Each tablet contains :
Olmesartan medoxomil 20mg
Olmesartan medoxomil 40mg
Treatment of essential hypertension.
DOSAGE AND ADMINISTRATION
The recommended starting dose of Olmesartan medoxomil in adult patients who are not salt or volume depleted is 20 mg once daily. In patients whose blood pressure is not adequately controlled at this dose, the dose of Olmesartan medoxomil may be increased to a maximum of 40 mg once daily. 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. Olmesartan medoxomil can be taken with or without food. It is recommended that Olmesartan medoxomil be taken at about the same time each day.
Volume or salt depleted patients
In patients who are salt and/or volume depleted, the recommended starting dose is 10mg (1/2 20mg tablet) once daily. Treatment should commence under close medical supervision.
The maximum dose in elderly patients is 20 mg Olmesartan medoxomil once daily, owing to limited experience of higher dosages in this patient group.
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.
The use of Olmesartan medoxomil is not recommended in patients with hepatic impairment, since there is only limited experience in this patient group.
Children and adolescents
The safety and efficacy of Olmesartan medoxomil has not been established in children and adolescents up to 18 years of age.
Patients who are hypersensitive to any component of this product. Second and third trimesters of pregnancy. Lactation. Biliary obstruction.
SPECIAL WARNINGS AND PRECAUTIONS FOR USE
Intravascular volume depletion
Symptomatic hypotension, especially after the first dose, may occur in patients who are volume and/or salt depleted. Such conditions should be corrected before the administration of Olmesartan medoxomil. If hypotension does occur, the patient should be placed in the supine position and, if necessary, given an intravenous infusion of normal saline. A transient hypotensive response is not a contraindication to further treatment, which usually can be continued without difficulty once the blood pressure has stabilized.
Pregnancy Categories C (first trimester) and D (second and third trimester)
There is no experience with the use of Olmesartan medoxomil in pregnant women. However, drugs that act directly on the renin-angiotensin system administered during the second and third trimesters of pregnancy have been reported to cause fetal and neonatal injury (hypotension, renal dysfunction, oliguria and/or anuria, oligohydramnios, skull hypoplasia, intrauterine growth retardation, lung hypoplasia, facial abnormalities, limb contracture) and even death. Thus, as for any drug in this class, Olmesartan medoxomil is contraindicated during the second and third trimesters of pregnancy. In addition, Olmesartan medoxomil must not be used during the first trimester. If pregnancy occurs during therapy, Olmesartan medoxomil must be discontinued as soon as possible.
Use during lactation
Olmesartan medoxomil is excreted in the milk of lactating rats but it is not known whether Olmesartan is excreted in human milk. Mothers must not breast-feed if they are taking Olmesartan medoxomil.
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 < 20mL/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 (creatinine clearance < 12 mL/min).
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.
There is currently limited experience in patients with mild to moderate hepatic impairment and no experience in patients with severe hepatic impairment, therefore the use of Olmesartan medoxomil in these patient groups is not recommended.
As with other angiotensin II antagonists and ACE inhibitors, hyperkalemia may occur during treatment with olmesartan medoxomil, especially in the presence of renal impairment and/or heart failure. Close monitoring of serum potassium levels in at risk patients is recommended.
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.
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.
As with any antihypertensive agent, excessive blood pressure reductions in patients with ischemic heart disease or ischemic cerebrovascular disease could result in myocardial infarction or stroke.
Mechanism of Action
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 AT1 receptor. Olmesartan medoxomil is a potent, orally active, selective angiotensin II receptor (type AT1) antagonist. It blocks all actions of angiotensin II mediated by the AT1 receptor.
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. The mean absolute bioavailability of Olmesartan from a tablet form is 25.6%.
The mean peak plasma concentration (Cmax) of Olmesartan is reached within about 2 hours after oral dosing with Olmesartan medoxomil. Olmesartan plasma concentrations increase approximately linearly with increasing single oral doses up to about 80mg. Steady-state levels of Olmesartan are achieved within 3 to 5 days and no accumulation in plasma occurs with once-daily dosing. Food has 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. The binding of Olmesartan to blood cells is negligible. The mean volume of distribution after intravenous dosing is low (16 – 29 L).
In rats, Olmesartan passes across the placental barrier and is distributed to milk.
Metabolism and Excretion
Total plasma clearance is typically 1.3 L/h and was relatively slow compared to hepatic blood flow (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 radioactivity was excreted in the faeces. Based on the systemic availability of 25.6%, it can be calculated that absorbed olmesartan is cleared by both renal excretion (40%) and hepato-biliary excretion (60%). All recovered radioactivity as identified as Olmesartan. No other significant metabolite was detected. Enteroheopatic recycling of Olmesartan is minimal. Since a large portion of Olmesartan is excreted via the biliary route, use in patients with biliary obstruction is contraindicated.
The terminal elimination half life of olmesartan varies between 12 and 15 hours after multiple dosing. Steady state is reached after the first few doses and no further accumulation is evident after 14 days or repeated dosing. Renal clearance is approximately 0.5 – 0.7 L/h and is independent of dose.
Pharmacokinetics in special populations
In hypertensive patients, the AUC at steady state was increased by 35% in elderly patients (65-75 years of age) and by 44% in elderly subjects 75 years of age or older compared with younger aged patients.
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.
After single oral administration, oral 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. Olmesartan medoxomil has not been evaluated in patients with severe hepatic impairment.
PRECLINICAL SAFETY DATA
In chronic toxicity studies in rats and dogs, Olmesartan medoxomil showed similar effects to other AT1 receptor antagonists and ACE inhibitors: raised blood urea (BUN) and creatinine (through functional changes to the kidneys caused by blocking AT1 receptors); reduction in heart weight; a reduction of red cell parameters (erythrocytes, hemoglobin, hematocrit); histological indications of renal damage (regenerative lesions of the renal epithelium, thickening of the basal membrane, dilatation of the tubules). These adverse effects caused by the pharmacological action of Olmesartan medoxomil have also occurred in preclinical trials on other AT1 receptor antagonists and ACE inhibitors and can be reduced by simultaneous oral administration of sodium chloride.
In both rats and dogs, increased plasma renin activity and hypertrophy/hyperplasia of the juxtaglomerular cells of the kidney were observed. These changes, which are a typical effect of the class of ACE inhibitors and other AT1 receptor antagonists, would appear to have no clinical relevance.
Like other AT1 receptor antagonists Olmesartan medoxomil was found to increase the incidence of chromosome breaks in cell cultures in vitro. No relevant effects were observed in several in vivo studies using Olmesartan medoxomil at very high oral doses of up to 2000 mg/kg. The overall data of a comprehensive genotoxicity testing suggest that Olmesartan is very unlikely to exert genotoxic effects under conditions of clinical use.
Olmesartan medoxomil was not carcinogenic, neither in rats in a 2 year study nor in mice when tested in two 6 month carcinogenicity studies using transgenic models.
In reproductive studies in rats, Olmesartan medoxomil did not affect fertility and there was no evidence of a teratogenic effect. In common with other angiotensin II antagonists, survival of offspring was reduced following exposure to Olmesartan medoxomil and pelvic dilatation of the kidney was seen after exposure of the dams in late pregnancy and lactation. In common with other antihypertensive agents, Olmesartan medoxomil was shown to be more toxic to pregnant rabbits than to pregnant rats, however, there was no indication of a fetotoxic effect.
Olmesartan has no clinically relevant inhibitory effects on in vitro human cytochrome P450 enzymes 1A1/2, 2A6, 2C8/9, 2C19, 2D6, 2E1 and 3A4, and has 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 above cytochrome P450 enzymes are expected.
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.
Other antihypertensive medications:
The blood pressure lowering effect of Olmesartan medoxomil can be increased by concomitant use of other antihypertensive medications.
Non-steroidal anti-inflammatory drugs (NSAIDs):
NSAIDs (including acetylsalicylic acid at doses> 3g/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.
After treatment with antacid (aluminium magnesium hydroxide), a modest reduction in bioavailability of Olmesartan was observed.
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.
No clinically relevant interactions were observed and in particular Olmesartan medoxomil had no significant effect on the pharmacokinetics or pharmacodynamics of warfarin.
No clinically relevant interactions were observed and in particular Olmesartan medoxomil had no significant effect on the pharmacokinetics or pharmacodynamics of digoxin.
In double-blind, placebo-controlled monotherapy studies, the overall incidence of treatment-emergent adverse events was 42.4% on Olmesartan medoxomil and 40.9% on placebo. 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).
In long-term (2-year) treatment, the incidence of withdrawals due to adverse events on Olmesartan medoxomil 10 – 20 mg once daily was 3.7%. The following adverse events have been reported across all clinical trials with Olmesartan medoxomil (including trials with active as well as placebo control), irrespective of causality or incidence relative to placebo. They are listed under headings of frequency:
Common (≥1/100, < 1/10) dizziness, bronchitis, cough, pharyngitis, rhinitis, abdominal pain, diarrhea, dyspepsia, gastroenteritis, nausea, arthritis, back pain, skeletal pain, hematuria, UTI, chest pain, fatigue, influenza-like symptoms, peripheral oedema, pain.
Uncommon (≥1/1,000, <1/100) Vertigo, angina pectoris, rash
Rare (≥1/10,000, <1/1,000) Hypotension
In placebo-controlled monotherapy studies, the incidence was somewhat higher on Olmesartan medoxomil compared with placebo for hypertriglyceridaemia (2.0% versus 1.1%) and for raised creatine phosphokinase (1.3% versus 0.7%). Laboratory adverse events reported across all clinical trials with Olmesartan medoxomil (including trials without a placebo control), irrespective of causality or incidence relative to placebo, included: increased creatine phosphokinase, hypertriglyceridaemia, hyperuricaemia, hyperkalaemia and liver enzyme elevations.
Rare cases of rhabdomyolysis have been reported in patients receiving angiotensin II receptor blockers.
Limited data is 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.
STORE AT TEMPERATURES NOT EXCEEDING 30ºC.
Foods, Drugs, Devices and Cosmetics Act prohibits dispensing without prescription.
Olmesartan medoxomil (Alzor) 20mg Tablet X 30 tablets / box / blister pack X 10’s
Olmesartan medoxomil (Alzor) 40mg Tablet X 30 tablets / box / blister pack X 10’s