Olmesartan medoxomil/Hydrochlorothiazide 20mg/25mg Tablets USP Taj Pharma

Olmesartan medoxomil/Hydrochlorothiazide 20mg/25mg tablets USP

1. Name of the medicinal product

Olmesartan medoxomil/Hydrochlorothiazide 20mg /12.5mg film-coated tablets Taj Pharma
Olmesartan medoxomil/Hydrochlorothiazide 20mg /25mg film-coated tablets Taj Pharma
Olmesartan medoxomil/Hydrochlorothiazide 40mg /12.5mg film-coated tablets Taj Pharma
Olmesartan medoxomil/Hydrochlorothiazide 40mg /25mg film-coated tablets Taj Pharma

Qualitative and quantitative composition
a) Olmesartan medoxomil/Hydrochlorothiazide 20mg /12.5mg film-coated tablets:
Each film-coated tablet contains 20mg olmesartan medoxomil USP and 12.5mg hydrochlorothiazide USP

b) Olmesartan medoxomil/Hydrochlorothiazide 20mg /25mg film-coated tablets:
Each film-coated tablet contains 20mg olmesartan medoxomil USP and 25mg hydrochlorothiazide USP

c) Olmesartan medoxomil/Hydrochlorothiazide 40mg /12.5mg film-coated tablets:
Each film-coated tablet contains 20mg olmesartan medoxomil  USP and 25mg hydrochlorothiazide USP

d) Olmesartan medoxomil/Hydrochlorothiazide 40mg /25mg film-coated tablets:
Each film-coated tablet contains 20mg olmesartan medoxomil USP and 25mg hydrochlorothiazide USP

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

Film-coated tablets.

4. Clinical particulars

4.1 Therapeutic indications

Treatment of essential hypertension.

Olmesartan medoxomil/Hydrochlorothiazide fixed dose combination is indicated in adult patients whose blood pressure is not adequately controlled on olmesartan medoxomil alone.

4.2 Posology and method of administration

Posology

Adults

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

When clinically appropriate, direct change from monotherapy with 20mg olmesartan medoxomil to the fixed combination may be considered, taking into account that the antihypertensive effect of olmesartan medoxomil is maximal by about 8 weeks after initiating therapy (see section 5.1). Dose titration of the individual components is recommended:

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

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

Elderly (age 65 years or over)

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

Renal impairment

When Olmesartan medoxomil/Hydrochlorothiazide is used in patients with mild to moderate renal impairment (creatinine clearance of 30 – 60 mL/min) periodic monitoring of renal function is advised (see section 4.4). Olmesartan medoxomil/Hydrochlorothiazide is contraindicated in patients with severe renal impairment (creatinine clearance < 30 mL/min) (see section 4.3).

Hepatic impairment

Olmesartan medoxomil/Hydrochlorothiazide should be used with caution in patients with mild to moderate hepatic impairment (see sections 4.4, 5.2). In patients with moderate hepatic impairment, an initial dose of 10mg olmesartan medoxomil once daily is recommended and the maximum dose should not exceed 20mg once daily. Close monitoring of blood pressure and renal function is advised in hepatically-impaired patients who are receiving diuretics and/or other antihypertensive agents. There is no experience of olmesartan medoxomil in patients with severe hepatic impairment.

Olmesartan medoxomil/Hydrochlorothiazide should not be used in patients with severe hepatic impairment (see sections 4.3, 5.2), cholestasis and biliary obstruction (see section 4.3).

Paediatric population

The safety and efficacy of Olmesartan medoxomil/Hydrochlorothiazide in children and adolescents below 18 years has not been established. No data are available.

Method of administration

The tablet should be swallowed with a sufficient amount of fluid (e.g. one glass of water). The tablet should not be chewed and should be taken at the same time each day.

4.3 Contraindications

Hypersensitivity to the active substances, to any of the excipients listed in section 6.1 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.

2nd and 3rd trimester of pregnancy (see sections 4.4 and 4.6).

The concomitant use of Olmesartan medoxomil/Hydrochlorothiazide with aliskiren-containing products is contraindicated in patients with diabetes mellitus or renal impairment (GFR < 60 mL/min/1.73 m²) (see sections 4.5 and 5.1).

4.4 Special warnings and precautions for use

Intravascular volume depletion:

Symptomatic hypotension, especially after the first dose, may occur in patients who are volume and/or sodium depleted by vigorous diuretic therapy, dietary salt restriction, diarrhoea or vomiting. Such conditions should be corrected before the administration of 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 (e.g. patients with severe congestive heart failure or underlying renal disease, including renal artery stenosis), treatment with medicinal products that affect this system has been associated with acute hypotension, azotaemia, oliguria or, rarely, acute renal failure.

Renovascular hypertension:

There is an increased risk of severe hypotension and renal insufficiency when patients with bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney are treated with medicinal products that affect the renin-angiotensin-aldosterone system.

Renal impairment and kidney transplantation:

Olmesartan medoxomil/Hydrochlorothiazide should not be used in patients with severe renal impairment (creatinine clearance < 30 mL/min) (see section 4.3). 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 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 Olmesartan medoxomil/Hydrochlorothiazide in patients with a recent kidney transplantation.

Dual blockade of the renin-angiotensin-aldosterone system (RAAS):

There is evidence that the concomitant use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren increases the risk of hypotension, hyperkalaemia and decreased renal function (including acute renal failure). Dual blockade of RAAS through the combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is therefore not recommended (see sections 4.5 and 5.1).

If dual blockade therapy is considered absolutely necessary, this should only occur under specialist supervision and subject to frequent close monitoring of renal function, electrolytes and blood pressure.

ACE-inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy.

Hepatic impairment:

There is currently no experience of olmesartan medoxomil 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 care should be taken in patients with mild to moderate hepatic impairment (see section 4.2). Use of Olmesartan medoxomil/Hydrochlorothiazide in patients with severe hepatic impairment, cholestasis and biliary obstruction is contraindicated (see sections 4.3, 5.2).

Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy:

As with other vasodilators, special caution is indicated in patients suffering from aortic or mitral stenosis, or obstructive hypertrophic cardiomyopathy.

Primary aldosteronism:

Patients with primary aldosteronism generally will not respond to anti-hypertensive medicinal products acting through inhibition of the renin-angiotensin system. Therefore, the use of 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 section 4.5). Latent diabetes mellitus may become manifest during thiazide therapy.

Increases in cholesterol and triglyceride levels are undesirable effects known to be associated with thiazide diuretic therapy.

Hyperuricaemia may occur or frank gout may be precipitated in some patients receiving thiazide therapy.

Electrolyte imbalance:

As for any patient receiving diuretic therapy, periodic determination of serum electrolytes should be performed at appropriate intervals.

Thiazides, including hydrochlorothiazide, can cause fluid or electrolyte imbalance (including hypokalaemia, hyponatraemia and hypochloraemic alkalosis). Warning signs of fluid or electrolyte imbalance are dryness of the mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pain or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea or vomiting (see section 4.8).

The risk of hypokalaemia is greatest in patients with cirrhosis of the liver, in patients experiencing brisk diuresis, in patients who are receiving inadequate oral intake of electrolytes and in patients receiving concomitant therapy with corticosteroids or ACTH (see section 4.5).

Conversely, due to antagonism at the angiotensin-II receptors (AT₁) through the olmesartan medoxomil component of 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 and other medicinal products that may increase serum potassium levels (e.g. heparin) should be co-administered cautiously with Olmesartan medoxomil/Hydrochlorothiazide (see section 4.5).

There is no evidence that olmesartan medoxomil would reduce or prevent diuretic-induced hyponatraemia. Chloride deficit is generally mild and usually does not require treatment.

Thiazides may decrease urinary calcium excretion and cause an intermittent and slight elevation of serum calcium in the absence of known disorders of calcium metabolism. Hypercalcaemia may be evidence of hidden hyperparathyroidism. Thiazides should be discontinued before carrying out tests for parathyroid function.

Thiazides have been shown to increase the urinary excretion of magnesium, which may result in hypomagnesaemia.

Dilutional hyponatraemia may occur in oedematous patients in hot weather.

Lithium:

As with other medicinal products containing angiotensin II receptor antagonists and thiazide in combination, the coadministration of Olmesartan medoxomil/Hydrochlorothiazide and lithium is not recommended (see section 4.5).

Sprue-like enteropathy:

In very rare cases severe, chronic diarrhoea with substantial weight loss has been reported in patients taking olmesartan few months to years after drug initiation, possibly caused by a localized delayed hypersensitivity reaction. Intestinal biopsies of patients often demonstrated villous atrophy. If a patient develops these symptoms during treatment with olmesartan, and in the absence of other apparent etiologies, olmesartan treatment should be immediately discontinued and should not be restarted. If diarrhoea does not improve during the week after the discontinuation, further specialist (e.g. a gastro-enterologist) advice should be considered.

Acute Myopia and Secondary Angle-Closure Glaucoma:

Hydrochlorothiazide, a sulfonamide, can cause an idiosyncratic reaction, resulting in acute transient myopia and acute angle-closure glaucoma. Symptoms include acute onset of decreased visual acuity or ocular pain and typically occur within hours to weeks of drug initiation. Untreated acute angle-closure glaucoma can lead to permanent vision loss. The primary treatment is to discontinue hydrochlorothiazide as rapidly as possible. Prompt medical or surgical treatments may need to be considered if the intraocular pressure remains uncontrolled. Risk factors for developing acute angle-closure glaucoma may include a history of sulfonamide or penicillin allergy.

Non-melanoma skin cancer:

An increased risk of non-melanoma skin cancer (NMSC) [basal cell carcinoma (BCC) and squamous cell carcinoma (SCC)] with increasing cumulative dose of hydrochlorothiazide (HCTZ) exposure has been observed in two epidemiological studies based on the Danish National Cancer Registry. Photosensitizing actions of HCTZ could act as a possible mechanism for NMSC.

Patients taking HCTZ should be informed of the risk of NMSC and advised to regularly check their skin for any new lesions and promptly report any suspicious skin lesions. Possible preventive measures such as limited exposure to sunlight and UV rays and, in case of exposure, adequate protection should be advised to the patients in order to minimize the risk of skin cancer. Suspicious skin lesions should be promptly examined potentially including histological examinations of biopsies. The use of HCTZ may also need to be reconsidered in patients who have experienced previous NMSC (see also section 4.8).

Ethnic differences:

As with all other angiotensin II receptor 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.

Pregnancy:

Angiotensin II receptor antagonists should not be initiated during pregnancy. Unless continued angiotensin II receptor antagonists therapy is considered essential, patients planning pregnancy should be changed to alternative anti-hypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with angiotensin II receptor antagonists should be stopped immediately, and, if appropriate, alternative therapy should be started (see sections 4.3 and 4.6)

Other:

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 malabsorption should not take this medicinal product.

4.5 Interaction with other medicinal products and other forms of interaction

Potential interactions related to both olmesartan medoxomil and hydrochlorothiazide:

Concomitant use not recommended

Lithium:

Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with angiotensin converting enzyme inhibitors and, rarely, with angiotensin II receptor antagonists. In addition, renal clearance of lithium is reduced by thiazides and consequently the risk of lithium toxicity may be increased. Therefore use of Olmesartan medoxomil/Hydrochlorothiazide and lithium in combination is not recommended (see section 4.4). If use of the combination proves necessary, careful monitoring of serum lithium levels is recommended.

Concomitant use requiring caution

Baclofen:

Potentiation of antihypertensive effect may occur.

Non-steroidal anti-inflammatory medicinal products:

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

In some patients with compromised renal function (e.g. dehydrated patients or elderly people with compromised renal function) the co-administration of angiotensin II receptor antagonists and agents that inhibit cyclo-oxygenase may result in further deterioration of renal function, including possible acute renal failure, which is usually reversible. Therefore, the combination should be administered with caution, especially in elderly people. 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 Olmesartan medoxomil/Hydrochlorothiazide 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

ACE-inhibitors, angiotensin II receptor blockers or aliskiren:

Clinical trial data has shown that dual blockade of the renin-angiotensin-aldosterone-system (RAAS) through the combined use of ACE-inhibitors, angiotensin II receptor blockers or aliskiren is associated with a higher frequency of adverse events such as hypotension, hyperkalaemia and decreased renal function (including acute renal failure) compared to the use of a single RAAS-acting agent (see sections 4.3, 4.4 and 5.1).

Medicinal products affecting potassium levels:

Based on experience with the use of other medicinal products that affect the renin-angiotensin system, concomitant use of potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium or other medicinal products that may increase serum potassium levels (e.g. heparin, ACE inhibitors) may lead to increases in serum potassium (see section 4.4). If medicinal products which affect potassium levels are to be prescribed in combination with Olmesartan medoxomil/Hydrochlorothiazide, monitoring of potassium plasma levels is advised.

Bile acid sequestering agent colesevelam:

Concurrent administration of the bile acid sequestering agent colesevelam hydrochloride reduces the systemic exposure and peak plasma concentration of olmesartan and reduces t1/2. Administration of olmesartan medoxomil at least 4 hours prior to colesevelam hydrochloride decreased the drug interaction effect. Administering olmesartan medoxomil at least 4 hours before the colesevelam hydrochloride dose should be considered (see section 5.2).

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 (see section 4.4) may be potentiated by the coadministration of other medicinal products associated with potassium loss and hypokalaemia (e.g. 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 Olmesartan medoxomil/Hydrochlorothiazide is administered with medicinal products affected by serum potassium disturbances (e.g. digitalis glycosides and antiarrhythmics) and with the following torsades de pointes (ventricular tachycardia)-inducing medicinal products (including some antiarrhythmics), hypokalaemia being a predisposing factor to torsades de pointes (ventricular tachycardia):

– Class Ia antiarrythmics (e.g. quinidine, hydroquinidine, disopyramide).

– Class III antiarrythmics (e.g. amiodarone, sotalol, dofetilide, ibutilide).

– Some antipsychotics (e.g. thioridazine, chlorpromazine, levomepromazine, trifluoperazine, cyamemazine, sulpiride, sultopride, amisulpride, tiapride, pimozide, haloperidol, droperidol).

– Others (e.g. bepridil, cisapride, diphemanil, erythromycin IV, halofantrin, mizolastin, pentamidine, sparfloxacin, terfenadine, vincamine IV).

Non-depolarizing skeletal muscle relaxants (e.g. tubocurarine):

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

Anticholinergic agents (e.g. atropine, biperiden):

Increase of the bioavailability of thiazide-type diuretics by decreasing gastrointestinal motility and stomach emptying rate.

Antidiabetic medicinal products (oral agents and insulin):

The treatment with a thiazide may influence the glucose tolerance. Dosage adjustment of the antidiabetic medicinal product may be required (see section 4.4).

Metformin:

Metformin should be used with caution because of the risk of lactic acidosis induced by possible functional renal failure linked to hydrochlorothiazide.

Beta-blockers and diazoxide:

The hyperglycaemic effect of beta-blockers and diazoxide may be enhanced by thiazides.

Pressor amines (e.g. noradrenaline):

The effect of pressor amines may be decreased.

Medicinal products used in the treatment of gout (e.g. 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 (e.g. cyclophosphamide, methotrexate):

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

Salicylates:

In case of high dosages of salicylates hydrochlorothiazide may enhance the toxic effect of the salicylates on the central nervous system.

Methyldopa:

There have been isolated reports of haemolytic anaemia occurring with concomitant use of hydrochlorothiazide and methyldopa.

Cyclosporine:

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.

4.6 Fertility, pregnancy and lactation

Pregnancy (see section 4.3)

Given the effects of the individual components in this combination product on pregnancy, the use of Olmesartan medoxomil/Hydrochlorothiazide is not recommended during the first trimester of pregnancy (see section 4.4). The use of Olmesartan medoxomil/Hydrochlorothiazide is contra-indicated during the 2nd and 3rd trimester of pregnancy (see sections 4.3 and 4.4).

Olmesartan medoxomil:

The use of angiotensin II receptor antagonists is not recommended during the first trimester of pregnancy (see section 4.4). The use of angiotensin II receptor antagonists is contra-indicated during the 2nd and 3rd trimester of pregnancy (see sections 4.3 and 4.4).

Epidemiological evidence regarding the risk of teratogenicity following exposure to ACE inhibitors during the first trimester of pregnancy has not been conclusive; however a small increase in risk cannot be excluded. Whilst there is no controlled epidemiological data on the risk with angiotensin II receptor antagonists, similar risks may exist for this class of drugs. Unless continued angiotensin receptor blocker therapy is considered essential, patients planning pregnancy should be changed to alternative anti-hypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with angiotensin II receptor antagonists should be stopped immediately, and, if appropriate, alternative therapy should be started.

Exposure to angiotensin II receptor antagonists therapy during the 2nd and 3rd trimesters is known to induce human fetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia). (See also 5.3 “Preclinical safety data”.)

Should exposure to angiotensin II receptor antagonists have occurred from the 2nd trimester of pregnancy, ultrasound check of renal function and skull is recommended.

Infants whose mothers have taken angiotensin II receptor antagonists should be closely observed for hypotension (see also sections 4.3 and 4.4).

Hydrochlorothiazide:

There is limited experience with hydrochlorothiazide during pregnancy, especially during the first trimester. Animal studies are insufficient.

Hydrochlorothiazide crosses the placenta. Based on the pharmacological mechanism of action of hydrochlorothiazide its use during the 2nd and 3rd trimester may compromise foeto-placental perfusion and may cause foetal and neonatal effects like icterus, disturbance of electrolyte balance and thrombocytopenia.

Hydrochlorothiazide should not be used for gestational oedema, gestational hypertension or preeclampsia due to the risk of decreased plasma volume and placental hypoperfusion, without a beneficial effect on the course of the disease.

Hydrochlorothiazide should not be used for essential hypertension in pregnant women except in rare situations where no other treatment could be used.

Breast-feeding

Olmesartan medoxomil:

Because no information is available regarding the use of Olmesartan medoxomil/Hydrochlorothiazide during breast-feeding, Olmesartan medoxomil/Hydrochlorothiazide is not recommended and alternative treatments with better established safety profiles during breast-feeding are preferable, especially while nursing a newborn or preterm infant.

Hydrochlorothiazide:

Hydrochlorothiazide is excreted in human milk in small amounts. Thiazides in high doses causing intense diuresis can inhibit the milk production.

The use of Olmesartan medoxomil/Hydrochlorothiazide during breast-feeding is not recommended. If Olmesartan medoxomil/Hydrochlorothiazide is used during breast-feeding, doses should be kept as low as possible.

4.7 Effects on ability to drive and use machines

Olmesartan medoxomil/Hydrochlorothiazide has minor or moderate influence on the ability to drive and use machines. Dizziness or fatigue may occasionally occur in patients taking antihypertensive therapy, which may impair the ability to react.

4.8 Undesirable effects

The most commonly reported adverse reactions during treatment with Olmesartan medoxomil/Hydrochlorothiazide are headache (2.9%), dizziness (1.9%) and fatigue (1.0%).

Hydrochlorothiazide may cause or exacerbate volume depletion which may lead to electrolyte imbalance (see section 4.4).

In clinical trials involving 1155 patients treated with olmesartan medoxomil/ hydrochlorothiazide combinations at dosages of 20/12.5mg or 20/25mg and 466 patients treated with placebo for periods of up to 21 months, the overall frequency of adverse reactions on olmesartan medoxomil/hydrochlorothiazide combination therapy was similar to that on placebo. Discontinuations due to adverse reactions were also similar for olmesartan medoxomil/hydrochlorothiazide 20/12.5mg – 20/25mg (2%) and placebo (3%). The frequency of adverse reactions 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.

In addition, the safety of Olmesartan medoxomil/Hydrochlorothiazide as a high dose combination was investigated in clinical trials in 3709 patients receiving olmesartan medoxomil in combination with hydrochlorothiazide in the dose strengths 40mg/12.5mg and 40mg/25mg.

Adverse reactions from Olmesartan medoxomil/Hydrochlorothiazide in clinical trials, post-authorisation safety studies and spontaneous reporting are summarised in the below table as well as adverse reactions from the individual components olmesartan medoxomil and hydrochlorothiazide based on the known safety profile of these substances.

The following terminologies have been used in order to classify the occurrence of adverse reactions: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000), not known (cannot be estimated from the available data).

Single cases of rhabdomyolysis have been reported in temporal association with the intake of angiotensin II receptor blockers.

Non-melanoma skin cancer: Based on available data from epidemiological studies, cumulative dose-dependent association between HCTZ and NMSC has been observed (see also sections 4.4 and 5.1).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.

4.9 Overdose

No specific information is available on the effects or treatment of Olmesartan medoxomil/Hydrochlorothiazide overdose. 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 overdose. 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 medoxomil overdose are expected to be hypotension and tachycardia; bradycardia might also occur. Overdose with hydrochlorothiazide is associated with electrolyte depletion (hypokalaemia, hypochloraemia) and dehydration resulting from excessive diuresis. The most common signs and symptoms of overdose 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 medicinal products.

No information is available regarding the dialysability of olmesartan or hydrochlorothiazide.

5. Pharmacological properties

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Angiotensin II antagonists and diuretics.

Mechanism of action / Pharmacodynamic effects

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 hour dose interval.

Olmesartan medoxomil is an 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 hour dose interval. Once daily dosing produced similar decreases in blood pressure as twice daily dosing at the same total daily dose.

With continuous treatment, maximum reductions in blood pressure are achieved by 8 weeks after the initiation of therapy, although a substantial proportion of the blood pressure lowering effect is already observed after 2 weeks of treatment.

The effect of olmesartan medoxomil on mortality and morbidity is not yet known.

The Randomised Olmesartan and Diabetes Microalbuminuria Prevention (ROADMAP) study in 4447 patients with type 2 diabetes, normo-albuminuria and at least one additional cardiovascular risk factor, investigated whether treatment with olmesartan could delay the onset of microalbuminuria. During the median follow-up duration of 3.2 years, patients received either olmesartan or placebo in addition to other antihypertensive agents, except ACE inhibitors or ARBs.

For the primary endpoint, the study demonstrated a significant risk reduction in the time to onset of microalbuminuria, in favour of olmesartan. After adjustment for BP differences this risk reduction was no longer statistically significant. 8.2% (178 of 2160) of the patients in the olmesartan group and 9.8% (210 of 2139) in the placebo group developed microalbuminuria.

For the secondary endpoints, cardiovascular events occurred in 96 patients (4.3%) with olmesartan and in 94 patients (4.2%) with placebo. The incidence of cardiovascular mortality was higher with olmesartan compared to placebo treatment (15 patients (0.7%) vs. 3 patients (0.1%)), despite similar rates for non-fatal stroke (14 patients (0.6%) vs. 8 patients (0.4%)), non-fatal myocardial infarction (17 patients (0.8%) vs. 26 patients (1.2%)) and non-cardiovascular mortality (11 patients (0.5%) vs. 12 patients (0.5%)). Overall mortality with olmesartan was numerically increased (26 patients (1.2%) vs. 15 patients (0.7%)), which was mainly driven by a higher number of fatal cardiovascular events.

The Olmesartan Reducing Incidence of End-stage Renal Disease in Diabetic Nephropathy Trial (ORIENT) investigated the effects of olmesartan on renal and cardiovascular outcomes in 577 randomized Japanese and Chinese type 2 diabetic patients with overt nephropathy. During a median follow-up of 3.1 years, patients received either olmesartan or placebo in addition to other antihypertensive agents including ACE inhibitors.

The primary composite endpoint (time to first event of the doubling of serum creatinine, end-stage renal disease, all-cause death) occurred in 116 patients in the olmesartan group (41.1%) and 129 patients in the placebo group (45.4%) (HR 0.97 (95% CI 0.75 to 1.24); p=0.791). The composite secondary cardiovascular endpoint occurred in 40 olmesartan-treated patients (14.2%) and 53 placebo-treated patients (18.7%). This composite cardiovascular endpoint included cardiovascular death in 10 (3.5%) patients receiving olmesartan versus 3 (1.1%) receiving placebo, overall mortality 19 (6.7%) versus 20 (7.0%), non-fatal stroke 8 (2.8%) versus 11 (3.9%) and non-fatal myocardial infarction 3 (1.1%) versus 7 (2.5%), respectively.

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 coadministration 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 hours and peak effect occurs at about 4 hours post-dose, whilst the action persists for approximately 6-12 hours.

Epidemiological studies have shown that long-term treatment with hydrochlorothiazide monotherapy reduces the risk of cardiovascular mortality and morbidity.

Clinical efficacy and safety

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 /12.5mg and 20 /25mg combinations of olmesartan medoxomil/hydrochlorothiazide resulted in mean placebo-subtracted systolic/diastolic blood pressure reductions at trough of 12/7 mmHg and 16/9 mmHg, respectively. Age and gender had no clinically relevant effect on response to treatment with olmesartan medoxomil/hydrochlorothiazide combination therapy.

Administration of 12.5mg and 25mg hydrochlorothiazide in patients insufficiently controlled by olmesartan medoxomil 20mg monotherapy gave additional reductions in 24-hour systolic/diastolic 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 effectiveness of olmesartan medoxomil/hydrochlorothiazide combination therapy was maintained over long-term (one-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.

Other information:

Two large randomised, controlled trials (ONTARGET (ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial) and VA NEPHRON-D (The Veterans Affairs Nephropathy in Diabetes)) have examined the use of the combination of an ACE-inhibitor with an angiotensin II receptor blocker.

ONTARGET was a study conducted in patients with a history of cardiovascular or cerebrovascular disease, or type 2 diabetes mellitus accompanied by evidence of end-organ damage. VA NEPHRON-D was a study in patients with type 2 diabetes mellitus and diabetic nephropathy.

These studies have shown no significant beneficial effect on renal and/or cardiovascular outcomes and mortality, while an increased risk of hyperkalaemia, acute kidney injury and/or hypotension as compared to monotherapy was observed. Given their similar pharmacodynamic properties, these results are also relevant for other ACE-inhibitors and angiotensin II receptor blockers.

ACE-inhibitors and angiotensin II receptor blockers should therefore not be used concomitantly in patients with diabetic nephropathy.

ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints) was a study designed to test the benefit of adding aliskiren to a standard therapy of an ACE-inhibitor or an angiotensin II receptor blocker in patients with type 2 diabetes mellitus and chronic kidney disease, cardiovascular disease, or both. The study was terminated early because of an increased risk of adverse outcomes. Cardiovascular death and stroke were both numerically more frequent in the aliskiren group than in the placebo group and adverse events and serious adverse events of interest (hyperkalaemia, hypotension and renal dysfunction) were more frequently reported in the aliskiren group than in the placebo group.

Non-melanoma skin cancer:

Based on available data from epidemiological studies, cumulative dose-dependent association between HCTZ and NMSC has been observed. One study included a population comprised of 71,533 cases of BCC and of 8,629 cases of SCC matched to 1,430,833 and 172,462 population controls, respectively. High HCTZ use (≥50,000mg cumulative) was associated with an adjusted OR of 1.29 (95% CI: 1.23-1.35) for BCC and 3.98 (95% CI: 3.68-4.31) for SCC. A clear cumulative dose response relationship was observed for both BCC and SCC. Another study showed a possible association between lip cancer (SCC) and exposure to HCTZ: 633 cases of lip-cancer were matched with 63,067 population controls, using a risk-set sampling strategy. A cumulative dose-response relationship was demonstrated with an adjusted OR 2.1 (95% CI: 1.7-2.6) increasing to OR 3.9 (3.0-4.9) for high use (~25,000mg) and OR 7.7 (5.7-10.5) for the highest cumulative dose (~100,000mg) (see also section 4.4).

5.2 Pharmacokinetic properties

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 (C_max) of olmesartan is reached within about 2 hours after oral dosing with olmesartan medoxomil, and olmesartan plasma concentrations increase approximately linearly with increasing single oral doses up to about 80mg.

Food had minimal effect on the bioavailability of olmesartan and therefore olmesartan medoxomil may be administered with or without food.

No clinically relevant gender-related differences in the pharmacokinetics of olmesartan have been observed.

Olmesartan is highly bound to plasma protein (99.7%), but the potential for clinically significant protein binding displacement interactions between olmesartan and other highly bound coadministered active substances is low (as confirmed by the lack of a clinically significant interaction between olmesartan medoxomil and warfarin). The binding of olmesartan to blood cells is negligible. The mean volume of distribution after intravenous dosing is low (16 – 29 L).

Hydrochlorothiazide:

Following oral administration of olmesartan medoxomil and hydrochlorothiazide in combination, the median time to peak concentrations of hydrochlorothiazide was 1.5 to 2 hours after dosing. Hydrochlorothiazide is 68 % protein bound in the plasma and its apparent volume of distribution is 0.83 – 1.14 L/kg.

Biotransformation and elimination

Olmesartan medoxomil:

Total plasma clearance of olmesartan was typically 1.3 L/h (CV, 19%) and was relatively slow compared to hepatic blood flow (ca 90 L/h). 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 hours of dose administration) and the remainder of the recovered radioactivity was excreted in the faeces. Based on the systemic availability of 25.6%, it can be calculated that absorbed olmesartan is cleared by both renal excretion (ca 40%) and hepato-biliary 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 section 4.3).

The terminal elimination half life of olmesartan varied between 10 and 15 hours after multiple oral dosing. Steady state was reached after the first few doses and no further accumulation was evident after 14 days of repeated dosing. Renal clearance was approximately 0.5 – 0.7 L/h and was independent of dose.

Hydrochlorothiazide:

Hydrochlorothiazide is not metabolised in man and is excreted almost entirely as unchanged active substance in urine. About 60% of the oral dose is eliminated as unchanged active substance within 48 hours. Renal clearance is about 250 – 300 mL/min. The terminal elimination half-life of hydrochlorothiazide is 10 – 15 hours.

Olmesartan medoxomil/Hydrochlorothiazide

The systemic availability of hydrochlorothiazide is reduced by about 20% when co-administered with olmesartan medoxomil, but this modest decrease is not of any clinical relevance. The kinetics of olmesartan are unaffected by the co-administration of hydrochlorothiazide.

Pharmacokinetics in special populations

Elderly (age 65 years or over):

In hypertensive patients, the olmesartan AUC at steady state was increased by ca 35% in elderly people (65 – 75 years old) and by ca 44% in very elderly people (≥ 75 years old) compared with the younger age group (see section 4.2).

Limited data suggest that the systemic clearance of hydrochlorothiazide is reduced in both healthy and hypertensive elderly people compared to young healthy volunteers.

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 sections 4.2, 4.4).

The half-life of hydrochlorothiazide is prolonged in patients with impaired renal function.

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 hours 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. Following repeated dosing in patients with moderate hepatic impairment, olmesartan mean AUC was again about 65% higher than in matched healthy controls. Olmesartan mean C_max values were similar in hepatically-impaired and healthy subjects. Olmesartan medoxomil has not been evaluated in patients with severe hepatic impairment (see sections 4.2, 4.4).

Hepatic impairment does not significantly influence the pharmacokinetics of hydrochlorothiazide.

Drug interactions

Bile acid sequestering agent colesevelam:

Concomitant administration of 40mg olmesartan medoxomil and 3750mg colesevelam hydrochloride in healthy subjects resulted in 28% reduction in C_max and 39% reduction in AUC of olmesartan. Lesser effects, 4% and 15% reduction in C_max and AUC respectively, were observed when olmesartan medoxomil was administered 4 hours prior to colesevelam hydrochloride. Elimination half life of olmesartan was reduced by 50 – 52% irrespectively of whether administered concomitantly or 4 hours prior to colesevelam hydrochloride (see section 4.5).

5.3 Preclinical safety data

The toxic potential of olmesartan medoxomil/hydrochlorothiazide combinations was evaluated in repeated dose oral toxicity studies for up to six months in rats and dogs.

As for each of the individual substances and other medicinal products in this class, the main toxicological target organ of the combination was the kidney. The combination of olmesartan medoxomil/hydrochlorothiazide induced functional renal changes (increases in serum urea nitrogen and in serum creatinine). High dosages caused tubular degeneration and regeneration in the kidneys of rats and dogs, probably via a change in renal haemodynamics (reduced renal perfusion resulting from hypotension with tubular hypoxia and tubular cell degeneration). In addition, the olmesartan medoxomil/ hydrochlorothiazide combination caused a decrease in red blood cell parameters (erythrocytes, haemoglobin and haematocrit) and a reduction in heart weight in rats.

These effects have also been observed for other AT₁ receptor antagonists and for ACE inhibitors and they seem to have been induced by the pharmacological action of high dosages of olmesartan medoxomil and seem to be not relevant to humans at the recommended therapeutic doses.

Genotoxicity studies using combined olmesartan medoxomil and hydrochlorothiazide as well as the individual components have not shown any signs of a clinically relevant genotoxic activity.

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 two 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 medicinal product, fetal toxicity was observed in rats, as evidenced by significantly reduced fetal body weights, when treated with olmesartan medoxomil/hydrochlorothiazide combinations during gestation (see sections 4.3, 4.6).

6. Pharmaceutical particulars

6.1 List of excipients

Tablet core

Microcrystalline cellulose, Lactose monohydrate, Low substituted Hyprolose, Hyprolose, Magnesium stearate

Tablet coat

Talc, Hypromellose, Titanium dioxide, Iron (III) oxide yellow, Iron (III) oxide red

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

5 years.

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

Laminated polyamide / aluminium / polyvinyl chloride / aluminium blister.

Packs of 14, 28, 30, 56, 84, 90, 98 and 10 x 28 film-coated tablets.

Packs with perforated unit dose blisters of 10, 50 and 500 film-coated tablets.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

No special requirements.

7. Manufactured By:
   Taj Pharmaceuticals Ltd.
   at: Plot. No. 220, Mahagujarat
   Industrial Estate, At & Post-Moraiya,
   Tal-Sanand, Dist- Ahmedabad Gujarat (India)

Olmesartan medoxomil/ Hydrochlorothiazide 20mg /12.5mg, 20mg /25mg, 40mg /12.5mg and 40mg/25mg Tablets USP

Package Leaflet: Information for the user

Olmesartan medoxomil/hydrochlorothiazide   20mg /12.5mg tablets Taj Pharma
Olmesartan medoxomil/hydrochlorothiazide   20mg /25mg tablets Taj Pharma
Olmesartan medoxomil/hydrochlorothiazide   40mg /12.5mg tablets Taj Pharma
Olmesartan medoxomil/hydrochlorothiazide   40mg/25mg tablets Taj Pharma

olmesartan medoxomil/hydrochlorothiazide

Read all of this leaflet carefully before you start taking this medicine because it contains important information for you.

• Keep this leaflet. You may need to read it again.
• If you have any further questions, ask your doctor or pharmacist.
• This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours.
• If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. See section 4.

What is in this leaflet

1. What Olmesartan medoxomil/hydrochlorothiazide is and what it is used for
   2. What you need to know before you take Olmesartan medoxomil/hydrochlorothiazide
   3. How to take Olmesartan medoxomil/hydrochlorothiazide
   4. Possible side effects
   5. How to store Olmesartan medoxomil/hydrochlorothiazide
   6. Contents of the pack and other information
2. What Olmesartan medoxomil/hydrochlorothiazide is and what it is used for

Olmesartan medoxomil/hydrochlorothiazide   contains two active substances, olmesartan medoxomil and hydrochlorothiazide, that are used to treat high blood pressure (hypertension):

• Olmesartan medoxomil is one of a group of medicines called angiotensin II-receptor antagonists. It lowers blood pressure by relaxing the blood vessels.
• Hydrochlorothiazide is one of a group of medicines called thiazide diuretics (“water tablets”). It lowers blood pressure by helping the body to get rid of extra fluid by making your kidneys produce more urine.

You will only be given Olmesartan medoxomil/hydrochlorothiazide   if Olmesartan medoxomil/hydrochlorothiazide (olmesartan medoxomil) alone has not adequately controlled your blood pressure. When given together, the two active substances in Olmesartan medoxomil/hydrochlorothiazide   help to lower blood pressure more than if either of them were given alone.

You may already be taking medicines to treat your high blood pressure, but your doctor may want you to take Olmesartan medoxomil/hydrochlorothiazide   to lower it more.

High blood pressure can be controlled with medicines such as Olmesartan medoxomil/hydrochlorothiazide   tablets. Your doctor has probably also recommended that you make some changes in your lifestyle to help lower your blood pressure (for example losing weight, giving up smoking, reducing the amount of alcohol you drink and reducing the amount of salt in your diet). Your doctor may also have urged you to take regular exercise, such as walking or swimming. It is important to follow this advice from your doctor.

2. What you need to know before you take Olmesartan medoxomil/hydrochlorothiazide

Do not take Olmesartan medoxomil/hydrochlorothiazide  :

• if you are allergic to olmesartan medoxomil or hydrochlorothiazide, or any of the other ingredients of this medicine (listed in section 6) or substances similar to hydrochlorothiazide (sulfonamides)
• if you are more than 3 months pregnant (It is also better to avoid Olmesartan medoxomil/hydrochlorothiazide  in early pregnancy – see pregnancy section)
• if you have kidney problems
• if you have diabetes or impaired kidney function and you are treated with a blood pressure lowering medicine containing aliskiren
• if you suffer from low potassium, low sodium, high calcium or high uric acid levels in the blood (with symptoms of gout or kidney stones) that do not get better when treated
• if you suffer from moderate or severe liver problems or yellowing of the skin and eyes (jaundice) or problems with drainage of the bile from the gallbladder (biliary obstruction e.g. gallstones)

If you think any of these apply to you, or you are unsure, do not take the tablets. Talk to your doctor first and follow the advice given.

Warnings and precautions

Talk to your doctor before using Olmesartan medoxomil/hydrochlorothiazide  .

Before you take the tablets, tell your doctor if you are taking any of the following medicines used to treat high blood pressure:

• an ACE-inhibitor (for example enalapril, lisinopril, ramipril), in particular if you have diabetes-related kidney problems.
• aliskiren

Your doctor may check your kidney function, blood pressure, and the amount of electrolytes (e.g. potassium) in your blood at regular intervals.

See also information under the heading “Do not take Olmesartan medoxomil/hydrochlorothiazide  ”.

Before you take the tablets, tell your doctor if you have any of the following health problems:

• Kidney transplant
• Liver diseases
• Heart failure or problems with your heart valves or heart muscles
• Vomiting (being sick) or diarrhoea which is severe or it goes on for several days
• Treatment with high doses of water tablets (diuretics) or if you are on a low salt diet
• Problems with your adrenal glands (e.g. primary aldosteronism)
• Diabetes
• Lupus erythematosus (an autoimmune disease)
• Allergies or asthma
• If you have had skin cancer or if you develop an unexpected skin lesion during the treatment. Treatment with hydrochlorothiazide, particularly long term use with high doses, may increase the risk of some types of skin and lip cancer (non-melanoma skin cancer). Protect your skin from sun exposure and UV rays while taking Olmesartan medoxomil/hydrochlorothiazide .

Contact your doctor if you experience any of the following symptoms:

• diarrhoea that is severe, persistent and causes substantial weight loss. Your doctor may evaluate your symptoms and decide on how to continue your blood pressure medication.
• decrease in vision or eye pain. These could be symptoms of an increase of pressure in your eye and can happen within hours to weeks of taking Olmesartan medoxomil/hydrochlorothiazide . This can lead to permanent vision impairment, if not treated.

Your doctor may want to see you more often and do some tests if you have any of these conditions.

Olmesartan medoxomil/hydrochlorothiazide   may cause a rise in blood fat levels and uric acid levels (the cause of gout – painful swelling of the joints). Your doctor will probably want to do a blood test from time to time to check these.

It may change the levels of certain chemicals in your blood called electrolytes. Your doctor will probably want to do a blood test from time to time to check these. Signs of electrolyte changes are: thirst, dryness of the mouth, muscle pain or cramps, tired muscles, low blood pressure (hypotension), feeling weak, sluggish, tired, sleepy or restless, nausea, vomiting, less need to pass urine, a rapid heart rate. Tell your doctor if you notice these symptoms.

As with any medicine which reduces blood pressure, an excessive drop in blood pressure in patients with blood flow disturbances of the heart or brain could lead to a heart attack or stroke. Your doctor will therefore check your blood pressure carefully.

If you are due to have tests for parathyroid function, you should stop taking Olmesartan medoxomil/hydrochlorothiazide   before these tests are carried out.

If you are a sports person, this medicine could change the results of an anti-dope test to make it positive.

You must tell your doctor if you think that you are (or might become) pregnant. Olmesartan medoxomil/hydrochlorothiazide   is not recommended in early pregnancy, and must not be taken if you are more than 3 months pregnant, as it may cause serious harm to your baby if used at that stage (see pregnancy section).

Children and adolescents

Olmesartan medoxomil/hydrochlorothiazide   is not recommended for children and adolescents under the age of 18.

Other medicines and Olmesartan medoxomil/hydrochlorothiazide  

Tell your doctor or pharmacist if you are using, have recently used or might use any other medicines.

In particular, tell your doctor or pharmacist about any of the following:

• Other blood pressure lowering medicines (anti-hypertensives), as the effect of Olmesartan medoxomil/hydrochlorothiazide  can be increased.
  Your doctor may need to change your dose and/or to take other precautions:
  If you are taking an ACE-inhibitor or aliskiren (see also information under the headings “Do not take Olmesartan medoxomil/hydrochlorothiazide  ” and “Warnings and precautions”).
• Medicines which may alter the levels of potassium in your blood if used at the same time as Olmesartan medoxomil/hydrochlorothiazide . These include:
  • potassium supplements (as well as salt substitutes containing potassium)
  • water tablets (diuretics)
  • heparin (for thinning the blood)
  • laxatives
  • steroids
  • adrenocorticotrophic hormone (ACTH)
  • carbenoxolone (a medicine used to treat mouth and stomach ulcers)
  • penicillin G sodium (also called benzylpenicillin sodium, an antibiotic)
  • certain pain killers such as aspirin or salicylates
• Lithium (a medicine used to treat mood swings and some types of depression) used at the same time as Olmesartan medoxomil/hydrochlorothiazide  may increase the toxicity of lithium. If you have to take lithium, your doctor will measure your lithium blood levels.
• Non-steroidal anti-inflammatory (NSAIDs) medicines (medicines used to relieve pain, swelling and other symptoms of inflammation, including arthritis) used at the same time as Olmesartan medoxomil/hydrochlorothiazide  may increase the risk of kidney failure and the effect of Olmesartan medoxomil/hydrochlorothiazide   can be decreased by NSAIDs.
• Sleeping tablets, sedatives and anti-depressant medicines, as using these medicines together with Olmesartan medoxomil/hydrochlorothiazide  may cause a sudden drop in blood pressure when standing up.
• Certain medicines such as baclofen and tubocurarine, used to relax muscles.
• Amifostine and some other drugs used to treat cancers, such as cyclophosphamide or methotrexate.
• Colestyramine and colestipol, medicines for lowering blood fat levels.
• Colesevelam hydrochloride, a drug that lowers the level of cholesterol in your blood, as the effect of Olmesartan medoxomil/hydrochlorothiazide  may be decreased. Your doctor may advise you to take Olmesartan medoxomil/hydrochlorothiazide   at least 4 hours before colesevelam hydrochloride.
• Anticholinergic agents, such as atropine and biperiden.
• Drugs such as thioridazine, chlorpromazine, levomepromazine, trifluoperazine, cyamemazine, sulpiride, amisulpride, pimozide, sultopride, tiapride, droperidol or haloperidol, used to treat certain psychiatric disorders.
• Certain medicines such as quinidine, hydroquinidine, disopyramide, amiodarone, sotalol or digitalis, used to treat heart problems.
• Medicines such as mizolastine, pentamidine, terfenadine, dofetilide, ibutilide or erythromycin injections, which may change the heart rhythm.
• Oral anti-diabetic medicines, such as metformin, or insulin, used to lower blood sugar.
• Beta-blockers and diazoxide, medicines used to treat high blood pressure or low blood sugar, respectively, as Olmesartan medoxomil/hydrochlorothiazide  can enhance their blood-sugar-increasing effect.
• Methyldopa, a medicine used to treat high blood pressure.
• Medicines such as noradrenaline, used to increase blood pressure and slow heart rate.
• Diphemanil, used to treat a slow heartbeat or reduce sweating.
• Medicines such as probenecid, sulfinpyrazone and allopurinol, used to treat gout.
• Calcium supplements.
• Amantadine, an anti-viral drug.
• Ciclosporin, a medicine used to stop rejection of organ transplants.
• Certain antibiotics called tetracyclines or sparfloxacin.
• Amphotericin, a medicine used to treat fungal infections.
• Certain antacids, used to treat too much stomach acid, such as aluminium magnesium hydroxide, as the effect of Olmesartan medoxomil/hydrochlorothiazide  can be slightly decreased.
• Cisapride, used to increase food movement in the stomach and gut.
• Halofantrine, used for malaria.

Olmesartan medoxomil/hydrochlorothiazide   with food and drink

Olmesartan medoxomil/hydrochlorothiazide   can be taken with or without food.

Take care when drinking alcohol while you are taking Olmesartan medoxomil/hydrochlorothiazide  , as some people feel faint or dizzy. If this happens to you, do not drink any alcohol, including wine, beer or alcopops.

Black patients

As with other similar drugs the blood pressure lowering effect of Olmesartan medoxomil/hydrochlorothiazide   is somewhat less in black patients.

Pregnancy and breast-feeding

Pregnancy

You must tell your doctor if you think you are (or might become) pregnant. Your doctor will normally advise you to stop taking Olmesartan medoxomil/hydrochlorothiazide   before you become pregnant or as soon as you know you are pregnant and will advise you to take another medicine instead of Olmesartan medoxomil/hydrochlorothiazide  . Olmesartan medoxomil/hydrochlorothiazide   is not recommended during pregnancy, and must not be taken when more than 3 months pregnant, as it may cause serious harm to your baby if it is used after the third month of pregnancy.

Breast-feeding

Tell your doctor if you are breast-feeding or about to start breast-feeding. Olmesartan medoxomil/hydrochlorothiazide   is not recommended for mothers who are breast-feeding, and your doctor may choose another treatment for you if you wish to breast-feed.

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine.

Driving and using machines

You may feel sleepy or dizzy while being treated for your high blood pressure. If this happens, do not drive or use machines until the symptoms wear off. Ask your doctor for advice.

Olmesartan medoxomil/hydrochlorothiazide   contains lactose

This medicine contains lactose (a type of sugar). If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicine.

3. How to take Olmesartan medoxomil/hydrochlorothiazide

Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist if you are not sure.

The recommended dose is one Olmesartan medoxomil/hydrochlorothiazide   40 mg/12.5 mg tablet a day. However, if your blood pressure is not controlled, your doctor may decide to change your dose to one Olmesartan medoxomil/hydrochlorothiazide   40 mg/25 mg tablet a day.

Swallow the tablet with water. If possible, you should take your dose at the same time each day, for example at breakfast time. It is important to continue to take Olmesartan medoxomil/hydrochlorothiazide   until your doctor tells you to stop.

If you take more Olmesartan medoxomil/hydrochlorothiazide   than you should

If you take more tablets than you should, or if a child accidentally swallows one or more, go to your doctor or nearest accident and emergency (A&E) department immediately and take your medicine pack with you.

If you forget to take Olmesartan medoxomil/hydrochlorothiazide  

If you forget to take a dose, take your normal dose on the following day as usual. Do not take a double dose to make up for a forgotten dose.

If you stop taking Olmesartan medoxomil/hydrochlorothiazide  

It is important to continue to take Olmesartan medoxomil/hydrochlorothiazide   unless your doctor tells you to stop.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

However, the following two side effects can be serious:

• Allergic reactions that may affect the whole body, with swelling of the face, mouth and/or voice box (larynx) together with itching and rash may occur rarely. If this happens, stop taking Olmesartan medoxomil/hydrochlorothiazide  and contact your doctor immediately.
• Olmesartan medoxomil/hydrochlorothiazide  can cause the blood pressure to fall too low in susceptible individuals or as the result of an allergic reaction. Light-headedness or fainting may occur uncommonly. If this happens, stop taking Olmesartan medoxomil/hydrochlorothiazide  , contact your doctor immediately and lie down flat.

Olmesartan medoxomil/hydrochlorothiazide   is a combination of two active substances and the following information firstly gives the other side effects reported so far with the combination Olmesartan medoxomil/hydrochlorothiazide   (besides those already mentioned above) and, secondly, those which are known about for the separate active substances.

These are the other side effects known about so far with Olmesartan medoxomil/hydrochlorothiazide  :

If these side effects occur, they are often mild and you do not need to stop your treatment.

Common side effects (may affect up to 1 in 10 people):

Dizziness, weakness, headache, tiredness, chest pain, swelling of ankles, feet, legs, hands or arms.

Uncommon side effects (may affect up to 1 in 100 people):

Fluttering of the heartbeat (palpitations), rash, eczema, vertigo, cough, indigestion, abdominal pain, nausea, vomiting, diarrhoea, muscle cramps and muscular pain, pain in joints, arms and legs, back pain, erection difficulties in men, blood in urine.

Some changes in blood test results have also been seen uncommonly and include:

Rise in blood fat levels, rise in blood urea or uric acid, rise in creatinine, rise or decrease in blood potassium levels, rise in blood calcium levels, rise in blood sugar, increase in levels of liver function. Your doctor will know about these from a blood test and will tell you if you need to do anything.

Rare side effects (may affect up to 1 in 1,000 people):

Feeling unwell, disturbances in consciousness, skin lumps (wheals), acute kidney failure.

Some changes in blood test results have also been seen in rare cases and include:

Rise in blood urea nitrogen, decrease in haemoglobin and haematocrit values. Your doctor will know about these from a blood test and will tell you if you need to do anything.

Further side effects reported with use of olmesartan medoxomil or hydrochlorothiazide alone, but not with Olmesartan medoxomil/hydrochlorothiazide   or in a higher frequency:

Olmesartan medoxomil:

Common side effects (may affect up to 1 in 10 people):

Bronchitis, cough, runny or stuffy nose, sore throat, abdominal pain, indigestion, diarrhoea, nausea, gastroenteritis, pain in the joints or bones, back pain, blood in urine, urinary tract infection, flu-like symptoms, pain.

Some changes in blood test results have also been seen commonly and include:

Rise in blood fat levels, rise in blood urea or uric acid, increase in levels of liver and muscle function.

Uncommon side effects (may affect up to 1 in 100 people):

Quick allergic reactions that may affect the whole body and may cause breathing problems as well as a rapid fall of blood pressure that may even lead to fainting (anaphylactic reactions), swelling of the face, angina (pain or uncomfortable feeling in the chest; known as angina pectoris), feeling unwell, allergic skin rash, itching, exanthema (skin eruption), skin lumps (wheals).

Some changes in blood test results have also been seen uncommonly and include:

Reduced numbers of a type of blood cell, known as platelets (thrombocytopenia).

Rare side effects (may affect up to 1 in 1,000 people):

Impaired kidney function, lack of energy.

Some changes in blood test results have also been seen rarely and include:

Increase in blood potassium.

Hydrochlorothiazide:

Very common side effects (may affect more than 1 in 10 people):

Changes in blood results including: Increase in blood fat and uric acid levels.

Common side effects (may affect up to 1 in 10 people):

Feeling confused, abdominal pain, stomach upset, bloated feeling, diarrhoea, nausea, vomiting, constipation, excretion of glucose into the urine.

Some changes in blood results have also been seen and include:

Increase in blood creatinine, urea, calcium and sugar levels, decrease in blood chloride, potassium, magnesium and sodium levels. Increase of serum amylase (hyperamylasaemia).

Uncommon side effects (may affect up to 1 in 100 people):

Decreased or loss of appetite, severe difficulty breathing, anaphylactic skin reactions (hypersensitivity reactions), worsening of pre-existing myopia erythema, skin reactions to light, itching, purplish spots or patches on the skin due to small haemorrhages (purpura), skin lumps (wheals).

Rare side effects (may affect up to 1 in 1,000 people):

Swollen and sore salivary glands, decreased number of white blood cells, decreased number of blood platelets, anaemia, bone marrow damage, restlessness, feeling ‘down’ or depressed, problems sleeping, feeling un-interested (apathy), tingling and numbness, fits (convulsions), objects you look at appearing yellow, blurred vision, dry eyes, irregular heartbeat, inflammation of the blood vessels, blood clots (thrombosis or embolism), inflammation of the lung, fluid accumulation in the lungs, inflammation of the pancreas, jaundice, infection in the gall bladder, symptoms of lupus erythematosus (such as rash, joint pains and cold hands and fingers), allergic skin reactions, peeling and blistering of the skin, non-infectious inflammation of the kidney (interstitial nephritis), fever, muscle weakness (sometimes causing impaired movement).

Very rare side effects (may affect up to 1 in 10,000 people):

Electrolyte disturbance leading to an abnormally depleted level of chloride in the blood (hypochloraemic alkalosis), blockage in the gut (paralytic ileus).

Not known (frequency cannot be estimated from the available data):

Decrease in vision or eye pain (possible signs of acute angle-closure glaucoma).

Skin and lip cancer (Non-melanoma skin cancer).

Reporting of side effects:

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store. By reporting side effects you can help provide more information on the safety of this medicine.

5. How to store Olmesartan medoxomil/hydrochlorothiazide

Keep this medicine out of the sight and reach of children.

This medicinal product does not require any special storage conditions.

Do not use this medicine after the expiry date which is stated on the carton and on the blister strip after EXP. The expiry date refers to the last day of that month.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.

6. Contents of the pack and other information

What Olmesartan medoxomil/hydrochlorothiazide   contains

The active substances are:

Olmesartan medoxomil/hydrochlorothiazide   Each film-coated tablet contains 20mg /12.5mg, 20mg /25mg, 40mg /12.5mg and 40mg/25mg  olmesartan medoxomil and hydrochlorothiazide.

The other ingredients are:

Microcrystalline cellulose, lactose monohydrate*, low substituted hyprolose, hyprolose, magnesium stearate, titanium dioxide, talc, hypromellose, iron (III) oxides.

* See ‘Olmesartan medoxomil/hydrochlorothiazide   contains lactose’ section above

What Olmesartan medoxomil/hydrochlorothiazide   looks like and contents of the pack

They are available in packs of 14, 28, 30, 56, 84, 90, 98, 10 x 28 and 10 x 30 film-coated tablets and in packs with perforated unit dose blisters of 10, 50 and 500 film-coated tablets.

Not all pack sizes may be marketed.

7. Manufactured By:
   Taj Pharmaceuticals Ltd.
   at: Plot. No. 220, Mahagujarat
   Industrial Estate, At & Post-Moraiya,
   Tal-Sanand, Dist- Ahmedabad Gujarat (India)