FORMULATION
Each film coated tablet contains :
Olmesartan medoxomil 20mg
Hydrochlorothiazide 12.5mg
Each film coated tablet contains:
Olmesartan medoxomil 40mg
Hydrochlorothiazide 12.5mg
DESCRIPTION
Olmesartan medoxomil is described chemically as 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.
Olmesartan medoxomil, a prodrug, is hydrolyzed to Olmesartan during absorption from the gastrointestinal tract. It is a non-peptide angiotensin II which selectively and competitively inhibits the type 1 Angiotensin II receptors without affecting the other receptors regulating the cardiovascular system.
Hydrochlorothiazide is 6-chloro-3,4-dihydro-2H-1,2,4-benzo-thiadiazine-7-sulfonamide 1,1-dioxide. 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.
PHARMACOLOGY
Mechanism of Action
Olmesartan
Angiotensin II is formed from angiotensin I in a reaction catalyzed by angiotensin converting enzyme (ACE, kininase II). Angiotensin II is the principal pressor agent of the rennin-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 AT1 receptor in vascular smooth muscle. Its action is therefore, independent of the pathways for angiotensin II synthesis.
An AT2 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 AT1 receptor than for the AT2 receptor.
Blockade of the rennin-angiotensin system with ACE inhibitors, which inhibit the biosynthesis of angiotensin II from angiotensin I, is a mechanism of many drugs used to treat hypertension. ACE inhibitors also inhibit the degradation of bradykinin, a reaction also catalyzed by ACE. Because Olmesartan medoxomil does not inhibit Ace (kininase II), it does not affect the response to bradykinin. Whether this difference has clinical relevance is not yet known.
Blockade of the angiotensin II receptor inhibits the negative regulatory feedback of angiotensin II on rennin secretion, but the resulting increased plasma rennin activity and circulating angiotensin II levels do not overcome the effect of Olmesartan on blood pressure.
Hydrochlorothiazide
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 rennin activity, increases in aldosterone secretion, increases in urinary loss, and decreases in serum potassium. The rennin-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.
PHARMACOKINETICS
General
Olmesartan medoxomil
Olmesartan medoxomil is rapidly absorbed and completely bioactivated by ester hydrolysis to Olmesartan during absorption from the gastrointestinal tract. Olmesartan appears to be eliminated in a biphasic manner with a terminal elimination half-life of approximately 13 hours. Olmesartan shows linear pharmacokinetics following single oral doses of up to 320 mg and multiple doses of up to 80 mg. Steady-state levels of Olmesartan are achieved within 3 to 5 days and no accumulation in plasma occurs with once-daily dosing. The absolute bioavailability of Olmesartan is approximately 26%. After oral administration, the peak plasma concentration (Cmax) of Olmesartan is reached after 1 to 2 hours. Food does not affect the bioavailability of Olmesartan.
Hydrochlorothiazide
When plasma levels have been followed for at least 24 hours, the plasma half-life has been observed to vary between 5.6 and 14.8 hours.
Metabolism and Excretion
Olmesartan medoxomil
Following the rapid and complete conversion of Olmesartan medoxomil to Olmesartan during absorption, there is virtually no further metabolism of Olmesartan. 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.
Hydrochlorothiazide
Hydrochlorothiazide is not metabolized but is eliminated rapidly by the kidney. At least 61% of the oral dose is eliminated unchanged within 24 hours.
Distribution
Olmesartan medoxomil
The volume of distribution of Olmesartan is approximately 17L. 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. 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
Hydrochlorothiazide crosses the placental but not the blood-brain barrier and is excreted in breast milk.
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 rennin 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.
Hydrochlorothiazide
After oral administration of Hydrochlorothiazide, diuresis begins within 2 hours, peaks in about 4 hours and lasts about 6 to 12 hours.
INDICATIONS
For the treatment of hypertension. This fixed dose combination is not indicated for initial therapy.
CONTRAINDICATIONS
Contraindicated in patients who are hypersensitive to any component of this product. Because of the Hydrochlorothiazide component, this product is contraindicated in patients with anuria or hypersensitivity to other sulfonamide-derived drugs.
WARNINGS
Fetal/Neonatal Morbidity and Mortality
The use of drugs that act directly on the renin–angiotensin system during the second and third trimesters of pregnancy has been associated with fetal and neonatal injury including hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure and death. Oligohydramnios has also been reported, presumably resulting from decreased fetal function. Prematurity, intrauterine growth retardation and patent ductus arteriosus have also been reported, although it is not clear whether these occurrences were due to exposure to the drug.
These adverse effects do not appear to have resulted from intrauterine drug exposure that has been limited to the first trimester. Mothers whose embryos and fetuses are exposed to an angiotensin II receptor antagonist only during the first trimester should be so informed. Nonetheless, when patients become pregnant, physicians should have the patient discontinue the use of Olmesartan as soon as possible.
Infants with histories of in utero exposure to an angiotensin II receptor antagonist should be closely observed for hypotension, oliguria and hyperkalemia. If oliguria occurs, attention should be directed toward support of blood pressure and renal perfusion. Exchange transfusion or dialysis may be required as means of reversing hypotension and/or substituting for disordered renal function.
Hypotension in Volume- or Salt-Depleted Patients
In patients with activated renin-angiotensin system, such as volume- and/or salt-depleted patients (e.g. those being treated with high doses of diuretics), symptomatic hypotension may occur after initiation of treatment with Olmesartan. Treatment should start under close medical supervision. If hypotension does occur, the patient should be placed in the supine position and. If necessary, given an intravenous infusion of normal saline (See Dosage and Administration). A transiet hypotensive response is not a contraindication to further treatmentm, which usually can ve continued without difficulty once the blood pressure has stabilized.
Hydrochlorothiazide
Hepatic impairment
Thiazides should be used with caution in patients with imapired hepatic function or progressive liver disease, since minor alterations of fluid and electrolyte balance may precipitate hepatic coma.
Hypersensitivity Reaction
Hypersensitivity reactions to hydrochlorothiazide may occur in patients with or wihout a history of allergy or bronchial asthma, but are more likely in patients with such a history.
Systemic Lupus Erythematosus
Thiazide diuretics have been reported to cause exacerbation or activation of systemic lupus erythematosus.
Lithium Interaction
Lithium generally shoud not be given with thiazides.
PRECAUTIONS
General
Impaired Renal Function: As a consequence of inhibiting the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in susceptible individuals treated with Olmesartan medoxomil. In patients hose renal function may depend upon the activity of the renin-angiotensin-aldosterone system (e.g. patients with severe congestive heart failure), treatment with angiotensin converting enzyme inhibitors and angiotensin receptor antagonistshas been associated with oliguria and/or progressive azotemia and (rarely) with acute renal failure and/or death. Similar results may be anticipated in patients treated with Olmesartan medoxomil.
In studies of ACE inhibitors in patients with unilateral or bilateral artery stenosis, increases in serum creatinine or blood aurea nitrogen (BUN) have been reported. There has been a long-term use of olmesartan medoxomil in patients with unilateral or bilateral renal artery stenosis, but similar results may be expected.
Pregnancy: Female patients of childbearing age should be told about the consequences of second and third trimester exposure to drugs that act on the renin-angiotensin system and they should be told also that these consequences do not appear to have resulted from intrauterine drug exposure that has been limited to the first trimester. These patients should be asked to report pregnancies to their physicians as soon as possible.
Symptomatic Hypotension: A patient receiving Olmesartan medoxomil + Hydrochlorothiazide should be cautioned that light-headedness can occur, especially during the first days of therapy, and that it should be reported to the prescribing physician. The patients should be told that if syncope occurs, Olmesartan medoxomil + Hydrochlorothiazide should be discontinued until the physician has been consulted.
All patients should be cautioned that inadequate fluid intake, excessive perspiration, diarrhea or vomiting can lead to an excessive fall in blood pressure, with the same consequences of light headedness and possible syncope
DRUG INTERACTIONS
Olmesartan medoxomil. 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 was not significantly altered by a 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.
Hydrochlorothiazide. When administered concurrently the following drugs may interact with thiazide diuretics:
Alcohol, Barbituarates, Or Narcotics – potentiation of orthostatic hypotension may occur.
Antidiabetic Drugs (oral agents and insulin) –dosage adjustment of the antidiabetic drug may be required.
Other Antihypertensive Drugs – additive effect or potentiation.
Cholestyramine and Colestipol Resins – absorption of Hydrochlorothiazide is impaired in the presence of anionic exchange resins. Single doses of either cholestyramine or colestipol resins bind the hydrochlorothiazide and reduce its absorption from the gastrointestinal tract by up to 85 and 43 percent, respectively.
Corticosteroids, ACTH – intensified electrolyte depletion, particularly hypokalemia.
Pressor Amines (e.g. Norepinephrine) – possible decreased response to pressor amines but not sufficient to preclude their use.
Skeletal Muscle relaxants, Non depolarizing (e.g. Tubocurarine) – possible increased responsiveness to the muscle relaxant.
Lithium – should not generally be given with diuretics. Diuretic agents reduce the renal clearance of lithium and add a high risk of lithium toxicity. Refer to the package insert for lithium preparations before use of such preparation with olmesartan medoxomil-hydrochlorothiazide.
Non-steroidal Anti-inflammatory Drugs – in some patients the administration of a non-steroidal anti-inflammatory agent can reduce the diuretic, natriuretic and antihypertensive effects of loop, potassium-sparing and thiazide diuretics. Therefore, when Olmesartan medoxomil+Hydrochlorothiazide tablets and non-steroidal anti-inflammatory agents are used concomitantly, the patients should be observed closely to determine if the desired effect of the diuretic is obtained.
CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY
Olmesartan medoxomil + Hydrochlorothiazide
No carcinogenicity studies with Olmesartan medoxomil + Hydrochlorothiazide have been conducted.
Olmesartan medoxomil+Hydrochlorothiazide in a ratio of 20:12.5 was negative in the Salmonella-Escherichia coli mammalian microsome reverse mutation test up to the maximum recommended plate concentration for the standard assays. No studies of impairment of fertility with Olmesartan medoxomil+Hydrochlorothiazide have been conducted.
NURSING MOTHERS
It is not known whether Olmesartan is excreted in human milk, but Olmesartan is secreted at low concentration in the milk of lactating rats. Because of the potential for adverse effects on the nursing infant, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.
PEDIATRIC USE
Safety and effectiveness in pediatric patients have not been established.
GERIATRIC USE
No overall differences in effectiveness or safety were observed between elderly patients 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 medoxomil and Hydrochlorothiazide are substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function.
ADVERSE REACTIONS
Olmesartan medoxomil + Hydrochlorothiazide
Treatment with Olmesartan medoxomil + Hydrochlorothiazide was well tolerated. Events generally were mild, transient and had no relationship to the dose of Olmesartan medoxomil + Hydrochlorothiazide.
The following adverse events are headache and urinary tract infection.
Other adverse events are listed below:
Body as a Whole: chest pain, peripheral edema
Central and Peripheral Nervous System: vertigo
Gastrointestinal: abdominal pain, dyspepsia, gastroenteritis, nausea
Liver and Biliary System: SGOT increased, GGT increased, SGPT increased
Metabolic and Nutritional: hyperlipemia, creatine phosphokinase increased, hyperglycemia
Musculoskeletal: arthralgia, arthritis, myalgia
Respiratory System: coughing
Skin and Appendages Disorders: rash
Urinary System: hematuria
Facial edema may occur receiving Olmesartan medoxomil + Hydrochlorothiazide. Angioedema has been reported with angiotensin II antagonists.
Laboratory Test Findings
Clinically important changes in standard laboratory parameters were rarely associated with administration of Olmesartan medoxomil+Hydrochlorothiazide.
Creatinine, Blood Urea Nitrogen : Increases in blood urea nitrogen (BUN) and serum creatinine of >50% were observed. No patients were discontinued from clinical trials of Olmesartan medoxomil+Hydrochlorothiazide due to increased BUN or creatinine.
Hemoglobin and Hematocrit: A greater than 20% decrease in hemoglobin and hematocrit was observed. No patients were discontinued due to anemia.
Post-marketing Experience: The following adverse reactions have been reported in post-marketing experience:
Body as a whole :Asthenia, angiodema
Gastrointestinal :Vomiting
Musculoskeletal : Rhabdomyolysis
Urogenital System : Acute renal failure, increased blood creatinine levels
Skin and Appendages : Alopecia, pruritus, urticaria
OVERDOSAGE
Olmesartan medoxomil
Limited data are available related to overdosage 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.
Hydrochlorothiazide
The most common signs and symptoms of 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 LD50 of Hydrochlorothiazide is greater than 10g/kg in both mice and rats.
DOSAGE AND ADMINISTRATION
The usual recommended starting dose of Olmesartan 20 mg once daily when used as monotherapy in patients who are not volume contracted. For patients requiring further reduction in blood pressure after two weeks of therapy the dose of Olmesartan may be increased to 40 mg. Doses above 40 mg do not appear to have greater effect. Twice-daily dosing offers no advantage over the same total dose given once-daily.
No initial dosage adjustment is recommended for elderly patients, for patients with moderate to marked renal impairment (creatinine clearance <40mL/min) or with moderate to marked hepatic dysfunction. For patients with possible depletion of intravascular volume (e.g. patients treated with diuretics, particularly those with impaired renal function). No initial dosage adjustment is recommended for elderly patients, for patients with moderate to marked renal impairment (creatinine clearance <40mL/min) or with moderate to marked hepatic dysfunction (see CLINICAL PHARMACOLOGY, Special Populations). For patients with possible depletion of intravascular volume (e.g., patients treated with diuretics, particularly those with impaired renal function), Olmesartan medoxomil + Hydrochlorothiazide should be initiated under close medical supervision and consideration should be given to use of a lower starting dose (see WARNINGS, Hypotension in Volume- or Salt-Depleted Patients).
Hydrochlorothiazide is effective in doses between 12.5 mg and 50 mg once daily.
The side effects (see WARNINGS) of Olmesartan medoxomil + Hydrochlorothiazide are generally rare and independent of dose; those of Hydrochlorothiazides are most typically dose-dependent (primarily hypokalemia). Some dose-independent phenomena (e.g., pancreatitis) do occur with hydrochlorothiazide. Therapy with any combination of Olmesartan medoxomil and hydrochlorothiazide will be associated with both sets of dose-independent side effects. To minimize dose-independent side effects, it is usually appropriate to begin combination therapy only after a patient has failed to achieve the desired effect with monotherapy.
Replacement Therapy
Olmesartan medoxomil + Hydrochlorothiazide may be substituted for its titrated components.
Dose Titration by Clinical Effect
Olmesartan medoxomil + Hydrochlorothiazide are available in strengths of 20 mg/12.5 mg, 20mg/25mg, 40 mg/12.5 mg and 40 mg/25 mg. A patient whose blood pressure is inadequately controlled by Olmesartan medoxomil or Hydrochlorothiazide alone may be switched to once daily Olmesartan medoxomil + Hydrochlorothiazide.
Dosing should be individualized. Depending on the blood pressure response, the dose may be titrated at intervals of 2-4 weeks.
If blood pressure is not controlled by Olmesartan medoxomil alone, Hydrochlorothiazide may be added starting with a dose of 12.5 mg and later titrated to 25 mg once daily.
If a patient is taking Hydrochlorothiazide, Olmesartan medoxomil may be added starting with a dose of 20 mg once daily and titrated to 40 mg, for inadequate blood pressure control. If large doses of Hydrochlorothiazide have been used as monotherapy and volume depletion or hyponatremia is present, caution should be used when adding Olmesartan medoxomil or switching to Olmesartan medoxomil + Hydrochlorothiazide as marked decreases in blood pressure may occur (see WARNINGS, Hypotension in Volume- or Salt-Depleted Patients). Consideration should be given to reducing the dose of Hydrochlorothiazide to 12.5 mg before adding Olmesartan medoxomil. The antihypertensive effect of Olmesartan medoxomil + Hydrochlorothiazide is related to the dose of both components over the range of 10 mg/12.5 mg to 40 mg/25 mg (see CLINICAL PHARMACOLOGY, Clinical Trials). The dose of Olmesartan medoxomil + Hydrochlorothiazide is one tablet once daily. More than one tablet daily is not recommended.
Olmesartan medoxomil + Hydrochlorothiazide may be administered with other antihypertensive agents.
Patients with Renal Impairment
The usual regimens of therapy with Olmesartan medoxomil + Hydrochlorothiazide may be followed provided the patient’s creatinine clearance is >30 mL/min. In patients with more severe renal impairment, loop diuretics are preferred to thiazides, so Olmesartan medoxomil + Hydrochlorothiazide is not recommended.
Patients with Hepatic Impairment
No dosage adjustment is necessary with hepatic impairment (see CLINICAL PHARMACOLOGY, Special Populations).
Olmesartan medoxomil + Hydrochlorothiazide may be administered with or without food.
STORE AT TEMPERATURES NOT EXCEEDING 30ºC. PROTECT FROM LIGHT.
CAUTION
Foods, Drugs, Devices and Cosmetics Act prohibits dispensing without prescription.
AVAILABILITY
Olmesartan medoxomil + Hydrochlorothiazide 20 mg / 12.5 mg Tablet X 30 tablets / box / Alu-alu blister pack
Olmesartan medoxomil + Hydrochlorothiazide 40 mg / 12.5 mg Tablet X 30 tablets / box / Alu-alu blister pack
