Treatment of essential hypertension
 

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.
In order to assist compliance, it is recommended that Olmetec tablets be taken at
about the same time each day, with or without food, for example at breakfast time.
Elderly
No adjustment of dosage is generally required in elderly patients (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.
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 (see sections 4.4, 5.2).
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 (see sections 4.4 and 5.2). Olmesartan
medoxomil should not be used in patients with biliary obstruction (see 4.3).
Children and adolescents
Olmetec is not recommended for use in children below 18 years due to a lack of data
on safety and efficacy.
 

Dual Blockade of the Renin-Angiotensin-aldosterone System (RAAS):
Combination of Olmesartan with ACE inhibitors, or aliskiren may cause increased
risks of hyperkalemia, worsening of kidney function and hypotension. Therefore, this
combination should not be used, especially in patients with kidney problems.
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 reninangiotensin-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) (see sections 4.2, 5.2). 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 (see section 4.2
for dosage recommendations in patients with mild or moderate hepatic
impairment).
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 elderly, 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 reninangiotensin-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 reninangiotensin-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 (see section
4.5).
Lithium:
As with other angiotensin-II receptor antagonists, the combination of lithium and
Olmesartan medoxomil is not recommended (see section 4.5).
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.
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.
Sprue-like Enteropathy
Severe, chronic diarrhea with substantial weight loss has been reported in patients
taking olmesartan months to years after drug initiation. Intestinal biopsies of
patients often demonstrated villous atrophy. If a patient develops these symptoms
during treatment with olmesartan, exclude other etiologies. Consider
discontinuation of Olmetec in cases where no other etiology is identified.
Pregnancy:
Angiotensin II antagonists should not be initiated during pregnancy. Unless
continued angiotensin II antagonists 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 angiotensin II antagonists should be stopped immediately
and, if appropriate, alternative therapy should be started (see sections 4.3 and 4.6).
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.
This medicinal product contains lactose. Patients with rare hereditary problems of
galactose intolerance, the Lapp-lactase deficiency or glucose-galactose
malabsorption should not take this medicinal product.
 

Interaction studies have only been performed in adults.
Dual RAAS Blockade:
The combination of Olmesartan with Aliskiren, ACEIs or other ARBs is
contraindicated in patients with diabetes mellitus or renal impairment.

Aliskiren fumarate (In patients with diabetes, except for patients with very poor blood pressure control with other antihypertensive treatment)

Dual blockade (e.g by adding ACE inhibitor to Olmesartan ) should not be used,
especially in patients with Kidney problems.
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 (see
section 4.4). 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.
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.
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 (see section 4.4). 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.

1.1.   Pregnancy:

Epidemiological evidence regarding the risk of teratogenicity following exposure to ACE inhibitors during the first trimester of pregnancy has not been conclusive; however a small increase in risk cannot be excluded. Whilst there is no controlled epidemiological data on the risk with angiotensin II antagonists, similar risks may exist

for this class of drugs. Unless continued angiotensin receptor blocker therapy is considered essential, 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 angiotensin II antagonists should be stopped immediately, and, if appropriate, alternative therapy should be started.

Angiotensin II antagonists therapy exposure 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). (See also 5.3 “Preclinical Safety Data”.)

Should exposure to angiotensin II antagonists have occurred from the second trimester of pregnancy, ultrasound check of renal function and skull is recommended. Infants whose mothers have taken angiotensin II antagonists should be closely observed for hypotension (see also sections 4.3 and 4.4).

Lactation:

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 Olmetec during breast-feeding, Olmetec is not recommended and alternative treatments with better established safety profiles during breast-feeding are preferable, especially while nursing a newborn or preterm infant.

No studies on the effect on the ability to drive and use machines have been
performed. With respect to driving vehicles or operating machines, it should be
taken into account that occasionally dizziness or fatigue may occur in patients taking
antihypertensive therapy.
 

a. Tabulated list of Adverse reaction:
Market experience
The following adverse reactions have been reported in post-marketing experience.
They are listed by System Organ Class and ranked under headings of frequency using
the following convention: very common (≥1/10); common (≥1/100, <1/10);
uncommon (≥1/1,000, <1/100); rare (≥1/10,000, <1/1,000); very rare (<1/10,000)
including isolated reports.

Clinical trials

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 by body system and ranked under headings of frequency using the conventions described :

Additional information on special populations

In elderly patients the frequency of hypotension is slightly increased from rare to uncommon.

b. Description of selected adverse reaction:
Single cases of rhabdomyolysis have been reported in temporal association with the
intake of angiotensin II receptor blockers. A causal relationship, however, has not
been established.

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.

Post Marketing Experience
Data from one controlled trial and an epidemiologic study have suggested that highdose olmesartan may increase cardiovascular (CV) risk in diabetic patients, but the
overall data are not conclusive. The randomized, placebo-controlled, double-blind
ROADMAP trial (Randomized Olmesartan And Diabetes MicroAlbuminuria
Prevention trial, n=4447) examined the use of olmesartan, 40 mg daily, vs. placebo in
patients with type 2 diabetes mellitus, normoalbuminuria, and at least one
additional risk factor for CV disease. The trial met its primary endpoint, decrease in
time-to-onset of microalbuminuria, but olmesartan had no beneficial effect on
decline in glomerular filtration rate (GFR). There was a finding of increased CV
mortality (adjudicated sudden cardiac death, fatal myocardial infarction, fatal stroke,
revascularization death) in the olmesartan group compared to the placebo group (15
olmesartan vs. 3 placebo, HR 4.9, 95% confidence interval [CI], 1.4, 17), but the risk
of non-fatal myocardial infarction was lower with olmesartan (HR 0.64, 95% CI 0.35,
1.18).
The epidemiologic study included patients 65 years and older with overall exposure
of >300,000 patient-years. In the sub-group of diabetic patients receiving high-dose
olmesartan (40 mg/d) for > 6 months, there appeared to be an increased risk of
death (HR 2.0, 95% CI 1.1, 3.8) compared to similar patients taking other angiotensin
receptor blockers. In contrast, high-dose olmesartan use in non-diabetic patients
appeared to be associated with a decreased risk of death (HR 0.46, 95% CI 0.24,
0.86) compared to similar patients taking other angiotensin receptor blockers. No
differences were observed between the groups receiving lower doses of olmesartan
compared to other angiotensin blockers or those receiving therapy for < 6 months.
Overall, these data raise a concern of a possible increased CV risk associated with the
use of high-dose olmesartan in diabetic patients. There are, however, concerns with
the credibility of the finding of increased CV risk, notably the observation in the large
epidemiologic study for a survival benefit in non-diabetics of a magnitude similar to
the adverse finding in diabetics.
c. Other special population:
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) (see sections 4.2, 5.2). 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 (see section 4.2
for dosage recommendations in patients with mild or moderate hepatic
impairment).
Pregnancy:
The use of angiotensin II antagonists is not recommended during the first trimester
of pregnancy (see section 4.4). The use of angiotensin II antagonists is
contraindicated during the second and third trimester of pregnancy
Elderly
No adjustment of dosage is generally required in elderly patients (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.
Children and adolescents
Olmetec is not recommended for use in children below 18 years due to a lack of data
on safety and efficacy.
 

-To report any side effect (s)

·         Saudi Arabia :

Other GCC states /other countries

-Please contact the relevant competent authority.

Only limited information is available regarding over dosage in humans. The most
likely effect of over dosage is hypotension. In the event of over dosage, the patient
should be carefully monitored and treatment should be symptomatic and
supportive.
No information is available regarding the dialysability of Olmesartan.
 

Pharmaco-therapeutic group:
Angiotensin II antagonists, ATC code: C09C A 08.
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-angiotensinaldosterone system and plays a significant role in the pathophysiology of
hypertension via the type 1 (AT1) receptor.
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.
 

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 coadministered 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).
Metabolism 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 (see section 4.3).
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
Elderly:
In hypertensive patients, the AUC at steady state was increased by ca 35% in elderly
patients (65 – 75 years old) and by ca 44% in very elderly patients ( 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 (see sections 4.2, 4.4).
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 (see sections 4.2, 4.4).
 

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.
 

Microcrystalline cellulose, Lactose monohydrate, Low substitute Hydroxy propylcellulose, Hydroxy propylcellulose, magnesium stearate, and Opadry

white

Not applicable.
 

Store below 30°C.
 

Forming Aluminium / aluminium blister pack.
Packs of 28 film-coated tablets.
 

No special requirements.