Not used during pregnancy, it may cause injury Of death of the fetus
1- NAME OF THE MEDICINAL PRODUCTS :
Normesar 20 mg film coated tablets.
Nonnesar 40 mg film coated tablets.
2- QUALITATIVE AND QUANTITATIVE COMPOSITION :
Each film coated tablets contains Active ingredients
Olmesartan medoxomil 20 or 40 mg.
Inactive ingredients : Lactose monohydrate, Miaoaystaline cetIOOse, Magnesium stearate, Povidone K30, Sodium siaM glycolate, Hydroxypropyl methyl ce11u1ose, Titanium dioxide and Polyelhylene glycol 6000.
3- PHARMACEUTICAL FORM :
Film coated tablets for oral administration.
4- CLINICAL PARTICULARS :
– Therapeutic indications: Treatment of essential hypertension.
– Posology and method of administration
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 Normesar tablets be taken at about the same time each day, with or without food, for example at breakfast time.
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 (creattntne ceerence of 20-60 mtlmin) is 20 mg’OImesartan 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 mUmin) is not recommended, since there is only
limited experience in this patient group.
Hepatic impairment :
No adjustment of dosage recommendations is required for patients with mild hepatic impairment. In patients with moderate hepatic impainnent, 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.
Children and adolescents :
Normesar is not recommended for use in children below 18 years due to a lack of data on safety and efficacy.
• Contraindications : Hypersensitivity to the active substance or to any of the excipients. Second and third trimesters of pregnancy.
• 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–angiotensln-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 exduded with angiotensin 11 recaptor 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 aeatinine levels is recommended renal impairment (creatinine dearance < 20 mUmin). 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 <12mUmin).
Hepatic impairment :
There is no experience in patients with severe hepatic impainnent and therefore use of otmesartan medoxomil in this patient group is not recommended for dosage recommendations in patients with mild or moderate hepatic impairment.
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 medlcirral products tMt affect the renin-angiotensin-aldosterone system, the benefit risk ratio should be evaluated and other altematives 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 dass of medicinal products may provoke a hyperkalaemia: salt substitutes containing potassium, potassium-sparing diuretics,
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.
As with other angiotensin-II receptor antagonists, the combination of lithium and Olmesartan medoxomil is not recommended.
Aortic or mmal 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 wilt not respond to antihypertensive drugs acting through inhibition of the renin-angiotensin system. Therefore, the use of Olmesartan medoxcrnil is not recommended in such patients.
Ethnic differences :
As with all other angiotensin 11 antagonists, the blood pressure lowering effect of Olmesartan rnedoxomil 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.
Angiotensin 11 antagonists should not be initiated during pregnancy. Unless continued angiotensin 11 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 11 antagonists should be stopped immediately and, if appropriate, alternative therapy
should be started.
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 oontains lactose. Patients with rare hereditary problems of galactose intolerance, the lapp-Iactase deficiency or glucose-galactose malabsorption should not take this medicinal product. Interaction with other medicinal products and other fonns of interactions Interaction studies have only been performed 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-steroldal 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 11 antagonists is the occurrence of acute renal failure. Monitorinq 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 11 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. Co-administration of warfarin and digoxin had no effect on the pharmacokinetics of Olmesartan.
Effects of Olmesartan medoxomil on other medicinal products:
Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with angiotensin converting enzyme inhibitors and angiotensin 11 antagonists. Therefore use of OImesartan 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 indude warfarin, digoxin, an antacid (magnesium aluminium hydroxide), hydrochlorothiazide and pravastatin. No clinically relevant interactions were observed and in particular OJmesartan 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, 2C6I9, 2C19, 206, 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.
-Pregnancy and lactation
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 antagontsts-shoukI-be-sIapped-ffnmedtalely, and, if-appropriate;-atternative therapy should be started.Angiotensin 11 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).
Should exposure to angiotensin 11 antagonists have occurred from the second trimester of pregnancy, ultrasound check of renal function and skull is recommended.
Infants whose mothers have taken angiotensin 11 antagonists should be closely observed for hypotension.
Otmesartan is excreted in the milk of lactating rats but it is not known whether Otmesartan is excreted in human milk. Because no information is available regarding the use of Normesar during breast-feeding, Normesar is not recommended and alternative treatments with better established safety profiles during breast-feeding are preferable, especially while nursing a newborn or
Effects on ability to drive and to use machines
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.
-Undesfrable side effects Common (i!:1/100, <1/10): Dizziness, Bronchitis, cough, pharyngitis, rhinitis, abdominal pain, diarrhea, dyspepsia, gastroenteritis, nausea, arthritis, back phosphokinase, hypertriglyceridaemia, hyperuricaemia, liver enzyme elevation.
Uncommon (i!:1/1,000. <1/100): Vertigo, angina pectoris, rash.
Rare (2:1/10,000, <1/1,000): Hypotension.
Very rare «1/10,000) including isolated reports: Thromtx>cytopenia, hyperkalaemia, dizziness, headache, cough, abdominal pain, nausea, vomiting, pruritus, exanthema, rash, Allergic conditions such as angioneurotic oedema, dermatitis allergic, face oedema and urticaria, muscle cramp, myalgia, Acute renal failure and renal insufficiency (See also under Investigations), Asthenic conditions such as asthenia, fatigue, lethargy, malaise, Abnormal renal function tests such as blood creatinine
increased and blood urea increased and increased hepatic enzymes.
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- PHARMACOLOGICAL PROPERTIES :
• Phannacodynamlc properties
Olmesartan medoxomil is a potent, orally active, selective angiotensin 11 receptor (type AT1) antagonist. It is expected to block all actions of angiotensin 11 mediated by the AT1 receptor, regardless of the souree or route of synthesis of angiotensin
11. The selective antagonism of the angiotensin 11 (An) receptors results in increases in plasma renin levels and angiotensin I and 11 concentrations, and some decrease in plasma aldosterone concentrations. Angiotenstl 11 is the primary vasoactive honnone of the renin-angiotensin-aldosterone system and plays a significant role in the pathophysiology of hypertension via the type 1 (An) receptor. In hypertension, Oimesartan 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 Co–administration is well tolerated. The effect of Olmesartan on mortality and morbidity is not yet known.
• Phannacoklnetics 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 bloavailebility of Olmesartan from a t!lblet formulation was 25.6%. The mean peak plasma concentration of Olmesartan is reached within about
2 hours after oral dosing with Oimesartan 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 LIh). Following a single oral dose of C labelled OImesartan 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 (ea 40%) and hepato-blltary excretion (ca 60%).
All recovered radioactivity was identified as Olmesartan. No other significant metabollte was detected. Enterohepatic recyding of Olmesartan is minimal. Sinee 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 LIh and was independent of dose.
6- PACKAGE ANO STORAGE :
Carton box of one, two or three (AluIPVC) strip(s) each of 10 film coated tablets and insert leaflet Normesar 20 mg.
Carton box of one, two or three (Alu/PVC) strip(s) each of 10 film coated tablets and insert leaflet Normesar 40 mg.
7- Storage :
Store at temperature not exceeding 300 C., in dry place.
8- Produced by :
Jedco international phannaceuticals eo. for FOUR A PHARMA for pharmaceutical industries (FAP), Cairo- Egypt.