Olmetec Plus

Olmetec Plus

olmesartan + hydrochlorothiazide

Manufacturer:

Pfizer

Distributor:

Zuellig Pharma
Full Prescribing Info
Contents
Olmesartan medoxomil, hydrochlorothiazide
Description
Each olmesartan medoxomil-hydrochlorothiazide 20/12.5- or 40/12.5-mg tablet contains olmesartan medoxomil 20 or 40 mg, respectively, and hydrochlorothiazide 12.5 mg.
It also contains the following excipients: Tablet Core: Microcrystalline cellulose, lactose monohydrate, hydroxypropylcellulose, magnesium stearate.
Action
Pharmacology: Pharmacodynamics: Olmesartan medoxomil-hydrochlorothiazide is a combination of an angiotensin II receptor antagonist, olmesartan medoxomil, and a thiazide diuretic, hydrochlorothiazide. The combination of these ingredients has an additive antihypertensive effect, reducing blood pressure to a greater degree than either component alone.
Once daily dosing with olmesartan medoxomil-hydrochlorothiazide provides an effective and smooth reduction in blood pressure over the 24-hr dose interval.
Olmesartan medoxomil is a potent, orally active, selective angiotensin II receptor (type AT1) antagonist. Angiotensin II is the primary vasoactive hormone of the renin-angiotensin-aldosterone system and plays a significant role in the pathophysiology of hypertension. The effects of angiotensin II include vasoconstriction, stimulation of the synthesis and release of aldosterone, cardiac stimulation and renal reabsorption of sodium. Olmesartan blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II by blocking its binding to the AT1 receptor in tissues including vascular smooth muscle and the adrenal gland. The action of olmesartan is independent of the source or route of synthesis of angiotensin II. The selective antagonism of the angiotensin II (AT1) receptors by olmesartan results in increases in plasma renin levels and angiotensin I and II concentrations, and some decrease in plasma aldosterone concentrations.
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 abrupt cessation of therapy.
Once daily dosing with olmesartan medoxomil provides an effective and smooth reduction in blood pressure over the 24-hr 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 observed after 2 weeks of treatment.
The effect of olmesartan medoxomil on mortality and morbidity is not yet known.
Hydrochlorothiazide is a thiazide diuretic. The mechanism of the antihypertensive effect of thiazide diuretics is not fully known. Thiazides affect the renal tubular mechanisms of electrolyte reabsorption, directly increasing excretion of sodium and chloride in approximately equivalent amounts. The diuretic action of hydrochlorothiazide reduces plasma volume, increases plasma-renin activity and increases aldosterone secretion, with consequent increases in urinary potassium and bicarbonate loss and decreases in serum potassium. The renin-aldosterone link is mediated by angiotensin II and therefore co-administration of an angiotensin II receptor antagonist tends to reverse the potassium loss associated with thiazide diuretics. With hydrochlorothiazide, onset of diuresis occurs at about 2 hrs and peak effect occurs at about 4 hrs post-dose, whilst the action persists for approximately 6-12 hrs.
Epidemiological studies have shown that long-term treatment with hydrochlorothiazide reduces the risk of cardiovascular mortality and morbidity.
The combination of olmesartan medoxomil and hydrochlorothiazide produces additive reductions in blood pressure which generally increase with the dose of each component. In pooled placebo-controlled studies, administration of the 20/12.5-, 40/12.5- and 40/25-mg combinations of olmesartan medoxomil-hydrochlorothiazide resulted in mean placebo-subtracted systolic/diastolic blood pressure reductions at trough ranging from 12/7 to 16/9 mmHg. Age and gender had no clinically relevant effect on response to treatment with olmesartan medoxomil-hydrochlorothiazide combination therapy.
Administration of hydrochlorothiazide 12.5 and 25 mg in patients insufficiently controlled by olmesartan medoxomil 20 mg monotherapy gave additional reductions in 24-hr diastolic/systolic blood pressures measured by ambulatory blood pressure monitoring of 7/5 and 12/7 mmHg, respectively, compared with olmesartan medoxomil-monotherapy baseline. The additional mean systolic/diastolic blood pressure reductions at trough compared with baseline, measured conventionally, were 11/10 and 16/11 mmHg, respectively. The addition of hydrochlorothiazide 12.5 mg in patients not achieving target blood pressure (≤130/85 mmHg) on olmesartan medoxomil 40 mg decreased systolic/diastolic blood pressure by an additional 13/6 mmHg, and titration of the hydrochlorothiazide dose to 25 mg in non-achievers at the lower add-on dose resulted in a further blood pressure decrease of 9/5 mmHg. Conversely, addition of olmesartan medoxomil 10-20 mg in patients with moderate to severe hypertension insufficiently controlled by hydrochlorothiazide 25 mg monotherapy provided mean systolic/diastolic blood pressure reductions at trough of 21/18 mmHg compared with hydrochlorothiazide-monotherapy baseline.
The effectiveness of olmesartan medoxomil-hydrochlorothiazide combination therapy was maintained over long-term (1-year) treatment. Withdrawal of olmesartan medoxomil therapy, with or without concomitant hydrochlorothiazide therapy, did not result in rebound hypertension.
The effects of fixed-dose combination of olmesartan medoxomil-hydrochlorothiazide on mortality and cardiovascular morbidity are currently unknown.
Pharmacokinetics: Concomitant administration of olmesartan medoxomil and hydrochlorothiazide had no clinically relevant effects on the pharmacokinetics of either component in healthy subjects.
Absorption and Distribution: Olmesartan Medoxomil: 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 hrs after oral dosing with olmesartan medoxomil, and olmesartan plasma concentrations increase approximately linearly with increasing single oral doses up to about 80 mg.
Food had minimal effect on the bioavailability of olmesartan and therefore olmesartan medoxomil may be administered with or without food.
No clinically relevant gender-related differences in the pharmacokinetics of olmesartan have been observed.
Olmesartan is highly bound to plasma protein (99.7%), but the potential for clinically significant protein-binding displacement interactions between olmesartan and other highly bound co-administered drugs is low (as confirmed by the lack of a clinically significant interaction between olmesartan medoxomil and warfarin). The binding of olmesartan to blood cells is negligible. The mean volume of distribution after IV dosing is low (16-29 L).
Hydrochlorothiazide: Following oral administration of olmesartan medoxomil and hydrochlorothiazide in combination, the median time to peak concentrations of hydrochlorothiazide was 1.5-2 hrs after dosing. Hydrochlorothiazide is 68% protein bound in the plasma and its apparent volume of distribution is 0.83-1.14 L/kg.
Metabolism and Elimination: Olmesartan Medoxomil: Total plasma clearance of olmesartan was typically 1.3 L/hr (CV, 19%) and was relatively slow compared to hepatic blood flow (ca 90 L/h). Following a single oral dose of 14C-labeled olmesartan medoxomil, 10-16% of the administered radioactivity was excreted in the urine (the vast majority within 24 hrs 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 hepatobiliary 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 Contraindications).
The terminal elimination half-life of olmesartan varied between 10 and 15 hrs 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/hr and was independent of dose.
Hydrochlorothiazide: Hydrochlorothiazide is not metabolised in man and is excreted almost entirely as unchanged drug in urine. About 60% of the oral dose is eliminated as unchanged drug within 48 hrs. Renal clearance is about 250-300 mL/min. The terminal elimination half-life of hydrochlorothiazide is 10-15 hrs.
Special Populations: Elderly: In hypertensive patients, the olmesartan AUC at steady state was increased by ca 35% in elderly patients (65-75 years) and by ca 44% in very elderly patients (≥75 years) compared with the younger age group (see Dosage & Administration).
Renal impairment: In renally impaired patients, the olmesartan 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 Dosage & Administration and Precautions).
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 hrs 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. Olmesartan medoxomil has not been evaluated in patients with severe hepatic impairment (see Dosage & Administration and Precautions).
Toxicology: Preclinical Safety Data: The toxic potential of olmesartan medoxomil-hydrochlorothiazide was evaluated in repeated dose oral toxicity studies with olmesartan medoxomil-hydrochlorothiazide combinations for up to 6 months in rats and dogs. Most observations were due to the pharmacological activity of the combination and there were no findings that would preclude administration to humans at the therapeutic dosage level.
There was no evidence of relevant genotoxic activity under conditions of clinical use. Olmesartan medoxomil-hydrochlorothiazide in a ratio of 20:12.5 was negative in the bacterial reverse mutation test up to the maximum recommended plate concentration for the standard assays. Olmesartan medoxomil and hydrochlorothiazide were tested individually and in combination ratios of 40:12.5, 20:12.5 and 10:12.5, for clastogenic activity in the in vitro Chinese hamster lung chromosomal aberration assay. As expected, a positive response was seen for each component and combination ratio. However, no synergism in clastogenic activity was detected between olmesartan medoxomil and hydrochlorothiazide at any combination ratio.
Olmesartan medoxomil-hydrochlorothiazide in a ratio of 20:12.5, administered orally, tested negative in the in vivo mouse bone marrow erythrocyte micronucleus assay at administered doses of up to 1935/1209 mg/kg.
The carcinogenic potential of a combination of olmesartan medoxomil and hydrochlorothiazide was not investigated, as there was no evidence of relevant carcinogenic effects for the 2 individual components under conditions of clinical use.
There was no evidence of teratogenicity in mice or rats treated with olmesartan medoxomil-hydrochlorothiazide combinations. As expected from this class of drug, fetal toxicity was observed in rats, as evidenced by significantly reduced fetal body weights, when treated with olmesartan medoxomil-hydrochlorothiazide combinations during gestation (see Contraindications, and Use in pregnancy and Use in lactation under Precautions).
Indications/Uses
Treatment of essential hypertension.
Patients whose blood pressure is not adequately controlled on olmesartan medoxomil or hydrochlorothiazide alone.
Dosage/Direction for Use
Adults: Olmesartan medoxomil-hydrochlorothiazide is administered once daily, with or without food, in patients whose blood pressure is not adequately controlled by olmesartan medoxomil or hydrochlorothiazide alone.
When clinically appropriate, direct change from monotherapy to the fixed combination may be considered. Dose titration of the individual components is recommended:
Olmesartan medoxomil-hydrochlorothiazide 20/12.5 mg may be administered in patients whose blood pressure is not adequately controlled with hydrochlorothiazide 12.5 or 25 mg monotherapy, or olmesartan medoxomil 20 mg alone. If additional blood pressure lowering is required the dose of each monocomponent may be titrated to the strength of olmesartan medoxomil-hydrochlorothiazide 40/12.5 mg and subsequently, if required to 40/25 mg.
Olmesartan medoxomil-hydrochlorothiazide 40/12.5 and 40/25 mg may be administered in patients whose blood pressure is not adequately controlled by olmesartan medoxomil 40 mg alone, hydrochlorothiazide alone or olmesartan medoxomil-hydrochlorothiazide 20/12.5 mg.
Elderly: No initial dosage adjustments recommended for elderly patients (see Pharmacokinetics under Actions).
Renal Impairment: In patients with mild to moderate renal impairment (creatinine clearance of 30-60 mL/min) the dosage of olmesartan medoxomil should not exceed 20 mg daily (ie, olmesartan medoxomil-hydrochlorothiazide 20/12.5 mg), owing to limited experience of higher dosages of olmesartan medoxomil in this patient group (see Pharmacokinetics under Actions). When olmesartan medoxomil-hydrochlorothiazide is used in such patients, periodic monitoring of renal function is advised (see Precautions). Olmesartan medoxomil-hydrochlorothiazide is contraindicated in patients with severe renal impairment (creatinine clearance <30 mL/min) (see Contraindications).
Hepatic Impairment: The use of olmesartan medoxomil-hydrochlorothiazide in patients with hepatic impairment is not recommended since there is currently limited experience of olmesartan medoxomil in this patient group (see Pharmacokinetics under Actions and Precautions).
Children and Adolescents: The safety and efficacy of olmesartan medoxomil-hydrochlorothiazide have not been established in children and adolescents up to 18 years.
Overdosage
No specific information is available on the effects or treatment of olmesartan medoxomil-hydrochlorothiazide overdosage.
Symptoms: The most likely manifestations of olmesartan overdosage are expected to be hypotension and tachycardia; bradycardia might also occur. Overdosage with hydrochlorothiazide is associated with electrolyte depletion (hypokalaemia, hypochloraemia) and dehydration resulting from excessive diuresis. The most common signs and symptoms of overdosage are nausea and somnolence. Hypokalaemia may result in muscle spasm and/or accentuate cardiac arrhythmias associated with the concomitant use of digitalis glycosides or certain antiarrhythmic drugs.
Treatment: The patient should be closely monitored, and the treatment should be symptomatic and supportive. Management depends upon the time since ingestion and the severity of the symptoms. Suggested measures include induction of emesis and/or gastric lavage. Activated charcoal may be useful in the treatment of overdosage. Serum electrolytes and creatinine should be monitored frequently. If hypotension occurs, the patient should be placed in a supine position, with salt and volume replacements given quickly.
No information is available regarding the dialysability of olmesartan or hydrochlorothiazide.
Contraindications
Hypersensitivity to olmesartan medoxomil, hydrochlorothiazide or to any of the excipients of Olmetec Plus (see Description for the list of excipients), or to other sulphonamide-derived substances (since hydrochlorothiazide is a sulphonamide-derived medicinal product).
Severe renal impairment (creatinine clearance <30 mL/min); refractory hypokalaemia; hypercalcaemia; chloestasis and biliary obstructive disorders, anuria.
Second and third trimester of pregnancy and lactation. (See Use in pregnancy and Use in lactation under Precaution.)
Special Precautions
Intravascular-Volume Depletion: Symptomatic hypotension, especially after the 1st dose, may occur in patients who are volume and/or sodium depleted by diuretic therapy, dietary salt restriction, diarrhoea or vomiting. Such conditions should be corrected before the administration of olmesartan medoxomil-hydrochlorothiazide.
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 other medicinal products that affect this system has been associated with acute hypotension, azotemia, 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: Olmesartan medoxomil-hydrochlorothiazide should not be used in patients with severe renal impairment (creatinine clearance <30 mL/min) (see Contraindications). 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 olmesartan medoxomil-hydrochlorothiazide should be administered with caution and periodic monitoring of serum potassium, creatinine and uric acid levels is recommended. Thiazide diuretic-associated azotemia may occur in patients with impaired renal function. There is no experience of the administration of olmesartan medoxomil-hydrochlorothiazide in patients with 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 olmesartan medoxomil-hydrochlorothiazide in patients with hepatic impairment is not recommended (see Dosage & Administration). Use of olmesartan medoxomil in patients with biliary obstruction is contraindicated (see Pharmacokinetics under Actions and Contraindications).
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 antihypertensive drugs acting through inhibition of the renin-angiotensin system. Therefore, the use of olmesartan medoxomil-hydrochlorothiazide 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 Interactions). Latent diabetes mellitus may become manifest during thiazide therapy.
Increases in cholesterol and triglyceride levels have been 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 eg, nausea or vomiting (see Adverse Reactions).
Although hypokalaemia may develop with the use of thiazide diuretics, concurrent therapy with olmesartan medoxomil may reduce diuretic-induced hypokalaemia. 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 olmesartan medoxomil-hydrochlorothiazide 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 should be co-administered cautiously with olmesartan medoxomil-hydrochlorothiazide (see Interactions).
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. Marked 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.
Lithium: As with other medicinal products containing angiotensin-II receptor antagonists and thiazide in combination, the co-administration of olmesartan medoxomil-hydrochlorothiazide and lithium is not recommended (see Interactions).
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.
Effects on the Ability to drive or Operate Machinery: The effect of olmesartan medoxomil-hydrochlorothiazide on the ability to drive and use machines has not been specifically studied. However, it should be born in mind that dizziness or fatigue may occasionally occur in patients taking antihypertensive therapy.
Use in pregnancy: There is no experience with the use of olmesartan medoxomil-hydrochlorothiazide in pregnant women. Studies in mice and rats using olmesartan medoxomil-hydrochlorothiazide combinations do not indicate a teratogenic effect, but foetotoxicity has been shown in rats. Thiazides cross the placental barrier and appear in cord blood. They may cause foetal electrolyte disturbances and possible other reactions that have occurred in adults. Cases of neonatal thrombocytopenia, or foetal or neonatal jaundice have been reported with maternal thiazide therapy.
Therefore, olmesartan medoxomil-hydrochlorothiazide is contraindicated during the 2nd and 3rd trimesters of pregnancy. In addition, olmesartan medoxomil-hydrochlorothiazide must not be used during the 1st trimester. If pregnancy occurs during therapy, olmesartan medoxomil-hydrochlorothiazide must be discontinued as soon as possible. (See Contraindications.)
Use in lactation: Olmesartan is excreted in the milk of lactating rats but it is not known whether olmesartan is excreted in human milk. Thiazides appear in human milk and may inhibit lactation. Mothers must not breastfeed if they are taking olmesartan medoxomil-hydrochlorothiazide. (See Contraindications.)
Use In Pregnancy & Lactation
Use in pregnancy: There is no experience with the use of olmesartan medoxomil-hydrochlorothiazide in pregnant women. Studies in mice and rats using olmesartan medoxomil-hydrochlorothiazide combinations do not indicate a teratogenic effect, but foetotoxicity has been shown in rats. Thiazides cross the placental barrier and appear in cord blood. They may cause foetal electrolyte disturbances and possible other reactions that have occurred in adults. Cases of neonatal thrombocytopenia, or foetal or neonatal jaundice have been reported with maternal thiazide therapy.
Therefore, olmesartan medoxomil-hydrochlorothiazide is contraindicated during the 2nd and 3rd trimesters of pregnancy. In addition, olmesartan medoxomil-hydrochlorothiazide must not be used during the 1st trimester. If pregnancy occurs during therapy, olmesartan medoxomil-hydrochlorothiazide must be discontinued as soon as possible. (See Contraindications.)
Use in lactation: Olmesartan is excreted in the milk of lactating rats but it is not known whether olmesartan is excreted in human milk. Thiazides appear in human milk and may inhibit lactation. Mothers must not breastfeed if they are taking olmesartan medoxomil-hydrochlorothiazide. (See Contraindications.)
Adverse Reactions
Fixed Dose Combination: In clinical trials involving 2341 patients treated with olmesartan medoxomil-hydrochlorothiazide combinations 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 (2%) and placebo (3%). The frequency of adverse events on olmesartan medoxomil-hydrochlorothiazide relative to placebo appeared to be unrelated to age (<65 years vs ≥65 years), gender or race.
The only adverse event, which was statistically significantly more frequent on olmesartan medoxomil-hydrochlorothiazide than on placebo, was dizziness (3% vs 1%). The incidence of dizziness was not dose related.
Adverse events of potential clinical relevance are listed as follows, by system organ class. Frequencies are defined as: Common (≥1/100, <1/10); uncommon (≥1/1000, <1/100); rare (≥1/10,000, <1/1000); very rare (<1/10,000).
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: Uncommon: Weakness.
Investigations: Uncommon: Decreased blood potassium; increased blood potassium or blood urea.
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 olmesartan medoxomil-hydrochlorothiazide, even if not observed in clinical trials with Olmetec Plus.
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: Blood and Lymphatic System Disorders: Very Rare: Thrombocytopenia.
Nervous System Disorders: Very Rare: Dizziness, headache.
Respiratory, Thoracic and Mediastinal Disorders: Very Rare: Cough.
Gastrointestinal Disorders: Very Rare: Abdominal pain, nausea, vomiting.
Skin and Subcutaneous Tissue Disorders: Very Rare: Pruritus, exanthem, rash, allergic conditions eg, angioneurotic oedema, allergic dermatitis, face oedema and urticaria.
Musculoskeletal and Connective Tissue Disorders: Very Rare: Muscle cramp, myalgia.
Renal and Urinary Disorders: Very Rare: Acute renal failure and renal insufficiency (see also under Investigations).
General Disorders and Administration Site Conditions: Very Rare: Asthenic conditions eg, asthenia, fatigue, lethargy, malaise.
Investigations: Very Rare: Abnormal renal function tests eg, increased blood creatinine, blood urea, hepatic enzymes.
Metabolic and Nutritional Disorders: Very Rare: Hyperkalaemia.
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 previously: 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 or 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% vs 1.1%) and for raised creatine phosphokinase (1.3% vs 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, are as follows: 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 (see Precautions).
Adverse events reported with the use of hydrochlorothiazide alone include: Gastrointestinal System Disorders: Anorexia, loss of appetite, gastric irritation, diarrhoea, constipation, sialadenitis, pancreatitis.
Hepatobiliary Disorders: Jaundice (intrahepatic cholestatic jaundice).
Eye Disorders: Xanthopsia, transient blurred vision.
Blood and Lymphatic System Disorders: Leukopenia, neutropenia/agranulocytosis, thrombocytopenia, aplastic anaemia, hemolytic anaemia, bone-marrow depression.
Skin and Subcutaneous Tissue Disorders: Photosensitivity reactions, rash, cutaneous lupus erythematosus-like reactions, reactivation of cutaneous lupus erythematosus, urticaria, necrotising angiitis (vasculitis, cutaneous vasculitis), anaphylactic reactions, toxic epidermal necrolysis.
General Disorders: Fever.
Respiratory System Disorders: Respiratory distress (including pneumonitis and pulmonary edema).
Renal and Urinary Disorders: Renal dysfunction, interstitial nephritis.
Musculoskeletal Disorders: Muscle spasm, weakness.
Nervous System Disorders: Restlessness, light-headedness, vertigo, paresthesiae.
Vascular Disorders: Postural hypotension.
Cardiac Disorders: Cardiac arrhythmias.
Psychiatric Disorders: Sleep disturbances, depression.
Laboratory Findings: Hyperglycaemia, glycosuria, hyperuricaemia, electrolyte imbalance (including hyponatraemia and hypokalaemia), increases in cholesterol and triglycerides.
Drug Interactions
Interaction with Other Medicinal Products and Other Forms of Interaction: Effects of Other Medicinal Products on Olmesartan Medoxomil-Hydrochlorothiazide: Medicinal Products Affecting Potassium Levels: The potassium-depleting effect of hydrochlorothiazide (see Precautions) may be potentiated by the co-administration of other medicinal products associated with potassium loss and hypokaaemia [eg, other kaliuretic diuretics, laxatives, corticosteroids, adrenocorticosteroid hormone (ACTH), amphotericin, carbenoxolone, penicillin G sodium or salicylic acid derivatives].
Conversely, 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 (eg, heparin) may lead to increases in serum potassium (see Precautions).
If drugs which affect potassium levels are to be prescribed in combination with olmesartan medoxomil-hydrochlorothiazide, monitoring of potassium plasma levels is advised.
Other Antihypertensive Agents: The blood-pressure lowering effect of olmesartan medoxomil-hydrochlorothiazide can be increased by concomitant use of other antihypertensive medications.
Nonsteroidal Anti-inflammatory Drugs (NSAIDs): The administration of a NSAID may reduce the diuretic, natriuretic and antihypertensive effects of thiazide diuretics in some patients. In elderly patients and patients who may be dehydrated there is a risk of acute renal failure, therefore monitoring of renal function at the initiation of treatment is recommended.
Alcohol, Barbiturates, Narcotics or Antidepressants: Potentiation of orthostatic hypotension may occur.
Baclofen, Amifostine: Potentiation of antihypertensive effect may occur.
Cholestyramine and Colestipol Resins: Absorption of hydrochlorothiazide is impaired in the presence of anionic exchange resins.
Anticholinergic Agents (eg, Atropine, Biperiden): Increase of the bioavailability of thiazide-type diuretics by decreasing gastrointestinal motility and stomach-emptying rate.
Effects of olmesartan medoxomil-hydrochlorothiazide 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, 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 olmesartan medoxomil-hydrochlorothiazide and lithium in combination is not recommended (see Precautions). If use of the combination proves necessary, careful monitoring of serum lithium levels is recommended.
Medicinal Products Affected by Serum Potassium Disturbances: Periodic monitoring of serum potassium and ECG is recommended when olmesartan medoxomil-hydrochlorothiazide is administered with drugs affected by serum potassium disturbances (eg, digitalis glycosides and antiarrhythmics) and with the following torsades de pointes-inducing medicinal products, hypokalaemia being a predisposing factor to torsades de pointes: 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).
Digitalis Glycosides: Thiazide-induced hypokalaemia or hypomagnesaemia may favor the onset of digitalis-induced cardiac arrhythmias.
Antidiabetic Drugs (Oral Agents and Insulin): The treatment with a thiazide may influence the glucose tolerance. Dosage adjustment of the antidiabetic drug may be required (see Precautions).
Metformin: Metformin should be used with caution because of the risk of lactic acidosis induced by possible functional renal failure linked to hydrochlorothiazide.
β-Blockers and Diazoxide: The hyperglycaemic effect of β-blockers and diazoxide may be enhanced by thiazides.
Pressor Amines (eg, Noradrenaline): The effect of pressor amines may be decreased.
Nondepolarizing Skeletal Muscle Relaxants (eg, Tubocurarine): The effect of nondepolarizing skeletal-muscle relaxants may be potentiated by hydrochlorothiazide.
Medicinal Products Used in the Treatment of Gout (Probenecid, Sulfinpyrazone and Allopurinol): Dosage adjustment of uricosuric medications may be necessary since hydrochlorothiazide may raise the level of serum uric acid. Increase in dosage of probenecid or sulfinpyrazone may be necessary. Co-administration of a thiazide may increase the incidence of hypersensitivity reactions to allopurinol.
Calcium Salts: Thiazide diuretics may increase serum calcium levels due to decreased excretion (see Precautions). If calcium supplements must be prescribed, serum calcium levels should be monitored and calcium dosage adjusted accordingly.
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 drugs and potentiate their myelosuppressive effects.
Additional Information: Concomitant administration of olmesartan medoxomil and hydrochlorothiazide had no clinically relevant effects on the pharmacokinetics of either component in healthy subjects.
Olmesartan medoxomil had no significant effect on the pharmacokinetics or pharmacodynamics of warfarin or the pharmacokinetics of digoxin.
Co-administration 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 P-450 enzymes 1A1/2, 2A6, 2C8/9, 2C19, 2D6, 2E1 and 3A4 in vitro, and had no or minimal inducing effects on rat cytochrome P-450 activities. No clinically relevant interactions between olmesartan and drugs metabolised by the above cytochrome P-450 enzymes are expected.
Storage
Store below 25°C.
ATC Classification
C09DA08 - olmesartan medoxomil and diuretics ; Belongs to the class of angiotensin II receptor blockers (ARBs) in combination with diuretics. Used in the treatment of cardiovascular disease.
Presentation/Packing
Film-coated tab 20/12.5 mg x 3 x 10's. 40/12.5 mg x 3 x 10's.
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