Olimestra

Olmesartan medoxomil.

10 mg: Each OLIMESTRA Film-coated Tablet 10 mg contains: White, round, slightly biconvex film-coated tablets, engraved with a mark S1 on one side of the tablet.
Each OLIMESTRA Film-coated Tablet 10 mg contains: Olmesartan medoxomil 10 mg.
20 mg: Each OLIMESTRA Film-coated Tablet 20 mg contains: White, round, slightly biconvex film-coated tablets, engraved with a mark S2 on one side of the tablet.
Each OLIMESTRA Film-coated Tablet 20 mg contains: Olmesartan medoxomil 20 mg.
Excipients/Inactive Ingredients: Magnesium Stearate, Low-substituted Hydroxypropyl Cellulose, Microcrystalline Cellulose, Lactose monohydrate, Polyvinyl Alcohol-Part, Titanium Dioxide (E 171), Macrogol 3000, Talc.

Pharmacology: Pharmacodynamics: Olmesartan is the first-line drug in a new class of antihypertensive agents that are selective angiotensin II receptors (AT1) antagonists. Angiotensin II is a potent vasoconstrictor and primary active hormone of the renin-angiotensin-aldosterone system, which plays a major role in the pathophysiology of hypertension. The cardiovascular homeostatic effects of angiotensin II are expressed through the AT1 receptor. Olmesartan has an affinity for the AT receptor 12,500 times that of the AT receptor, so it can be said that the Angiotensin receptor blocking effect of Olmesartan is highly selective.
Olmesartan is a potent, oral, synthetic active ingredient that selectively binds to AT1 receptors. In vitro and in vivo, both Olmesartan and its pharmacologically active metabolite (E-3174) block all physiologically relevant effects of angiotensin II, including vasoconstrictor effects, salt-water retention, and sympathetic stimulation. This leads to a drop in blood pressure. Olmesartan has no antagonistic activity and does not bind to or block other hormone receptors or ion channels important in cardiovascular regulation.
The effects of angiotensin II on AT₁ receptors can be summarized as follows: Vasoconstrictor effect.
Make the heart contract stronger and faster.
At low doses that do not cause vasoconstriction, angiotensin II and III stimulate the synthesis and secretion of aldosterone for sodium retention and potassium excretion.
Angiotensin II also has a spasmolytic effect on certain smooth muscles such as the ileum, uterus, and bronchi.
On the central nervous system, angiotensin II stimulates the sympathetic system and releases noradrenalin, causing the patient to thirst and drink water.
Blocking the AT₁ receptor would have the opposite effect of the previously mentioned effects.
Pharmacokinetics: Absorption: Olmesartan medoxomil is rapidly absorbed from the gastrointestinal tract and esterified to the active form. Absorption of the drug is not affected by food.
The drug is not metabolized by cytochrome P450. Olmesartan medoxomil is rapidly absorbed orally.
The mean peak plasma concentration: is reached within about 60-120 minutes after oral administration. Olmesartan is highly bound to plasma protein (99%). Therefore, the drug is released gradually and is stable for 24 hours.
Biotransformation and elimination: Bioavailability: 26%.
Half-life: 13 hours.
Elimination: 35-50% in the urine, the rest in the feces.
The terminal elimination half-life of olmesartan varied between 10 and 15 hours after multiple oral dosing. A 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: Paediatric 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 really impaired pediatric subjects.
Older people (age 65 years or older): In hypertensive patients, the AUC at steady state was increased by 35% in older people (65-75 years old) and by 44% in very old people (≥75 years old) compared with the younger group. This may be at least in part related to a mean decrease in renal function in this group of patients.
Renal impairment: In renal 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 mild and moderate hepatic 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 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 C_max values are 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.
Treatment of hypertension in children and adolescents from 6 to less than 18 years of age.

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.
A maximum of 40 mg daily or hydrochlorothiazide therapy may be added.
The antihypertensive effect is substantially present within 2-8 weeks of initiating therapy.
Elderly: No adjustment of dosage is generally required in elderly people. The maximum dose is 40 mg daily.
Renal impairment: The maximum dose in patients with mild to moderate renal impairment (creatinine clearance of 20-60 mL/min) is 20 mg once daily. The use in patients with severe renal impairment (creatinine clearance <20 mL/min) is not recommended.
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 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. Use is not recommended in severe hepatic impairment.
Pediatric population: From 6 to less than 18 years of age.
The starting dose of olmesartan medoxomil in children from 6 to less than 18 years of age is 10 mg 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 required, in children who weigh ≥ 35 kg, the olmesartan medoxomil dose may be increased to a maximum of 40 mg. In children who weigh < 35 kg, the daily dose should not exceed 20 mg.
Pediatric population: From 1 to 5 years old.
The safety and efficacy of olmesartan medoxomil in children aged 1 to 5 years old have not yet been established. Olmesartan medoxomil should not be used in children below 1 year of age because of safety concerns and lack of data in this age group.
Method of administration: It is recommended that Olimestra 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.

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.

Hypersensitivity to the active substance or to any of the excipients.
Second and third trimesters of pregnancy.
Biliary obstruction.
The concomitant use of Olimestra 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 treated 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.
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. The use of olmesartan medoxomil is not recommended in patients with severe renal impairment (creatinine clearance <20 mL/min). There is no experience with the administration of olmesartan medoxomil in patients with a recent kidney transplant or 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.
Hyperkalaemia: 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 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: 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 classes of medicinal products may provoke hyperkalemia: salt substitutes containing potassium, potassium-sparing diuretics, ACE inhibitors, angiotensin II receptor antagonists, nonsteroidal anti-inflammatory drugs (including selective COX-2 inhibitors), heparin, immunosuppressor 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 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 a 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 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 ischaemic heart disease or ischaemic cerebrovascular disease could result in a myocardial infarction or stroke.
Effects on Ability to Drive and Use Machines: The drug could cause dizziness or fatigue, use with caution when driving and operating machinery.
Use in Pregnancy: Angiotensin II antagonists should not be initiated during pregnancy. Unless continued angiotensin II antagonist therapy is considered essential, patients planning pregnancy should be changed to alternative anti-hypertensive treatments that 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 this drug is not recommended during the first trimester of pregnancy.
The use of this drug is contra-indicated 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. When pregnancy is diagnosed, treatment with angiotensin II antagonists should be stopped immediately, and, if appropriate, alternative therapy should be started.
Should exposure to angiotensin II antagonists have occurred from the second trimester of pregnancy, an ultrasound check of renal function and skull is recommended. Infants whose mothers have taken angiotensin II antagonists should be closely observed for hypotension.
Lactation: It is not known whether olmesartan is excreted in human milk. The benefits of treatment and the safety of the infant should be considered.

Dizziness, swelling of the face, throat, tongue, lips, eyes, hands, feet, ankles, or legs, severe diarrhea, weight loss, trouble breathing or swallowing, hoarseness. Olmesartan may cause other side effects.
A chronic gastrointestinal disease similar to sprue.
Inform a doctor of any side effects the patient may experience while taking the drug.

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: 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: 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.
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 t½. Administration of olmesartan medoxomil at least 4 hours before 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 an antacid (aluminum magnesium hydroxide), a modest reduction in the bioavailability of olmesartan was observed. Coadministration of warfarin and digoxin did not affect 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 the use of the combination proves necessary, careful monitoring of serum lithium levels is recommended.
Other compounds: Compounds that 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.

Store in a dry place, protected from light and moisture, below 30°C.
Shelf Life: 36 months from manufacturing date.

Angiotensin II Antagonists

C09CA08 - olmesartan medoxomil ; Belongs to the class of angiotensin II receptor blockers (ARBs). Used in the treatment of cardiovascular disease.