Olmetec Plus

Olmesartan medoxomil, hydrochlorothiazide.

Each 20/12.5-mg film-coated tablet contains olmesartan medoxomil 20 mg and hydrochlorothiazide 12.5 mg.
Each 40/12.5-mg film-coated tablet contains olmesartan medoxomil 40 mg and hydrochlorothiazide 12.5 mg.
Each film-coated tablet also contains the following excipients: Tablet Core: Microcrystalline cellulose, lactose monohydrate, hydroxypropylcellulose, magnesium stearate. Tablet Coat: Talc, hypromellose, titanium dioxide (E171), iron oxide yellow (E172), iron oxide red (E172).

Pharmacotherapeutic Group: Angiotensin II antagonists and diuretics. ATC Code: C09D A.
Pharmacology: Pharmacodynamics: Olmetec Plus 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 Olmetec Plus 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 reninangiotensin-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 1st-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, while 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 mg, 40/12.5 mg and 40/25 mg combinations of olmesartan medoxomil/hydrochlorothiazide resulted in mean placebo-subtracted systolic/diastolic blood pressure reductions at trough ranging from 12/7-16/9 mmHg. Age and gender had no clinically relevant effect on response to treatment with olmesartan medoxomil/hydrochlorothiazide combination therapy.
Administration of hydrochlorothiazide 12.5 mg 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 mmHg 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 mmHg and 16/11 mmHg, respectively. The addition 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 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 (C_max) 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 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/hr). Following a single oral dose of ¹⁴C-labelled olmesartan medoxomil, 10-16% of the administered radioactivity was excreted in the urine (the vast majority within 24 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 1st 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 metabolized 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 area under the curve (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 Interactions).
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 Interactions).
Toxicology: Preclinical Safety Data: The toxic potential of Olmetec Plus 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, foetal toxicity was observed in rats, as evidenced by significantly reduced foetal body weights, when treated with olmesartan medoxomil/hydrochlorothiazide combinations during gestation (see Contraindications and Use in pregnancy & lactation under Precautions).

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

Adults: Olmetec Plus 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: Olmetec Plus 20/12.5-mg tab may be administered in patients whose blood pressure is not adequately controlled with hydrochlorothiazide 12.5 or 25 mg monotherapy, or Olmetec 20 mg alone. If additional blood pressure lowering is required the dose of each monocomponent may be titrated to the strength of Olmetec Plus 40/12.5-mg tab and subsequently, if required to 40/25-mg tab.
Olmetec Plus 40/12.5 mg and 40/25mg may be administered in patients whose blood pressure is not adequately controlled by Olmetec 40 mg alone, hydrochlorothiazide alone, or Olmetec Plus 20/12.5 mg.
Renal Impairment: In patients with mild to moderate renal impairment [creatinine clearance (CrCl) of 30-60 mL/min] the dosage of olmesartan medoxomil should not exceed 20 mg daily (ie, Olmetec Plus 20/12.5 mg), owing to limited experience of higher dosages of Olmetec in this patient group (see Pharmacokinetics under Actions). When Olmetec Plus is used in such patients, periodic monitoring of renal function is advised (see Precautions).
Hepatic Impairment: The use of Olmetec Plus 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 Olmetec plus have not been established in children and adolescents up to 18 years.
Elderly: No initial dosage adjustments is recommended for elderly patients (see Pharmacokinetics under Actions).
Administration: Taken once daily, with or without food.

No specific information is available on the effects or treatment of Olmetec Plus overdosage. 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.
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 anti-arrhythmic drugs.
No information is available regarding the dialysability of olmesartan or hydrochlorothiazide.

Hypersensitivity to olmesartan medoxomil, hydrochlorothiazide or to any of the excipients of Olmesartan Plus, or to other sulphonamide-derived substances (since hydrochlorothiazide is a sulphonamide-derived medicinal product). Severe renal impairment (CrCl <30 mL/min). Refractory hypokalaemia, hypercalcaemia. Cholestasis and biliary obstructive disorders. Pregnancy (2nd and 3rd trimester), lactation.

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, diarrhea 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 underiying renal disease, including renal artery stenosis), treatment with other 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 (CrCl <30 mL/min) (see Contraindications). No dosage adjustment is necessary in patients with mild to moderate renal impairment (CrCl 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. 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 (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 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 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 adrenocorticotropic hormone (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 should be co-administered cautiously with Olmetec Plus (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 Olmetec Plus and lithium is not recommended (see Interactions).
Others: As with any antihypertensive agent, excessive blood pressure decrease in patients with ischaemic heart disease or ischaemic cerebrovascular disease could resuit 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 Olmetec Plus on the ability to drive and use machines has not been specifically studied. However, it should be borne in mind that dizziness or fatigue may occasionally occur in patients taking antihypertensive therapy.
Use in pregnancy & lactation: There is no experience with the use of Olmetec Plus 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, Olmetec Plus is contraindicated during the 2nd and 3rd trimesters of pregnancy. In addition, Olmetec Plus must not be used during the 1st trimester. If pregnancy occurs during therapy, Olmetec Plus must be discontinued as soon as possible.
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 Olmetec Plus.
Use in children: Safety and effectiveness in pediatric patients have not been established.
Use in the elderly: Clinical studies of olmesartan medoxomil and hydrochlorothiazide did not include sufficient numbers of subjects aged ≥65 to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant diseases or other drug therapy.
Olmesartan and hydrochlorothiazide are substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function.

There is no experience with the use of Olmetec Plus 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, Olmetec Plus is contraindicated during the 2nd and 3rd trimesters of pregnancy. In addition, Olmetec Plus must not be used during the 1st trimester. If pregnancy occurs during therapy, Olmetec Plus must be discontinued as soon as possible.
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 Olmetec Plus.

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 below 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, increased 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 Olmetec Plus, 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, diarrhea.
Skin and Subcutaneous Tissue Disorders: Pruritus, exanthem, rash, allergic conditions eg, angioneurotic oedema, allergic dermatitis, face oedema and urticaria, anaphylactic reaction.
Musculoskeletal and Connective Tissue Disorders: Very Rare: Muscle cramp, myalgia.
Renal and Urinary Disorders: Acute renal failure and renal insufficiency (see following texts under Investigations).
General Disorders and Administration Site: Very Rare: Asthenic conditions eg, asthenia, fatigue, lethargy, malaise, peripheral oedema.
Investigations: Very Rare: Abnormal renal function tests eg, increased blood creatinine and increased blood urea, increased 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 previously mentioned: Central Nervous System Disorders: Common: Dizziness. Uncommon: Vertigo.
Cardiovascular Disorders: Rare: Hypotension. Uncommon: Vertigo.
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% 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, 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 (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, haemolytic 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 oedema).
Renal and Urinary Disorders: Renal dysfunction, interstitial nephritis.
Musculoskeletal Disorders: Muscle spasm, weakness.
Nervous System Disorders: Restlessness, lightheadedness, vertigo, paraesthesiae.
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.

Effects of Other Medicinal Products on Olmetec Plus: 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 hypokalaemia (eg, other kaliuretic diuretics, laxatives, corticosteroids, 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 Olmetec Plus, monitoring of potassium plasma levels is advised.
Other Antihypertensive Agents: The blood pressure lowering effect of Olmetec Plus can be increased by concomitant use of other antihypertensive medications.
Nonsteroidal Anti-Inflammatory Drugs (NSAIDs): The administration of a NSAIDs 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): Increased bioavailability of thiazide-type diuretics by decreasing gastrointestinal motility and stomach emptying rate.
Effects of Olmetec Plus 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 Olmetec Plus 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 Olmetec Plus 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 Torsade 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 favour 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.
Beta-Blockers and Diazoxide: The hyperglyeaemic 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 hydrochlorothlazlde may raise the level of serum uric acid. Increased 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 the 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 3M 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.

Store below 25°C.
Shelf-Life: 3 years.

Angiotensin II Antagonists / Diuretics

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.

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