Olbet 40 mg Tablet
1.0 Generic Name
Olmesartan Medoxomil Tablets 20 mg/40 mg
2.0 Qualitative and quantitative composition
OLBET-20
Each film coated tablet contains:
Olmesartan Medoxomil Tablets 20 mg
Excipients q.s.
Colour: Titanium Dioxide IP
OLBET-40
Each film coated tablet contains:
Olmesartan Medoxomil Tablets 40 mg
Excipients q.s.
Colour: Titanium Dioxide IP
3.0 Dosage form and strength
Film coated tablet
20/ 40 mg
4.0 Clinical particulars
4.1 Therapeutic Indication
Anti- Hypertension
Olmesartan is indicated for the management of Essential hypertension
4.2 Posology and method of administration
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.
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.
Older people (65 years or older)
No adjustment of dosage is generally required in older people (see below for dose recommendations in patients with renal impairment). If up-titration to the maximum dose of 40 mg daily is required, blood pressure should be closely monitored.
Patients with 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.
Patients with 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.
Paediatric population
Children and adolescents from 6 to less than 18 years of age. The recommended starting dose of olmesartan medoxomil in children from 6 to less than 18 years of age is 10 mg olmesartan medoxomil 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.
Other paediatric population
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 years of age because of safety concerns and lack of data in this age group.
Method of administration
In order to assist compliance, it is recommended that Olmesartan 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 be swallowed whole without chewing.
4.3 Contraindications
- Hypersensitivity to the active substance or to any of the excipients.
- Second and third trimesters of pregnancy.
- Biliary obstruction.
- The concomitant use of Olmesartan with aliskiren-containing products is contraindicated in patients with diabetes mellitus or renal impairment (GFR < 60 ml/min/1.73 m2)
4.4 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 sodium depleted by vigorous diuretic therapy, dietary salt restriction, diarrhoea 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, azotaemia, 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.
Hyperkalaemia:
The use of medicinal products that affect the renin-angiotensin-aldosterone system may cause hyperkalaemia.
The risk, that may be fatal, is increased in older 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 hyperkalaemia 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 class of medicinal products may provoke a hyperkalaemia: 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 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.
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 diarrhoea 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, exclude other etiologies. Consider discontinuation of olmesartan medoxomil in cases where no other etiology is identified. In cases where symptoms disappear and sprue-like enteropathy is confirmed by biopsy, treatment with olmesartan medoxomil should not be restarted.
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.
Pregnancy:
Angiotensin II receptor antagonists (AIIRAs) should not be initiated during pregnancy. Unless continued AIIRA therapy is considered essential, patients planning pregnancy should be changed to alternative anti-hypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with AIIRAs should be stopped immediately and, if appropriate, alternative therapy should be started.
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.
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, hyperkalaemia 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.
Olmesartan contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.
4.5 Drugs interactions
Paediatric population:
Interaction studies have only been performed in adults.
It is not known if the interactions in children are similar to those in adults.
Effects of other medicinal products on olmesartan medoxomil:
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 (> 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 (aluminium magnesium hydroxide), a modest reduction in bioavailability of olmesartan was observed. Coadministration of warfarin and digoxin had no effect on the pharmacokinetics of olmesartan.
Dual blockade of the renin-angiotensin-aldosterone system (RAAS)
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, hyperkalaemia and decreased renal function (including acute renal failure) compared to the use of a single RAAS-acting agent.
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 aluminium 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 metabolised by the above cytochrome P450 enzymes are expected.
4.6 Use in special populations
Pregnancy
The use of AIIRAs is not recommended during the first trimester of pregnancy. The use of AIIRAs is contraindicated during the second and third 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 AIIRAs, similar risks may exist for this class of drugs. Unless continued AIIRA therapy is considered essential, patients planning pregnancy should be changed to alternative anti-hypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with AIIRAs should be stopped immediately, and, if appropriate, alternative therapy should be started.
Exposure to AIIRA therapy 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, hyperkalaemia).
Should exposure to AIIRAs have occurred from the second trimester of pregnancy, ultrasound check of renal function and skull is recommended.
Infants whose mothers have taken AIIRAs 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 during breastfeeding, Olmesartan is not recommended and alternative treatments with better established safety profiles during breast-feeding are preferable, especially while nursing a newborn or preterm infant.
4.7 Effects on ability to drive and use machines
Olmesartan has minor or moderate influence on the ability to drive and use machines. Dizziness or fatigue may occasionally occur in patients taking antihypertensive therapy, which may impair the ability to react.
4.8 Undesirable effects
Summary of the safety profile:
The most commonly reported adverse reactions during treatmentwith olmesartan medoxomil 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 hypertriglyceridaemia (2.0% versus 1.1%) and for raised creatine phosphokinase (1.3% versus 0.7%).
Tabulated list of adverse reactions:
Adverse reactions from olmesartan medoxomil in clinical trials, post-authorisation safety studies and spontaneous reporting are summarized in the below table.
They are listed by System Organ Class and ranked under headings of frequency using the following convention: 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); not known (cannot be estimated from available data).
*Cases of autoimmune hepatitis with a latency of few months to years have been reported post-marketing, that were reversible after the withdrawal of olmesartan.
Single cases of rhabdomyolysis have been reported in temporal association with the intake of angiotensin II receptor blockers.
Additional information on special populations
In older people the frequency of hypotension is slightly increased from rare to uncommon.
Paediatric population:
The safety of olmesartan medoxomil was monitored in 361 children and adolescents, aged 1-17 years old during 2 clinical trials. Whilst the nature and severity of the adverse events are similar to that of the adults, the frequency of the following is higher in the children:
- Epistaxis is a common adverse event in children (i.e. ≥ 1/100 to < 1/10) that has not been reported in adults.
- During the 3 weeks of double blind study, the incidence of treatment emergent dizziness and headache nearly doubled in children 6-17 years of age in the high olmesartan medoxomil dose group.
The overall safety profile for olmesartan medoxomil in paediatric patients does not differ significantly from the safety profile in adults.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via email to:medico@zuventus.com
Website: https://www.zuventus.co.in/drug-safety-reporting
4.9 Overdose
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.
5.0 Pharmacological properties
5.1 Mechanism of Action/ Pharmacodynamic properties
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.
Clinical efficacy and safety
In hypertension, olmesartan medoxomil causes a dose-dependent, long-lasting reduction in arterial blood pressure. There has been no evidence of first-dose hypotension, of tachyphylaxis during long-term treatment, or of rebound hypertension after cessation of therapy.
Once daily dosing with olmesartan medoxomil provides an effective and smooth reduction in blood pressure over the 24-hour dose interval. Once daily dosing produced similar decreases in blood pressure as twice daily dosing at the same total daily dose.
With continuous treatment, maximum reductions in blood pressure are achieved by 8 weeks after the initiation of therapy, although a substantial proportion of the blood pressure lowering effect is already observed after 2 weeks of treatment. When used together with hydrochlorothiazide, the reduction in blood pressure is additive and coadministration is well tolerated.
The effect of olmesartan on mortality and morbidity is not yet known.
The Randomised Olmesartan and Diabetes Microalbuminuria Prevention (ROADMAP) study in 4447 patients with type 2 diabetes, normo-albuminuria and at least one additional cardiovascular risk factor, investigated whether treatment with olmesartan could delay the onset of microalbuminuria. During the median follow-up duration of 3.2 years, patients received either olmesartan or placebo in addition to other antihypertensive agents, except ACE inhibitors or ARBs.
For the primary endpoint, the study demonstrated a significant risk reduction in the time to onset of microalbuminuria, in favour of olmesartan. After adjustment for BP differences this risk reduction was no longer statistically significant. 8.2% (178 of 2160) of the patients in the olmesartan group and 9.8% (210 of 2139) in the placebo group developed microalbuminuria.
For the secondary endpoints, cardiovascular events occurred in 96 patients (4.3%) with olmesartan and in 94 patients (4.2%) with placebo. The incidence of cardiovascular mortality was higher with olmesartan compared to placebo treatment (15 patients (0.7%) vs. 3 patients (0.1%)), despite similar rates for non-fatal stroke (14 patients (0.6%) vs. 8 patients (0.4%)), non-fatal myocardial infarction (17 patients (0.8%) vs. 26 patients (1.2%)) and non-cardiovascular mortality (11 patients (0.5%) vs. 12 patients (0.5%)). Overall mortality with olmesartan was numerically increased (26 patients (1.2%) vs. 15 patients (0.7%)), which was mainly driven by a higher number of fatal cardiovascular events.
The Olmesartan Reducing Incidence of End-stage Renal Disease in Diabetic Nephropathy Trial (ORIENT) investigated the effects of olmesartan on renal and cardiovascular outcomes in 577 randomized Japanese and Chinese type 2 diabetic patients with overt nephropathy. During a median follow-up of 3.1 years, patients received either olmesartan or placebo in addition to other antihypertensive agents including ACE inhibitors.
The primary composite endpoint (time to first event of the doubling of serum creatinine, end-stage renal disease, all-cause death) occurred in 116 patients in the olmesartan group (41.1%) and 129 patients in the placebo group (45.4%) (HR 0.97 (95% CI 0.75 to 1.24); p=0.791). The composite secondary cardiovascular endpoint occurred in 40 olmesartan-treated patients (14.2%) and 53 placebo-treated patients (18.7%). This composite cardiovascular endpoint included cardiovascular death in 10 (3.5%) patients receiving olmesartan versus 3 (1.1%) receiving placebo, overall mortality 19 (6.7%) versus 20 (7.0%), non-fatal stroke 8 (2.8%) versus 11 (3.9%) and non-fatal myocardial infarction 3 (1.1%) versus 7 (2.5%), respectively.
Two large randomised, controlled trials (ONTARGET (ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial) and VA NEPHRON-D (The Veterans Affairs Nephropathy in Diabetes)) have examined the use of the combination of an ACE-inhibitor with an angiotensin II receptor blocker.
ONTARGET was a study conducted in patients with a history of cardiovascular or cerebrovascular disease, or type 2 diabetes mellitus accompanied by evidence of end-organ damage. VA NEPHRON-D was a study in patients with type 2 diabetes mellitus and diabetic nephropathy.
These studies have shown no significant beneficial effect on renal and/or cardiovascular outcomes and mortality, while an increased risk of hyperkalaemia, acute kidney injury and/or hypotension as compared to monotherapy was observed. Given their similar pharmacodynamic properties, these results are also relevant for other ACE-inhibitors and angiotensin II receptor blockers.
ACE-inhibitors and angiotensin II receptor blockers should therefore not be used concomitantly in patients with diabetic nephropathy.
ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints) was a study designed to test the benefit of adding aliskiren to a standard therapy of an ACE-inhibitor or an angiotensin II receptor blocker in patients with type 2 diabetes mellitus and chronic kidney disease, cardiovascular disease, or both. The study was terminated early because of an increased risk of adverse outcomes. Cardiovascular death and stroke were both numerically more frequent in the aliskiren group than in the placebo group and adverse events and serious adverse events of interest (hyperkalaemia, hypotension and renal dysfunction) were more frequently reported in the aliskiren group than in the placebo group.
Paediatric population:
The antihypertensive effects of olmesartan medoxomil in the paediatric population were evaluated in a randomized, double-blind, placebo-controlled study in 302 hypertensive patients aged 6 to 17 years. The study population consisted of an all-black cohort of 112 patients and a mixed racial cohort of 190 patients, including 38 blacks. The aetiology of the hypertension was predominantly essential hypertension (87% of the black cohort and 67% of the mixed cohort). Patients who weighed 20 to <35 kg were randomized to 2.5 mg (low dose) or 20 mg (high dose) of olmesartan medoxomil once daily and patients who weighed ≥ 35 kg were randomized to 5 mg (low dose) or 40 mg (high dose) of olmesartan medoxomil once daily. Olmesartan medoxomil significantly reduced both systolic and diastolic blood pressure in a weight-adjusted dose-dependent manner. Olmesartan medoxomil at both low and high doses significantly reduced systolic blood pressure by 6.6 and 11.9 mmHg from the baseline, respectively. This effect was also observed during the 2 weeks randomized withdrawal phase, whereby both mean systolic and diastolic blood pressures demonstrated a statistically significant rebound in the placebo group compared to olmesartan medoxomil group. The treatment was effective in both, paediatric patients with primary and secondary hypertension. As observed in adult populations, the blood pressure reductions were smaller in black patients.
In the same study, 59 patients aged 1 to 5 years who weighed ≥ 5 kg received 0.3 mg/kg of olmesartan medoxomil once daily for three weeks in an open label phase and then were randomized to receiving olmesartan medoxomil or placebo in a double-blind phase. At the end of the second week of withdrawal, the mean systolic/diastolic blood pressure at trough was 3/3 mmHg lower in the group randomized to olmesartan medoxomil; this difference in blood pressure was not statistically significant (95% C.I. -2 to 7/-1 to 7).
5.3 Pharmacokinetic properties
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 faeces. 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
Older people (age 65 years or older):
In hypertensive patients, the AUC at steady state was increased by ca 35% in older people (65 – 75 years old) and by ca 44% in very old 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.
Paediatric population:
The pharmacokinetics of olmesartan was studied in paediatric hypertensive patients aged 1 to16 years. The clearance of olmesartan in paediatric patients was similar to that in adult patients when adjusted by the body weight.
There is no pharmacokinetic information available in renally impaired paediatric subjects.
Drug interactions
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 Cmaxand AUC respectively, were observed when olmesartan medoxomil was administered 4 hours prior to colesevelam hydrochloride. Elimination half-life of olmesartan was reduced by 50 – 52% irrespectively of whether administered concomitantly or 4 hours prior to colesevelam hydrochloride.
6.0 Nonclinical properties
6.1 Animal Toxicology or Pharmacology
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, haemoglobin, haematocrit); 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 species, 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.
7.0 Description
Olmesartan medoxomil, a prodrug, is hydrolyzed to olmesartan during absorption from the gastrointestinal tract. Olmesartan is a selective AT1 subtype angiotensin II receptor antagonist.
Chemical name: 2,3-dihydroxy-2-butenyl 4 (1-hydroxy-1-methylethyl)-2-propyl-1-[p-(o-1H-tetrazol-5-ylphenyl) benzyl] imidazole-5-carboxylate, cyclic 2,3-carbonate
Molecular formula: C29H30N6O6
Molecular mass: 558.59 g/mol
8.0 Pharmaceutical particulars
8.1 Incompatibilities
Not applicable.
8.2 Shelf-life
Refer on pack
8.3 Packaging information
10 blister strips of 10 tablets each
8.4 Storage and handing instructions
- Store below 25°C. Protected from light & moisture.
- Keep out of reach of children.
9.0 Patient Counselling Information
- Pregnancy: Advise female patients of childbearing age about the consequences of exposure to Olbet during pregnancy. Discuss treatment options with women planning to become pregnant. Tell patients to report pregnancies to their physicians as soon as possible.
- Lactation: Advise nursing women not to breastfeed during treatment with Olbet.
- Hyperkalemia: Advise patients not to use potassium supplements or salt substitutes that contain potassium without consulting their healthcare provider.
12.0 Date of revision
10/10/2024
About leaflet
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- Keep this leaflet. You may need to read it again.
- If you have any further questions, ask your doctor or pharmacist.
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours.
- If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. See section 4.
What is in this leaflet
- What Olbet is and what it is used for
- What you need to know before you take Olbet
- How to take Olbet
- Possible side effects
- How to store Olbet
- Contents of the pack and other information
1. What Olbet is and what it is used for
Olbet belongs to a group of medicines called angiotensin-II receptor antagonists. They lower blood pressure by relaxing the blood vessels.
Olbet is used for the treatment of high blood pressure (also known as ‘hypertension’) in adults and in children and adolescents aged 6 to less than 18 years. High blood pressure can damage blood vessels in organs such as the heart, kidneys, brain and eyes. In some cases, this may lead to a heart attack, heart or kidney failure, stroke or blindness. Usually high blood pressure has no symptoms. It is important to have your blood pressure checked to prevent damage occurring.
High blood pressure can be controlled with medicines such as Olbet tablets. Your doctor has probably also recommended that you make some changes in your lifestyle to help lower your blood pressure (for example losing weight, giving up smoking, reducing the amount of alcohol you drink and reducing the amount of salt in your diet). Your doctor may also have urged you to take regular exercise, such as walking or swimming. It is important to follow this advice from your doctor.
2. What you need to know before you take Olbet
Do not take Olbet:
if you are allergic to olmesartan medoxomil or any of the other ingredients of this medicine (listed in section 6). if you are more than 3 months pregnant. (It is also better to avoid Olbet tablets in early pregnancy – see pregnancy section.) if you suffer from yellowing of the skin and eyes (jaundice) or problems with drainage of the bile from the gallbladder (biliary obstruction e.g. gallstones). if you have diabetes or impaired kidney function and you are treated with a blood pressure lowering medicine containing aliskiren.
Warnings and precautions
Talk to your doctor before using Olbet.
Tell your doctor if you are taking any of the following medicines used to treat high blood pressure: an ACE-inhibitor (for example enalapril, lisinopril, ramipril), in particular if you have diabetesrelated kidney problems. aliskiren
Your doctor may check your kidney function, blood pressure, and the amount of electrolytes (e.g. potassium) in your blood at regular intervals.
See also information under the heading "Do not take Olbet".
Tell your doctor if you have any of the following health problems: Kidney problems Liver disease Heart failure or problems with your heart valves or heart muscle. Severe vomiting, diarrhoea, treatment with high doses of water tablets (diuretics) or if you are on a low salt diet. Increased levels of potassium in your blood. Problems with your adrenal glands.
Contact your doctor if you experience diarrhoea that is severe, persistent and causes substantial weight loss. Your doctor may evaluate your symptoms and decide on how to continue your blood pressure medication.
As with any medicine which reduces blood pressure, an excessive drop in blood pressure in patients with blood flow disturbances of the heart or brain could lead to a heart attack or stroke. Your doctor will therefore check your blood pressure carefully.
You must tell your doctor if you think you are (or might become) pregnant. Olbet is not recommended in early pregnancy, and must not be taken if you are more than 3 months pregnant, as it may cause serious harm to your baby if used at that stage (see pregnancy section).
Black patients
As with other similar drugs the blood pressure lowering effect of Olbet is somewhat less in black patients.
Elderly people
If you are 65 years or over and your doctor decides to increase your dose of olmesartan medoxomil to 40 mg daily, then you need to have your blood pressure regularly checked by your doctor to make sure that your blood pressure does not become too low.
Children and adolescents
Olbet has been studied in children and adolescents. For more information, talk to your doctor. Olbet is not recommended for children from 1 year to less than 6 years and should not be used in children under the age of 1 year as no experience is available.
Other medicines and Olbet
Tell your doctor or pharmacist if you are using, have recently used or might use any other medicines.
In particular, tell your doctor or pharmacist about any of the following:
- Other blood pressure lowering medicines, as the effect of Olbet can be increased. Your doctor may need to change your dose and/or to take other precautions: If you are taking an ACE-inhibitor or aliskiren (see also information under the headings “Do not take Olbet” and “Warnings and precautions”).
- Potassium supplements, a salt substitute which contains potassium, water tablets (diuretics) or heparin (for thinning the blood). Using these medicines at the same time as Olbet may raise the levels of potassium in your blood.
- Lithium (a medicine used to treat mood swings and some types of depression) used at the same time as Olbet may increase the toxicity of lithium. If you have to take lithium, your doctor will measure your lithium blood levels.
- Non-Steroidal Anti-Inflammatory (NSAIDs) medicines (medicines used to relieve pain, swelling and other symptoms of inflammation, including arthritis) used at the same time as Olbet may increase the risk of kidney failure and the effect of Olbet can be decreased by NSAIDs.
- Colesevelam hydrochloride, a drug that lowers the level of cholesterol in your blood, as the effect of Olbet may be decreased. Your doctor may advise you to take Olbet at least 4 hours before colesevelam hydrochloride.
- Certain antacids (indigestion remedies), as the effect of Olbet can be slightly decreased.
Olbet with food and drink
Olbet can be taken with or without food.
Pregnancy and breast-feeding
Pregnancy
You must tell your doctor if you think you are (or might become) pregnant. Your doctor will normally advise you to stop taking Olbet before you become pregnant or as soon as you know you are pregnant and will advise you to take another medicine instead of Olbet. Olbet is not recommended in early pregnancy, and must not be taken when more than 3 months pregnant, as it may cause serious harm to your baby if used after the third month of pregnancy.
Breast-feeding
Tell your doctor if you are breast-feeding or about to start breast-feeding. Olbet is not recommended for mothers who are breast-feeding, and your doctor may choose another treatment for you if you wish to breast-feed, especially if your baby is new-born, or was born prematurely.
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine.
Driving and using machines
You may feel sleepy or dizzy while being treated for your high blood pressure. If this happens, do not drive or use machines until the symptoms wear off. Ask your doctor for advice.
Olbet contains lactose
This medicine contains lactose (a type of sugar). If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicinal product.
3. How to take Olbet
Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist if you are not sure.
The recommended starting dose is one 10 mg tablet once a day. However, if your blood pressure is not controlled, your doctor may decide to change your dose up to 20 or 40 mg once a day, or prescribe additional medicines. In patients with mild to moderate kidney disease, your dose will not be higher than 20 mg once a day.
The tablets can be taken with or without food. Swallow the tablets with a sufficient amount of water (e.g. one glass). If possible, take your daily dose at the same time each day, for example at breakfast time.
Children and adolescents from 6 to less than 18 years of age: The recommended starting dose is 10 mg once daily. If the patient’s blood pressure is not adequately controlled, the doctor may decide to change the dose up to 20 or 40 mg once a day. In children who weigh less than 35 kg, the dose will not be higher than 20 mg once a day.
If you take more Olbet than you should
If you take more tablets than you should or if a child accidentally swallows some, go to your doctor or nearest emergency department immediately and take your medicine pack with you.
If you forget to take Olbet
If you forget a dose, take your normal dose on the following day as usual. Do not take a double dose to make up for a forgotten tablet.
If you stop taking Olbet
It is important to continue to take Olbet unless your doctor tells you to stop.
If you have any further questions on the use of this product, ask your doctor or pharmacist.
4. Possible side effects
Like all medicines, this medicine can cause side effects, although not everybody gets them. If they do occur, they are often mild and do not require treatment to be stopped.
Although not many people may get them, the following side effects can be serious: On rare occasions (may affect up to 1 in 1,000 people) the following allergic reactions that may affect the whole body have been reported: Swelling of the face, mouth and/or larynx (voice box) together with itching and rash may occur during treatment with Olbet. If this happens stop taking Olbet and contact your doctor immediately.
Rarely (but slightly more often in elderly people) Olbet can cause the blood pressure to fall too low in susceptible individuals or as the result of an allergic reaction. This could cause severe light-headedness or fainting. If this occurs stop taking Olbet, contact your doctor immediately and lie down flat.
Frequency not known: If you experience yellowing of the whites of the eyes, dark urine, itching of the skin, even if you started therapy with Olbet longer time ago, contact your doctor immediately who will evaluate your symptoms and decide on how to continue your blood pressure medication.
These are the other side effects known about so far with Olbet:
Common side effects (may affect up to 1 in 10 people):
Dizziness, headache, nausea, indigestion, diarrhoea, stomach ache, gastroenteritis, tiredness, sore throat, runny or stuffy nose, bronchitis, flu-like symptoms, cough, pain, pain in the chest, back, bones or joints, infection of the urinary tract, swelling of ankles, feet, legs, hands, or arms, blood in the urine. Some changes in blood test results have also been seen and include the following: increased fat levels (hypertriglyceridaemia), increased uric acid levels (hyperuricaemia), rise in blood urea, increases in tests of liver and muscle function.
Uncommon side effects (may affect up to 1 in 100 people):
Quick allergic reactions that may affect the whole body and may cause breathing problems as well as a rapid fall of blood pressure that may even lead to fainting (anaphylactic reactions), swelling of the face, vertigo, vomiting, weakness, feeling unwell, muscular pain, skin rash, allergic skin rash, itching, exanthema (skin eruption), skin lumps (wheals), angina (pain or uncomfortable feeling in the chest).
In blood tests a reduction of the numbers of a type of blood cell, known as platelets has been seen (thrombocytopenia).
Rare side effects (may affect up to 1 in 1,000 people):
Lack of energy, muscle cramps, impaired kidney function, kidney failure.
Some changes in blood test results have also been seen. These include increased potassium levels (hyperkalaemia) and increased levels of compounds related to kidney function.
Additional side effects in children and adolescents:
In children, side effects are similar to those reported in adults. However, dizziness and headache are seen more often in children, and nose bleeding is a common side effect seen in children only.
Reporting of side effects
If you get any side effects, talk to your doctor. This includes any possible side effects not listed in this leaflet. You can also report side effects directly: Website: www.zuventus.co.in and click the tab “Safety Reporting” located on the top right end of the home page. By reporting side effects, you can help provide more information on the safety of this medicine.
5. How to store Olbet
Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date which is stated on the carton and on the blister strip after “EXP”. The expiry date refers to the last day of that month.
This medicinal product does not require any special storage conditions.
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.
6. Contents of the pack and other information
What Olbet contains
The active substance is olmesartan medoxomil
Each film-coated tablet contains 10 mg, 20 mg or 40 mg olmesartan medoxomil.
The other ingredients are microcrystalline cellulose, lactose monohydrate, hydroxypropylcellulose, low substituted hydroxypropylcellulose, magnesium stearate, titanium dioxide (E171), talc and hypromellose. (See section 2 “Olbet contains lactose”)
What Olbet looks like and contents of the pack
Olbet 10 mg film-coated tablets are white, circular with C 13 on one side. Olbet 20 mg film-coated tablets are white, circular with C 14 on one side. Olbet 40 mg film-coated tablets are white, oval with C 15 on one side.
Olbet film-coated tablets are available in packs of 14, 28, 30, 56, 84, 90, 98 and 10 x 28 film-coated tablets and in packs with perforated unit dose blisters of 10, 50 and 500 film-coated tablets.