renal function (including acute renal failure) compared to the use of a single RAAS-acting agent.
Potassium supplements and potassium sparing diuretics: Based on experience with the use of other drugs that affect the renin-angiotensin system, concomitant use of potassium sparing diuretics, potassium supplements, salt substitutes containing potassium or other drugs that may increase serum potassium levels (e.g. heparin) may lead to increases in serum potassium. Such concomitant use is therefore not recommended.
Non-steroidal anti-inflammatory drugs (NSAIDs): NSAIDs (including acetylsalicylic acid at doses >3 g/day and also COX-2 inhibitors) and angiotensin II receptor antagonists may act synergistically by decreasing glomerular filtration. The risk of the concomitant use of NSAIDs and angiotensin II antagonists is the occurrence of acute renal failure. Monitoring of renal function at the beginning of treatment should be recommended as well as regular hydration of the patient. Additionally, concomitant treatment can reduce the antihypertensive effect of angiotensin II receptor antagonists, leading to their partial loss of efficacy.
Bile acid sequestering agent Colesevelam: Concurrent administration of the bile acid sequestering agent Colesevelam hydrochloride reduces the systemic exposure and peak plasma concentration of Olmesartan and reduces t1/2. Administration of Olmesartan medoxomil at least 4 hours prior to Colesevelam hydrochloride decreased the drug interaction effect. Administering Olmesartan medoxomil at least 4 hours before the Colesevelam hydrochloride dose should be considered.
Other compounds: After treatment with antacid (Aluminum magnesium hydroxide), a modest reduction in bioavailability of Olmesartan was observed. Co-administration of Warfarin and Digoxin had no effect on the pharmacokinetics of Olmesartan.
Effects of Olmesartan medoxomil on other medicinal products: Lithium: Reversible increases in serum Lithium concentrations and toxicity have been reported during concomitant administration of Lithium with angiotensin converting enzyme inhibitors and angiotensin II antagonists. Therefore use of Olmesartan medoxomil and Lithium in combination is not recommended. If use of the combination proves necessary, careful monitoring of serum Lithium levels is recommended.
Other compounds: Compounds which have been investigated in specific clinical studies in healthy volunteers include Warfarin, Digoxin, an antacid (Magnesium aluminum hydroxide), Hydrochlorothiazide and Pravastatin. No clinically relevant interactions were observed and in particular Olmesartan medoxomil had no significant effect on the pharmacokinetics or pharmacodynamics of Warfarin or the pharmacokinetics of Digoxin. Olmesartan had no clinically relevant inhibitory effects on in vitro human cytochrome P450 enzymes 1A1/2, 2A6, 2C8/9, 2C19, 2D6, 2E1 and 3A4, and had no or minimal inducing effects on rat cytochrome P450 activities. Therefore in vivo interaction studies with known cytochrome P450 enzyme inhibitors and inducers were not conducted, and no clinically relevant interactions between Olmesartan and drugs metabolized by the previously mentioned cytochrome P450 enzymes are expected.
Store at temperature not more than 30°C.
C09CA08 - olmesartan medoxomil ; Belongs to the class of angiotensin II receptor blockers (ARBs). Used in the treatment of cardiovascular disease.
Esatec 20 FC tab 20 mg
3 × 10's
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