OLBEK

Olmesartan medoxomil and hydrochlorothiazide is a combination of an angiotensin II receptor antagonist (AT 1 subtype), olmesartan medoxomil, and a thiazide diuretic, hydrochlorothiazide (HCTZ).

Olmesartan medoxomil is 2,3-dihydroxy-2-butenyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1-[ p -( o -1 H -tetrazol-5-ylphenyl)benzyl]imidazole-5-carboxylate, cyclic 2,3-carbonate.

Its empirical formula is

C 29 H 30 N 6 O and its structural formula is: Olmesartan medoxomil is a white to light yellowish-white powder or crystalline powder with a molecular weight of 558.6.

It is practically insoluble in water and sparingly soluble in methanol.

Hydrochlorothiazide is 6-chloro-3,4-dihydro-2 H -1,2,4-benzo-thiadiazine-7-sulfonamide 1,1-dioxide.

C 7 H 8 ClN 3 O 4 S and its structural formula is: Hydrochlorothiazide is a white, or practically white, crystalline powder with a molecular weight of 297.7.

Hydrochlorothiazide is slightly soluble in water but freely soluble in sodium hydroxide solution.

Olmesartan medoxomil and hydrochlorothiazide is available for oral administration in tablets containing 20 mg or 40 mg of olmesartan medoxomil combined with 12.5 mg of hydrochlorothiazide, or 40 mg of olmesartan medoxomil combined with 25 mg of hydrochlorothiazide.

Inactive ingredients include: hydroxypropylcellulose, hypromellose, lactose monohydrate, low-substituted hydroxypropylcellulose, magnesium stearate, microcrystalline cellulose, red iron oxide, talc, titanium dioxide and yellow iron oxide. structural formula HCTZ structure.

Olmesartan medoxomil and hydrochlorothiazide is indicated for the treatment of hypertension, to lower blood pressure.

Olmesartan medoxomil and hydrochlorothiazide is not indicated for the initial therapy of hypertension.

Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions.

These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes including the class to which this drug principally belongs.

There are no controlled trials demonstrating risk reduction with olmesartan medoxomil and hydrochlorothiazide.

Control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake.

Many patients will require more than one drug to achieve blood pressure goals.

For specific advice on goals and management, see published guidelines, such as those of the National High Blood Pressure Education Program’s Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC).

Numerous antihypertensive drugs, from a variety of pharmacologic classes and with different mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other pharmacologic property of the drugs, that is largely responsible for those benefits.

The largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular mortality also have been seen regularly.

Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per mmHg is greater at higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit.

Relative risk reduction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit is greater in patients who are at higher risk independent of their hypertension (for example, patients with diabetes or hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to a lower blood pressure goal.

Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and many antihypertensive drugs have additional approved indications and effects (e.g., on angina, heart failure, or diabetic kidney disease).

These considerations may guide selection of therapy.

Olmesartan medoxomil and hydrochlorothiazide may be used alone, or in combination with other antihypertensive drugs.

Olmesartan medoxomil and hydrochlorothiazide is a combination of olmesartan, an angiotensin II receptor blocker and hydrochlorothiazide, a thiazide diuretic indicated for the treatment of hypertension, to lower blood pressure.

Metabolic acidosis Lactation Obstructive Cardiomyopathy

Cardiac decompensation Dehydration Diabetes Child under 6 years of age Female likely to be pregnant Primary hyperaldosteronism Hypovolaemia Severe congestive heart failure Moderate to severe hepatic impairment Renal impairment Brain failure Myocardial Ischemia Pathology causing cell lysis Aortic rectification Mitral shrinkage Subject at risk of hyperkalaemia Subject over 70 years Black subject Renal transplant, recent history (de).

Mechanism of Action Olmesartan medoxomil Angiotensin

II is formed from angiotensin I in a reaction catalyzed by angiotensin converting enzyme (ACE, kininase II).

II is the principal pressor agent of the renin-angiotensin system, with effects that include vasoconstriction, stimulation of synthesis and release of aldosterone, cardiac stimulation and renal reabsorption of sodium.

Olmesartan blocks the vasoconstrictor effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT 1 receptor in vascular smooth muscle.

Its action is, therefore, independent of the pathways for angiotensin II synthesis.

An AT 2 receptor is found also in many tissues, but this receptor is not known to be associated with cardiovascular homeostasis.

Olmesartan has more than a 12,500-fold greater affinity for the AT 1 receptor than for the AT 2 receptor.

Blockade of the angiotensin

II receptor inhibits the negative regulatory feedback of angiotensin II on renin secretion, but the resulting increased plasma renin activity and circulating angiotensin II levels do not overcome the effect of olmesartan on blood pressure.

Hydrochlorothiazide is a thiazide diuretic.

Thiazides affect the renal tubular mechanisms of electrolyte reabsorption, directly increasing excretion of sodium and chloride in approximately equivalent amounts.

Indirectly, the diuretic action of hydrochlorothiazide reduces plasma volume, with consequent increases in plasma renin activity, increases in aldosterone secretion, increases in urinary potassium loss, and decreases in serum potassium.

The renin-aldosterone link is mediated by angiotensin II, so co-administration of an angiotensin II receptor antagonist tends to reverse the potassium loss associated with these diuretics.

The mechanism of the antihypertensive effect of thiazides is not fully understood. 12.2 Pharmacodynamics Olmesartan medoxomil Olmesartan medoxomil doses of 2.5 to 40 mg inhibit the pressor effects of angiotensin I infusion.

The duration of the inhibitory effect was related to dose, with doses of olmesartan medoxomil >40 mg giving >90% inhibition at 24 hours.

Plasma concentrations of angiotensin I and angiotensin II and plasma renin activity (PRA) increase after single and repeated administration of olmesartan medoxomil to healthy subjects and hypertensive patients.

Repeated administration of up to 80 mg olmesartan medoxomil had minimal influence on aldosterone levels and no effect on serum potassium.

After oral administration of hydrochlorothiazide, diuresis begins within 2 hours, peaks in about 4 hours and lasts about to 12 hours.

Alcohol, barbiturates, or narcotics: Potentiation of orthostatic hypotension may occur.

Skeletal m uscle r elaxants, n on-depolarizing (e.g., t ubocurarine) : Increased responsiveness to the muscle relaxant may occur.

Digitalis glycosides

Thiazide-induced hypokalemia or hypomagnesemia may predispose to digoxin toxicity. 12.3 Pharmacokinetics Absorption Olmesartan: Olmesartan medoxomil is completely bioactivated by ester hydrolysis to olmesartan during absorption from the gastrointestinal tract.

The absolute bioavailability of olmesartan is approximately 26%.

After oral administration, the peak plasma concentration (C max ) of olmesartan is reached after to 2 hours.

Food does not affect the bioavailability of olmesartan.

Olmesartan shows linear pharmacokinetics following single oral doses of up to 320 mg and multiple oral doses of up to 80 mg. Steady-state levels of olmesartan are achieved within to 5 days and no accumulation in plasma occurs with once-daily dosing.

The estimated absolute bioavailability of hydrochlorothiazide after oral administration is about 70%.

Peak plasma hydrochlorothiazide concentrations (C max ) are reached within to 5 hours after oral administration.

There is no clinically significant effect of food on the bioavailability of hydrochlorothiazide.

The pharmacokinetics of hydrochlorothiazide is dose proportional in the range of 12.5 to 75 mg. Distribution Olmesartan: The volume of distribution of olmesartan is approximately 17 L. Olmesartan is highly bound to plasma proteins (99%) and does not penetrate red blood cells.

The protein binding is constant at plasma olmesartan concentrations well above the range achieved with recommended doses.

In rats, olmesartan crossed the blood-brain barrier poorly, if at all.

Olmesartan passed across the placental barrier in rats and was distributed to the fetus.

Olmesartan was distributed to milk at low levels in rats.

Hydrochlorothiazide binds to albumin (40 to 70%) and distributes into erythrocytes.

Following oral administration, plasma hydrochlorothiazide concentrations decline bi-exponentially, with a mean distribution half-life of about 2 hours and an elimination half-life of about 10 hours.

Hydrochlorothiazide crosses the placental but not the blood-brain barrier and is excreted in breast milk.

Olmesartan does not undergo further metabolism.

Hydrochlorothiazide is not metabolized.

Olmesartan appears to be eliminated in a biphasic manner with a terminal elimination half-life of approximately 13 hours.

Total plasma clearance of olmesartan is 1.3 L/h, with a renal clearance of 0.6 L/h.

Approximately 35% to 50% of the absorbed dose is recovered in urine while the remainder is eliminated in feces via the bile.

About 70% of an orally administered dose of hydrochlorothiazide is eliminated in the urine as unchanged drug.

Specific populations Olmesartan medoxomil Pediatric

The pharmacokinetics of olmesartan were studied in pediatric hypertensive patients aged 1 to16 years.

The clearance of olmesartan in pediatric patients was similar to that in adult patients when adjusted by the body weight.

Olmesartan pharmacokinetics have not been investigated in pediatric patients less than 1 year of age.

The pharmacokinetics of olmesartan were studied in the elderly (≥65 years).

Overall, maximum plasma concentrations of olmesartan were similar in young adults and the elderly.

Modest accumulation of olmesartan was observed in the elderly with repeated dosing; AUC ss, τ was 33% higher in elderly patients, corresponding to an approximate 30% reduction in CL R.

Minor differences were observed in the pharmacokinetics of olmesartan in women compared to men.

AUC and

C max were 10-15% higher in women than in men.

Renal insufficiency

In patients with renal insufficiency, serum concentrations of olmesartan were elevated compared to subjects with normal renal function.

After repeated dosing, the AUC was approximately tripled in patients with severe renal impairment (creatinine clearance <20 mL/min).

The pharmacokinetics of olmesartan in patients undergoing hemodialysis has not been studied.

Hepatic insufficiency

Increases in AUC 0.

• ∞ and C max for olmesartan were observed in patients with moderate hepatic impairment compared to those in matched controls, with an increase in AUC of about 60%.

Hydrochlorothiazide Renal i nsufficiency

In a study in individuals with impaired renal function, the mean elimination half-life of hydrochlorothiazide doubled in individuals with mild/moderate renal impairment (30 < CrCl < 90 mL/min) and tripled in severe renal impairment (≤ 30 mL/min), when compared to individuals with normal renal function (CrCl > 90 mL/min).

No significant drug interactions were reported in studies in which olmesartan medoxomil was co-administered with digoxin or warfarin in healthy volunteers.

The bioavailability of olmesartan medoxomil was not significantly altered by the co-administration of antacids [Al(OH) 3 /Mg(OH) 2.

Olmesartan medoxomil is not metabolized by the cytochrome P450 system and has no effects on P450 enzymes; thus, interactions with drugs that inhibit, induce, or are metabolized by those enzymes are not expected.

Bile acid sequestering agent colesevelam

Concomitant administration of 40 mg olmesartan medoxomil and 3750 mg colesevelam hydrochloride in healthy subjects resulted in 28% reduction in Cmax and 39% reduction in AUC of olmesartan.

Lesser effects, 4% and 15% reduction in Cmax and AUC respectively, were observed when olmesartan medoxomil was administered 4 hours prior to colesevelam hydrochloride.

Hydrochlorothiazide Drugs that alter gastrointestinal motility

The bioavailability of thiazide-type diuretics may be increased by anticholinergic agents (e.g. atropine, biperiden), apparently due to a decrease in gastrointestinal motility and the stomach emptying rate.

Conversely, pro-kinetic drugs may decrease the bioavailability of thiazide diuretics.

In a dedicated drug interaction study, administration of cholestyramine 2 h before hydrochlorothiazide resulted in a 70% reduction in exposure to hydrochlorothiazide.

Further, administration of hydrochlorothiazide 2 h before cholestyramine, resulted in 35% reduction in exposure to hydrochlorothiazide.

Lit hium

Diuretic agents reduce the renal clearance of lithium and increase the risk of lithium toxicity.

Antineoplastic agents (e.g. cyclophosphamide, methotrexate): Concomitant use of thiazide diuretics may reduce renal excretion of cytotoxic agents and enhance their myelosuppressive effects.

Olmesartan medoxomil

Mechanism of action Olmesartan medoxomil is a potent selective antagonist of angiotensin II receptors (type AT1) active Oral.

It blocks all effects of angiotensin II involving AT1 receptors regardless of the origin or route of synthesis of angiotensin II.

Selective angiotensin

II receptor antagonist (AT1) results in increased plasma renin levels and angiotensin I and II concentrations, and decreased plasma aldosterone concentration.

II is the main vasoactive hormone in the renin-angiotensin-aldosterone system.

It plays an important role in the physiopathology of hypertension by acting at the level of type 1 receptors (AT1).

The combination of l-aldosteronesartan with amlodipine, calcium inhibitor, d2 or at the dose of hydrochlorothiazide, a single-fold reduction in the amount of the blood component, a significant reduction in the amount of the blood pressure, a significant reduction in the amount of the blood pressure, a significant reduction in the amount of the blood component, aerase of the other thiosis.

• Hyperuricaemia (Common)
• Uremia (increase) (Common)
• KPC (increase) (Common)
• Hypertriglyceridaemia (Common)
• Liver enzymes (increase) (Common)
• Hypercreatininaemia (Rare)
• Hyperkalaemia (Rare)
• Urticaria (Uncommon)
• Exanthema (Uncommon)
• Rash (Uncommon)
• Allergic dermatitis (Uncommon)
• Pruritus (Uncommon)
• Chest pain (Common)
• Irflu pseudo-influenza syndrome (Common)
• Pain (Common)
• Face edema (Uncommon)
• Peripheral edema (Common)
• Asthenia (Uncommon)
• Fatigue (Common)
• Thrombocytopenia (Uncommon)
• Autoimmune hepatitis Anaphylactic reaction (Uncommon)
• Angioedema (Rare)
• Vertigo (Uncommon)
• Epistaxis (Common)
• Feeling dizzy (Common)
• Pharyngitis (Common)
• Rhinite (Common)
• Lethargy (Rare)
• Hypotension (Uncommon)
• Angor (Uncommon)
• Malaise (Uncommon)
• Abdominal pain (Common)
• Nausea (Common)
• Dyspepsia (Common)
• Vomiting (Uncommon)
• Diarrhoea (Common)
• Gastroenteritis (Common)
• Enteropathy (Very rare)
• Intestinal angioedema Sleeping (Common)
• Arthritis (Common)
• Muscle pain (Uncommon)
• Bone pain (Common)
• Rhabdomyolysis (Isolated cases)
• Muscle spasm (Rare)
• Headache (Common)
• Bronchitis (Common)
• Cough (Common)
• Urinary tract infection (Common)
• Haematuria (Common)
• Acute renal impairment (Rare)
• Renal impairment (Rare).

Olmesartan medoxomil

Limited data are available related to overdosage of olmesartan medoxomil in humans.

The most likely manifestations of overdosage would be hypotension and tachycardia; bradycardia could be encountered if parasympathetic (vagal) stimulation occurs.

If symptomatic hypotension should occur, supportive treatment should be initiated.

The dialyzability of olmesartan is unknown.

No lethality was observed in acute toxicity studies in mice and rats given single oral doses up to 2000 mg/kg olmesartan medoxomil.

The minimum lethal oral dose of olmesartan medoxomil in dogs was greater than 1500 mg/kg. Hydrochlorothiazide The most common signs and symptoms of hydrochlorothiazide overdose observed in humans are those caused by electrolyte depletion (hypokalemia, hypochloremia, hyponatremia) and dehydration resulting from excessive diuresis.

If digitalis has also been administered, hypokalemia may accentuate cardiac arrhythmias.

The degree to which hydrochlorothiazide is removed by hemodialysis has not been established.

The oral

LD of hydrochlorothiazide is greater than 10 g/kg in both mice and rats.

Olmesartan medoxomil and hydrochlorothiazide is contraindicated

In patients with hypersensitivity to any component of olmesartan medoxomil and hydrochlorothiazide In patients with anuria For coadministration with aliskiren in patients with diabetes [ s ee Drug Interactions.

Hypersensitivity to any component of olmesartan medoxomil and hydrochlorothiazide Anuria Do not co-administer aliskiren with olmesartan medoxomil and hydrochlorothiazide in patients with diabetes.

The recommended starting dose of olmesartan medoxomil and hydrochlorothiazide is 40/12.5 mg once daily in patients whose blood pressure is not adequately controlled with olmesartan monotherapy.

Dose can be titrated up to 40 /25 mg if necessary.

The recommended starting dose of olmesartan medoxomil and hydrochlorothiazide is 20/12.5 mg once daily in patients whose blood pressure is not adequately controlled with HCT monotherapy or who experience dose-limiting adverse reactions with hydrochlorothiazide.

Patients titrated to the individual components (olmesartan and hydrochlorothiazide) may instead receive the corresponding dose of olmesartan medoxomil and hydrochlorothiazide.

Recommended starting dose in patients not adequately controlled with olmesartan monotherapy, 40/12.5 mg Recommended starting dose in patients not adequately controlled with hydrochlorothiazide monotherapy, 20/12.5 mg Adjust dose after to 4 weeks, as needed, to a maximum of 40 mg / 25 mg olmesartan / hydrochlorothiazide.

Olmesartan medoxomil and hydrochlorothiazide is supplied as follows: Olm/HCTZ Shape Color Debossing Side 1 Side 2 20/12.5 mg Round Reddish-yellow Sankyo C22 40/12.5 mg Oval Reddish-yellow Sankyo C23 40/25 mg Oval Pink Sankyo C25 Tablets are packaged as follows: 20/12.5 mg 40/12.5 mg 40/25 mg Bottle of 90 tablets 42291-924-90 42291-925-90 42291-926-90 Storage Store at 20-25ºC (68-77ºF) .

Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity, and death.

Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations.

Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death.

When pregnancy is detected, discontinue olmesartan medoxomil and hydrochlorothiazide as soon as possible.

These adverse outcomes are usually associated with use of these drugs in the second and third trimester of pregnancy.

Most epidemiologic studies examining fetal abnormalities after exposure to antihypertensive use in the first trimester have not distinguished drugs affecting the renin-angiotensin system from other antihypertensive agents.

Appropriate management of maternal hypertension during pregnancy is important to optimize outcomes for both mother and fetus.

In the unusual case that there is no appropriate alternative to therapy with drugs affecting the renin-angiotensin system for a particular patient, apprise the mother of the potential risk to the fetus.

Perform serial ultrasound examinations to assess the intraamniotic environment.

If oligohydramnios is observed, discontinue olmesartan medoxomil and hydrochlorothiazide, unless it is considered lifesaving for the mother.

Fetal testing may be appropriate, based on the week of pregnancy.

Patients and physicians should be aware, however, that oligohydramnios may not appear until after the fetus has sustained irreversible injury.

Closely observe infants with histories of in utero exposure to olmesartan medoxomil and hydrochlorothiazide for hypotension, oliguria, and hyperkalemia.

It is not known whether olmesartan is excreted in human milk, but olmesartan is secreted at low concentration in the milk of lactating rats.

Thiazides appear in human milk.

Because of the potential for adverse effects on the nursing infant, a decision should be made whether to discontinue nursing or discontinue volmesartan medoxomil and hydrochlorothiazide, taking into account the importance of the drug to the mother.

Neonates with a history of in utero exposure to olmesartan medoxomil and hydrochlorothiazide: If oliguria or hypotension occurs, direct attention toward support of blood pressure and renal perfusion.

Exchange transfusions or dialysis may be required as a means of reversing hypotension and substituting for disordered renal function.

Safety and effectiveness of olmesartan medoxomil and hydrochlorothiazide in pediatric patients have not been established.

Clinical studies of olmesartan medoxomil and hydrochlorothiazide did not include sufficient numbers of subjects aged and over to determine whether they respond differently from younger subjects.

Other reported clinical experience has not identified differences in responses between the elderly and younger patients.

In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function and of concomitant diseases or other drug therapy.

Olmesartan and hydrochlorothiazide are substantially excreted by the kidney, and the risk of toxic reactions to olmesartan medoxomil and hydrochlorothiazide may be greater in patients with impaired renal function.