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Drug Details

OLMETEC Plus Film-Coated Tablets

• Drug Class Description
  Angiotensin II antagonists and diuretics
• Generic Name
  Olmesartan Medoxomil
• Presentation
  Film-coated tablet. Olmetec Plus 20 mg/12.5 mg film-coated tablets: Reddish-yellow, round, film-coated tablet with C22 debossed on one side. Olmetec Plus 20 mg/25 mg film-coated tablets: Pinkish, round, film-coated tablet with C24 debossed on one side.
• Description
  Olmetec Plus 20 mg/12.5 mg film-coated tablets: Each film-coated tablet contains 20 mg olmesartan medoxomil and 12.5 mg hydrochlorothiazide Olmetec Plus 20 mg/25 mg film-coated tablets: Each film-coated tablet contains 20 mg olmesartan medoxomil and 25 mg hydrochlorothiazide
• Indications
  

  Treatment of essential hypertension. Olmetec Plus fixed dose combination is indicated in patients whose blood pressure is not adequately controlled on olmesartan medoxomil alone.

• Adult Dosage
  

  lmetec Plus is not for use as initial therapy, but in patients whose blood pressure is not adequately controlled by 20 mg olmesartan medoxomil alone. Olmetec Plus is administered once daily, with or without food.

  When clinically appropriate, direct change from monotherapy with 20 mg olmesartan medoxomil to the fixed combination may be considered, taking into account that theantihypertensive effect of olmesartan medoxomil is maximal by about 8 weeks after initiating therapy. Dose titration of the individual components is recommended:

  20 mg olmesartan medoxomil/12.5 mg hydrochlorothiazide may be administered in patients whose blood pressure is not adequately controlled by the optimal monotherapy olmesartan medoxomil 20 mg alone.

  20 mg olmesartan medoxomil/25 mg hydrochlorothiazide may be administered in patients whose blood pressure is not adequately controlled by 20 mg olmesartan medoxomil/ 12.5 mg hydrochlorothiazide.

  A maximum daily dose of 20 mg olmesartan medoxomil and 25 mg hydrochlorothiazide in combination should not be exceeded.

  Renal impairment

  When Olmetec Plus is used in patients with mild to moderate renal impairment (creatinine clearance of 30 – 60 ml/min) periodic monitoring of renal function is advised. Olmetec Plus is contraindicated in patients with severe renal impairment (creatinine clearance < 30 mL/min).

  Hepatic impairment

  The use of Olmetec Plus in patients with hepatic impairment is not recommended since there is currently only limited experience of olmesartan medoxomil in this patient group.

• Child Dosage
  

  As the safety and efficacy of administration of Olmetec Plus to children have not been established, treatment of children up to 18 years is not recommended.

• Elderly Dosage
  

  In  elderly patients the same dosage of the combination is recommended as for adults

• Contra Indications
  

  Hypersensitivity to the active substances, to any of the excipients or to other sulfonamide-derived substances (since hydrochlorothiazide is a sulfonamide-derived medicinal product).

  Severe renal impairment (creatinine clearance < 30 mL/min).

  Refractory hypokalaemia, hypercalcaemia, hyponatraemia and symptomatic hyperuricaemia.

  Severe hepatic impairment, cholestasis and biliary obstructive disorders.

  Second and third trimesters of pregnancy.

  Lactation.

• Special Precautions
  

  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 (eg 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). No dosage adjustment is necessary in patients with mild to moderate renal impairment (creatinine clearance is 30 ml/min, < 60 mL/min). However, in such patients Olmetec Plus 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. There is no experience of the administration of Olmetec Plus in patients with a recent kidney transplantation.

  Hepatic impairment:

  There is currently limited experience of olmesartan medoxomil in patients with mild to moderate hepatic impairment and no experience in patients with severe hepatic impairment. 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 use of Olmetec Plus in patients with hepatic impairment is not recommended. Use of Olmetec Plus in patients with severe hepatic impairment, cholestasis and biliary obstruction is contraindicated.

  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. 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.

  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. 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.

  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 medicinal products containing angiotensin II receptor antagonists and thiazide in combination, the coadministration of Olmetec Plus and lithium is not recommended.

  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.

  Anti-doping test:

  Hydrochlorothiazide contained in this medicinal product could produce a positive analytic result in an anti-doping test.

  Other:

  In general arteriosclerosis, in patients with ischaemic heart disease or ischaemic cerebrovascular disease, there is always a risk that excessive blood pressure decrease 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 malapsorption should not take this medicinal product.

• Interactions
  

  Potential interactions related to both olmesartan medoxomil and hydrochloro-thiazide:

  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 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. 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 (ie acetylsalicylic acid > 3 g/day), COX-2 inhibitors and non-selective NSAIDs) may reduce the antihypertensive effect of thiazide diuretics and angiotensin II antagonists.

  In some patients with compromised renal function (eg dehydrated patients or elderly patients with compromised renal function) the co-administration of angiotensin II 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 (eg heparin, ACE inhibitors) may lead to increases in serum potassium. If medicinal product 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.

  Coadministration of olmesartan medoxomil with pravastatin had no clinically relevant effects on the pharmacokinetics of either component in healthy subjects.

  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 may be potentiated by the coadministration of other medicinal products associated with potassium loss and hypokalaemia (eg other kaliuretic diuretics, laxatives, corticosteroids, ACTH, amphotericin, carbenoxolone, penicillin G sodium or salicylic acid derivatives). Such concomitant use is therefore not recommended.

  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 (eg 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 (eg quinidine, hydroquinidine, disopyramide).

  - Class III antiarrythmics (eg amiodarone, sotalol, dofetilide, ibutilide).

  - Some antipsychotics (eg thioridazine, chlorpromazine, levomepromazine, trifluoperazine, cyamemazine, sulpiride, sultopride, amisulpride, tiapride, pimozide, haloperidol, droperidol).

  - Others (eg bepridil, cisapride, diphemanil, erythromycin IV, halofantrin, mizolastin, pentamidine, sparfloxacin, terfenadine, vincamine IV).

  Non-depolarizing skeletal muscle relaxants (eg tubocurarine):

  The effect of nondepolarizing skeletal muscle relaxants may be potentiated by hydrochlorothiazide.

  Anticholinergic agents (eg 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.

  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 (eg 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. Coadministration of a thiazide may increase the incidence of hypersensitivity reactions to allopurinol.

  Amantadine:

  Thiazides may increase the risk of adverse effects caused by amantadine.

  Cytotoxic agents (eg cyclophosphamide, methotrexate):

  Thiazides may reduce the renal excretion of cytotoxic medicinal products and potentiate their myelosuppressive effects.

  Salicylates:

  In cases 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 cyclosporine 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.

• Adverse Drug Reactions
  

  Fixed dose combination:

  In clinical trials involving 1155 patients treated with olmesartan medoxomil/hydrochlorothiazide combinations at dosages of 20/12.5 mg or 20/25 mg and 466 patients treated with placebo for periods of up to 21 months, the overall frequency of adverse events on olmesartan medoxomil/hydrochlorothiazide combination therapy was similar to that on placebo. Discontinuations due to adverse events were also similar for olmesartan medoxomil/hydrochlorothiazide 20/12.5 mg - 20/25 mg (2%) and placebo (3%). The frequency of adverse events on olmesartan medoxomil/hydrochlorothiazide overall relative to placebo appeared to be unrelated to age (<65 years versus 65 years), gender or race although the frequency of dizziness was somewhat increased in patients aged > 75 years.

  The most frequent adverse event on olmesartan medoxomil/hydrochlorothiazide 20/12.5 mg – 20/25 mg, and the only adverse event for which the frequency exceeded that on placebo by at least 1%, was dizziness (2.6% on olmesartan medoxomil/hydrochlorothiazide 20/12.5 mg - 20/25 mg and 1.3% on placebo).

  Adverse events of potential clinical relevance are listed below by system organ class. Frequencies are defined as: common (1/100, <1/10); uncommon (1/1000, <1/100); rare (1/10000, <1/1000); very rare (<1/10000).

  Metabolism and nutrition disorders:

  Uncommon: Hyperuricaemia, hypertriglyceridaemia

  Nervous system disorders:

  Common: Dizziness

  Uncommon: Syncope

  Cardiac disorders:

  Uncommon: Palpitations

  Vascular disorders:

  Uncommon: Hypotension, orthostatic hypotension

  Skin and subcutaneous tissue disorders:

  Uncommon: Rash, eczema

  General disorders and administration site conditions:

  Common: Fatigue

  Uncommon: Weakness

  Investigations:

  Uncommon: Blood potassium decreased, blood potassium increased, blood calcium increased, blood urea increased, blood lipids increased

  Laboratory findings

  In clinical trials, clinically important changes in standard laboratory parameters were rarely associated with olmesartan medoxomil/hydrochlorothiazide.

  Minor increases in mean uric acid, blood urea nitrogen and creatinine values and minor decreases in mean haemoglobin and haematocrit values were observed during treatment with olmesartan medoxomil/hydrochlorothiazide.

  Additional information on individual components:

  Undesirable effects previously reported with either of the individual components may be potential undesirable effects with Olmetec Plus, even if not observed in clinical trials with this product.

  Olmesartan medoxomil:

  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.

  System Organ Class	Very rare
  Blood and lymphatic system disorders	Thrombocytopenia
  Nervous system disorders	Dizziness, headache
  Respiratory, thoracic and mediastinal disorders	Cough
  Gastrointestinal disorders	Abdominal pain, nausea, vomiting
  Skin and subcutaneous tissue disorders	Pruritus, exanthem, rash Allergic conditions such as angioneurotic oedema, dermatitis allergic, face oedema and urticaria
  Musculoskeletal and connective tissue disorders	Muscle cramp, myalgia
  Renal and urinary disorders	Acute renal failure and renal insufficiency (See also under Investigations)
  General disorders and administration site conditions	Asthenic conditions such as asthenia, fatigue, lethargy, malaise
  Investigations	Abnormal renal function tests such as blood creatinine increased and blood urea increased Increased hepatic enzymes

  Clinical trials

  In double-blind, placebo-controlled monotherapy studies, the overall incidence of treatment-emergent adverse events was similar on olmesartan medoxomil and 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 1020 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 above:

  Central nervous system disorders:

  Common: Dizziness

  Uncommon: Vertigo

  Cardiovascular disorders:

  Rare: Hypotension

  Uncommon: Angina pectoris

  Respiratory system disorders:

  Common: Bronchitis, cough, pharyngitis, rhinitis

  Gastrointestinal disorders:

  Common: Abdominal pain, diarrhoea, dyspepsia, gastroenteritis, nausea

  Skin and appendages disorders:

  Uncommon: Rash

  Musculoskeletal disorders:

  Common: Arthritis, back pain, skeletal pain

  Urinary system disorders:

  Common: Haematuria, urinary tract infection

  General disorders:

  Common: Chest pain, fatigue, influenza-like symptoms, peripheral oedema, pain

  Laboratory findings

  In placebo-controlled monotherapy studies the incidence was somewhat higher on olmesartan medoxomil compared with placebo for hypertriglyceridaemia (2.0% versus 1.1%) and for raised creatine phosphokinase (1.3% versus 0.7%).

  Laboratory adverse events reported across all clinical trials with olmesartan medoxomil (including trials without a placebo control), irrespective of causality or incidence relative to placebo, included:

  Metabolic and nutritional disorders:

  Common: Increased creatine phosphokinase, hypertriglyceridaemia, hyperuricaemia.

  Rare: Hyperkalaemia

  Liver and biliary disorders:

  Common: Liver enzyme elevations.

  Hydrochlorothiazide:

  Hydrochlorothiazide may cause or exacerbate volume depletion which may lead to electrolyte imbalance.

  Infections and infestations:

  Rare: Sialadenitis

  Blood and lymphatic system disorders:

  Rare: Leukopenia, neutropenia/agranulocytosis, thrombocytopenia, aplastic anaemia, haemolytic anaemia, bone marrow depression

  Metabolism and nutrition disorders:

  Common: Hyperglycaemia, glycosuria, hyperuricaemia, electrolyte imbalance (including hyponatraemia, hypomagnesaemia, hypochloraemia, hypokalaemia and hypercalcaemia), increases in cholesterol and triglycerides

  Uncommon: Anorexia

  Psychiatric disorders:

  Rare: Restlessness, depression, sleep disturbances, apathy

  Nervous system disorders:

  Common: Light-headedness, confusional state

  Uncommon: Loss of appetite

  Rare: Paraesthesia, convulsions

  Eye disorders:

  Rare: Xanthopsia, transient blurred vision, lacrimation decreased

  Ear and labyrinth disorders:

  Common: Vertigo

  Cardiovascular disorders:

  Uncommon: Orthostatic hypotension

  Rare: Cardiac arrhythmias, necrotising angiitis (vasculitis, cutaneous vasculitis), thrombosis, embolism

  Respiratory, thoracic and mediastinal disorders:

  Rare: Dispnoea (including interstitial pneumonia and pulmonary oedema)

  Gastrointestinal disorders:

  Common: Gastric irritation, nausea, vomiting, diarrhoea, constipation, meteorism and abdominal pain

  Rare: Pancreatitis

  Very rare: Paralytic ileus

  Hepatobiliary disorders:

  Rare: Jaundice (intrahepatic cholestatic icterus), acute cholecystitis

  Skin and subcutaneous tissue disorders:

  Uncommon: Photosensitivity reactions, rash, urticaria

  Rare: Cutaneous lupus erythematosus-like reactions, reactivation of cutaneous lupus erythematosus, anaphylactic reactions, toxic epidermal necrolysis

  Musculoskeletal and connective tissue disorders:

  Rare: Muscle spasm, muscle weakness, paresis

  Renal and urinary disorders:

  Rare: Renal dysfunction, increase of substances in the serum that are obligatory excreted by urine (creatinine, urea), interstitial nephritis, acute renal failure

  Reproductive Symptoms and Breast disorders

  Rare: Erectile dysfunction

  General disorders and administration site conditions:

  Common: Weakness, headache and fatigue

  Rare: Fever