1. Name Of The Medicinal Product
Olmetec Plus 40 mg/12.5 mg film-coated tablets
2. Qualitative And Quantitative Composition
Each film-coated tablet contains 40 mg olmesartan medoxomil and 12.5 mg hydrochlorothiazide.
Excipients:
Each film-coated tablet contains 233.9 mg lactose monohydrate.
For a full list of excipients, see section 6.1.
3. Pharmaceutical Form
Film-coated tablet.
Reddish-yellow, oval, film-coated tablet with C23 debossed on one side.
4. Clinical Particulars
4.1 Therapeutic Indications
Treatment of essential hypertension.
Olmetec Plus 40 mg/12.5 mg and 40 mg/25 mg fixed dose combinations are indicated in patients whose blood pressure is not adequately controlled on olmesartan medoxomil 40 mg alone.
4.2 Posology And Method Of Administration
Adults
The recommended dose of Olmetec Plus 40 mg/12.5 mg or 40 mg/25 mg is 1 tablet per day.
Olmetec Plus 40 mg/12.5 mg may be administered in patients whose blood pressure is not adequately controlled by olmesartan medoxomil 40 mg alone.
Olmetec Plus 40 mg/25 mg may be administered in patients whose blood pressure is not adequately controlled on Olmetec Plus 40 mg/12.5 mg fixed dose combination.
For convenience, patients receiving olmesartan medoxomil and hydrochlorothiazide from separate tablets may be switched to Olmetec Plus 40 mg/12.5 mg and 40 mg/25 mg tablets containing the same component doses.
Method of administration:
The tablet should be swallowed with a sufficient amount of fluid (e.g. one glass of water). The tablet should not be chewed and should be taken at the same time each day.
Olmetec Plus 40 mg/12.5 mg and 40 mg/25 mg can be taken with or without food.
Elderly (age 65 years or over)
In elderly patients the same dosage of the combination is recommended as for adults.
Blood pressure should be closely monitored.
Renal impairment
Olmetec Plus is contraindicated in patients with severe renal impairment (creatinine clearance < 30 mL/min).
The maximum dose of olmesartan medoxomil in patients with mild to moderate renal impairment (creatinine clearance of 30–60 mL/min) is 20 mg olmesartan medoxomil once daily, owing to limited experience of higher dosages in this patient group, and periodic monitoring is advised.
Olmetec Plus 40 mg/12.5 mg and 40 mg/25 mg are therefore contraindicated in all stages of renal impairment (see sections 4.3, 4.4, 5.2).
Hepatic impairment
Olmetec Plus 40 mg/12.5 mg and 40 mg/25 mg should be used with caution in patients with mild hepatic impairment (see sections 4.4, 5.2). Close monitoring of blood pressure and renal function is advised in hepatically-impaired patients who are receiving diuretics and/or other antihypertensive agents. 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. There is no experience of olmesartan medoxomil in patients with severe hepatic impairment. Olmetec Plus 40 mg/12.5 mg and 40 mg/25 mg therefore should not be used in patients with moderate and severe hepatic impairment (see sections 4.3, 5.2), as well as in cholestasis and biliary obstruction (see section 4.3).
Children and adolescents
Olmetec Plus 40 mg/12.5 mg and 40 mg/25 mg are not recommended for use in children below 18 years due to a lack of data on safety and efficacy.
4.3 Contraindications
Hypersensitivity to the active substances, to any of the excipients (see section 6.1) or to other sulfonamide-derived substances (since hydrochlorothiazide is a sulfonamide-derived medicinal product).
Renal impairment (see sections 4.4 and 5.2).
Refractory hypokalaemia, hypercalcaemia, hyponatraemia and symptomatic hyperuricaemia.
Moderate and severe hepatic impairment, cholestasis and biliary obstructive disorders (see section 5.2).
Second and third trimester of pregnancy (see sections 4.4 and 4.6).
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 Olmetec Plus.
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 medicinal products that affect this system has been associated with acute hypotension, azotaemia, oliguria or, rarely, acute renal failure.
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:
Olmetec Plus should not be used in patients with severe renal impairment (creatinine clearance < 30 ml/min).
The maximum dose of olmesartan medoxomil in patients with mild to moderate renal impairment (creatinine clearance of 30–60 mL/min) is 20 mg olmesartan medoxomil once daily. However, in such patients Olmetec Plus 20 mg/12.5 mg and 20 mg/25 mg should be administered with caution and periodic monitoring of serum potassium, creatinine and uric acid levels is recommended. Thiazide diuretic-associated azotaemia may occur in patients with impaired renal function. If progressive renal impairment becomes evident, careful reappraisal of therapy is necessary, with consideration given to discontinuing diuretic therapy.
Olmetec Plus 40 mg/12.5 mg and 40 mg/25 mg are therefore contraindicated in all stages of renal impairment (see section 4.3).
There is no experience of the administration of Olmetec Plus in patients with a recent kidney transplantation.
Hepatic impairment:
There is currently no experience of olmesartan medoxomil in patients with severe hepatic impairment. In patients with moderate hepatic impairment, the maximum dose is 20 mg olmesartan medoxomil.
Furthermore, minor alterations of fluid and electrolyte balance during thiazide therapy may precipitate hepatic coma in patients with impaired hepatic function or progressive liver disease.
Therefore the use of Olmetec Plus 40 mg/12.5 mg and 40 mg/25 mg in patients with moderate and severe hepatic impairment, cholestasis and biliary obstruction is contraindicated (see sections 4.3, 5.2). Care should be taken in patients with mild impairment (see section 4.2).
Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy:
As with other vasodilators, special caution is indicated in patients suffering from aortic or mitral stenosis, or obstructive hypertrophic cardiomyopathy.
Primary aldosteronism:
Patients with primary aldosteronism generally will not respond to anti-hypertensive medicinal products acting through inhibition of the renin-angiotensin system. Therefore, the use of Olmetec Plus is not recommended in such patients.
Metabolic and endocrine effects:
Thiazide therapy may impair glucose tolerance. In diabetic patients dosage adjustments of insulin or oral hypoglycaemic agents may be required (see section 4.5). Latent diabetes mellitus may become manifest during thiazide therapy.
Increases in cholesterol and triglyceride levels are undesirable effects known to be associated with thiazide diuretic therapy.
Hyperuricaemia may occur or frank gout may be precipitated in some patients receiving thiazide therapy.
Electrolyte imbalance:
As for any patient receiving diuretic therapy, periodic determination of serum electrolytes should be performed at appropriate intervals.
Thiazides, including hydrochlorothiazide, can cause fluid or electrolyte imbalance (including hypokalaemia, hyponatraemia and hypochloraemic alkalosis). Warning signs of fluid or electrolyte imbalance are dryness of the mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pain or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea or vomiting (see section 4.8).
The risk of hypokalaemia is greatest in patients with cirrhosis of the liver, in patients experiencing brisk diuresis, in patients who are receiving inadequate oral intake of electrolytes and in patients receiving concomitant therapy with corticosteroids or ACTH (see section 4.5).
Conversely, due to antagonism at the angiotensin-II receptors (AT1) through the olmesartan medoxomil component of Olmetec Plus, hyperkalaemia may occur, especially in the presence of renal impairment and/or heart failure, and diabetes mellitus. Adequate monitoring of serum potassium in patients at risk is recommended. Potassium-sparing diuretics, potassium supplements or potassium-containing salt substitutes and other medicinal products that may increase serum potassium levels (e.g. heparin) should be co-administered cautiously with Olmetec Plus (see section 4.5).
There is no evidence that olmesartan medoxomil would reduce or prevent diuretic-induced hyponatraemia. Chloride deficit is generally mild and usually does not require treatment.
Thiazides may decrease urinary calcium excretion and cause an intermittent and slight elevation of serum calcium in the absence of known disorders of calcium metabolism. Hypercalcaemia may be evidence of hidden hyperparathyroidism. Thiazides should be discontinued before carrying out tests for parathyroid function.
Thiazides have been shown to increase the urinary excretion of magnesium, which may result in hypomagnesaemia.
Dilutional hyponatraemia may occur in oedematous patients in hot weather.
Lithium:
As with other angiotensin II receptor antagonists, the co
Ethnic differences:
As with all other angiotensin II receptor antagonist containing products, the blood pressure lowering effect of Olmetec Plus 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.
Anti-doping test:
Hydrochlorothiazide contained in this medicinal product could produce a positive analytic result in an anti-doping test.
Pregnancy:
Angiotensin II receptor antagonists should not be initiated during pregnancy. Unless continued angiotensin II receptor 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 receptor 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.
Hypersensitivity reactions to hydrochlorothiazide may occur in patients with or without a history of allergy or bronchial asthma, but are more likely in patients with such a history.
Exacerbation or activation of systemic lupus erythematosus has been reported with the use of thiazide diuretics.
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.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
Potential interactions related to the Olmetec Plus combination:
Concomitant use not recommended
Lithium:
Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with angiotensin converting enzyme inhibitors and, rarely, with angiotensin II receptor antagonists. In addition, renal clearance of lithium is reduced by thiazides and consequently the risk of lithium toxicity may be increased. Therefore use of Olmetec Plus 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.
Concomitant use requiring caution
Baclofen:
Potentiation of antihypertensive effect may occur.
Non-steroidal anti-inflammatory medicinal products:
NSAIDs (i.e. acetylsalicylic acid (> 3 g/day), COX-2 inhibitors and non-selective NSAIDs) may reduce the antihypertensive effect of thiazide diuretics and angiotensin II receptor antagonists.
In some patients with compromised renal function (e.g. dehydrated patients or elderly patients with compromised renal function) the co-administration of angiotensin II receptor antagonists and agents that inhibit cyclo-oxygenase may result in further deterioration of renal function, including possible acute renal failure, which is usually reversible. Therefore, the combination should be administered with caution, especially in the elderly. Patients should be adequately hydrated and consideration should be given to monitoring of renal function after initiation of concomitant therapy and periodically thereafter.
Concomitant use to be taken into account
Amifostine:
Potentiation of antihypertensive effect may occur.
Other antihypertensive agents:
The blood pressure lowering effect of Olmetec Plus can be increased by concomitant use of other antihypertensive medicinal products.
Alcohol, barbiturates, narcotics or antidepressants:
Potentiation of orthostatic hypotension may occur.
Potential interactions related to olmesartan medoxomil:
Concomitant use not recommended
Medicinal products affecting potassium levels:
Based on experience with the use of other medicinal products that affect the renin-angiotensin system, concomitant use of potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium or other medicinal products that may increase serum potassium levels (e.g. heparin, ACE inhibitors) may lead to increases in serum potassium (see section 4.4). If medicinal products which affect potassium levels are to be prescribed in combination with Olmetec Plus, monitoring of potassium plasma levels is advised.
Additional information
After treatment with antacid (aluminium magnesium hydroxide), a modest reduction in bioavailability of olmesartan was observed.
Olmesartan medoxomil had no significant effect on the pharmacokinetics or pharmacodynamics of warfarin or the pharmacokinetics of digoxin.
Co
Olmesartan had no clinically relevant inhibitory effects on human cytochrome P450 enzymes 1A1/2, 2A6, 2C8/9, 2C19, 2D6, 2E1 and 3A4 in vitro, and had no or minimal inducing effects on rat cytochrome P450 activities. No clinically relevant interactions between olmesartan and medicinal products metabolised by the above cytochrome P450 enzymes are expected.
Potential interactions related to hydrochlorothiazide:
Concomitant use not recommended
Medicinal products affecting potassium levels:
The potassium-depleting effect of hydrochlorothiazide (see section 4.4) may be potentiated by the co
Concomitant use requiring caution
Calcium salts:
Thiazide diuretics may increase serum calcium levels due to decreased excretion. If calcium supplements must be prescribed, serum calcium levels should be monitored and calcium dosage adjusted accordingly.
Cholestyramine and colestipol resins:
Absorption of hydrochlorothiazide is impaired in the presence of anionic exchange resins.
Digitalis glycosides:
Thiazide-induced hypokalaemia or hypomagnesaemia may favour the onset of digitalis-induced cardiac arrhythmias.
Medicinal products affected by serum potassium disturbances:
Periodic monitoring of serum potassium and ECG is recommended when Olmetec Plus is administered with medicinal products affected by serum potassium disturbances (e.g. digitalis glycosides and antiarrhythmics) and with the following torsades de pointes (ventricular tachycardia)-inducing medicinal products (including some antiarrhythmics), hypokalaemia being a predisposing factor to torsades de pointes (ventricular tachycardia):
- Class Ia antiarrythmics (e.g. quinidine, hydroquinidine, disopyramide).
- Class III antiarrythmics (e.g. amiodarone, sotalol, dofetilide, ibutilide).
- Some antipsychotics (e.g. thioridazine, chlorpromazine, levomepromazine, trifluoperazine, cyamemazine, sulpiride, sultopride, amisulpride, tiapride, pimozide, haloperidol, droperidol).
- Others (e.g. bepridil, cisapride, diphemanil, erythromycin IV, halofantrin, mizolastin, pentamidine, sparfloxacin, terfenadine, vincamine IV).
Non-depolarizing skeletal muscle relaxants (e.g. tubocurarine):
The effect of nondepolarizing skeletal muscle relaxants may be potentiated by hydrochlorothiazide.
Anticholinergic agents (e.g. atropine, biperiden):
Increase of the bioavailability of thiazide-type diuretics by decreasing gastrointestinal motility and stomach emptying rate.
Antidiabetic medicinal products (oral agents and insulin):
The treatment with a thiazide may influence the glucose tolerance. Dosage adjustment of the antidiabetic medicinal product may be required (see section 4.4).
Metformin:
Metformin should be used with caution because of the risk of lactic acidosis induced by possible functional renal failure linked to hydrochlorothiazide.
Beta-blockers and diazoxide:
The hyperglycaemic effect of beta-blockers and diazoxide may be enhanced by thiazides.
Pressor amines (e.g. noradrenaline):
The effect of pressor amines may be decreased.
Medicinal products used in the treatment of gout (probenecid, sulfinpyrazone and allopurinol):
Dosage adjustment of uricosuric medicinal products may be necessary since hydrochlorothiazide may raise the level of serum uric acid. Increase in dosage of probenecid or sulfinpyrazone may be necessary. Co
Amantadine:
Thiazides may increase the risk of adverse effects caused by amantadine.
Cytotoxic agents (e.g. cyclophosphamide, methotrexate):
Thiazides may reduce the renal excretion of cytotoxic medicinal products and potentiate their myelosuppressive effects.
Salicylates:
In case of high dosages of salicylates hydrochlorothiazide may enhance the toxic effect of the salicylates on the central nervous system.
Methyldopa:
There have been isolated reports of haemolytic anaemia occurring with concomitant use of hydrochlorothiazide and methyldopa.
Ciclosporin:
Concomitant treatment with ciclosporin may increase the risk of hyperuricaemia and gout-type complications.
Tetracyclines:
Concomitant administration of tetracyclines and thiazides increases the risk of tetracycline-induced increase in urea. This interaction is probably not applicable to doxycycline.
4.6 Pregnancy And Lactation
Pregnancy
Given the effects of the individual components in this combination product on pregnancy, the use of Olmetec Plus is not recommended during the first trimester of pregnancy (see section 4.4). The use of Olmetec Plus is contraindicated during the second and third trimester of pregnancy (see sections 4.3 and 4.4).
Olmesartan medoxomil
The use of angiotensin II receptor antagonists is not recommended during the first trimester of pregnancy (see section 4.4). The use of angiotensin II receptor antagonists is contraindicated during the second and third trimester of pregnancy (see sections 4.3 and 4.4).
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 receptor 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 receptor antagonists should be stopped immediately, and, if appropriate, alternative therapy should be started.
Exposure to angiotensin II receptor antagonists 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). (See also 5.3 'Preclinical safety data'.)
Should exposure to angiotensin II receptor 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 receptor antagonists should be closely observed for hypotension (see also sections 4.3 and 4.4).
Hydrochlorothiazide
There is limited experience with hydrochlorothiazide during pregnancy, especially during the first trimester. Animal studies are insufficient.
Hydrochlorothiazide crosses the placenta. Based on the pharmacological mechanism of action of hydrochlorothiazide its use during the second and third trimester may compromise foeto-placental perfusion and may cause foetal and neonatal effects like icterus, disturbance of electrolyte balance and thrombocytopenia.
Hydrochlorothiazide should not be used for gestational oedema, gestational hypertension or pre-eclampsia due to the risk of decreased plasma volume and placental hypoperfusion, without a beneficial effect on the course of the disease.
Hydrochlorothiazide should not be used for essential hypertension in pregnant women except in rare situations where no other treatment could be used.
Lactation
Olmesartan medoxomil
Because no information is available regarding the use of Olmetec Plus during breast-feeding, Olmetec Plus is not recommended and alternative treatments with better established safety profiles during breast-feeding are preferable, especially while nursing a newborn or preterm infant.
Hydrochlorothiazide
Hydrochlorothiazide is excreted in human milk in small amounts. Thiazides in high doses causing intense diuresis can inhibit the milk production. The use of Olmetec Plus during breast-feeding is not recommended. If Olmetec Plus is used during breast-feeding, doses should be kept as low as possible.
4.7 Effects On Ability To Drive And Use Machines
No studies on the effects on the ability to drive and use machines have been performed. However, it should be borne in mind that dizziness or fatigue may occasionally occur in patients taking antihypertensive therapy.
4.8 Undesirable Effects
Fixed dose combination:
The safety of Olmetec Plus 40 mg/12.5 mg and 40 mg/25 mg was investigated in clinical trials in 3709 patients receiving olmesartan medoxomil in combination with hydrochlorothiazide.
Further adverse events reported with the fixed dose combination of olmesartan medoxomil and hydrochlorothiazide in the lower dose strengths 20 mg/12.5 mg and 20 mg/25 mg may be potential adverse reactions with Olmetec Plus 40 mg/12.5 mg and 40 mg/25 mg.
Adverse events of potential clinical relevance of all dose strengths of the fixed dose combination of olmesartan medoxomil and hydrochlorothiazide are listed below by System Organ Class. Frequencies are defined as: very common (
Adverse drug reactions additionally reported from post marketing experience are also listed. For all the adverse drug reactions reported from post marketing experience only, it is not possible to assign frequency and therefore they are mentioned with a “not known” frequency (cannot be estimated from the available data).
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Additional information on the individual components:
Adverse reactions previously reported with either of the individual components may be potential adverse reactions with Olmetec Plus, even if not observed in post marketing experience and clinical trials with this product.
Olmesartan medoxomil
Further adverse events reported in clinical trials with olmesartan medoxomil monotherapy in hypertension are listed by body system and ranked under headings of frequency.
Adverse drug reactions additionally reported from post marketing experience are also listed. For all the adverse drug reactions reported from post marketing experience only, it is not possible to assign frequency and therefore they are mentioned with a “not known” frequency (cannot be estimated from the available data).
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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.
Hydrochlorothiazide
Hydrochlorothiazide may cause or exacerbate volume depletion which may lead to electrolyte imbalance (see section 4.4).
Further adverse reactions reported with hydrochlorothiazide monotherapy include:
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