OLMEGAN - PACKAGE LEAFLET - LEAFLETS

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Olmegan - Package Leaflet

Indications Contraindications Precautions for use Interactions Warnings Dosage and method of use Overdose Undesirable Effects Shelf Life and Storage

Active ingredients: Olmesartan medoxomil, Hydrochlorothiazide

OLMEGAN 20 mg / 12.5 mg film-coated tablets
OLMEGAN 20 mg / 25 mg

Olmegan package inserts are available for pack sizes:

OLMEGAN 20 mg / 12.5 mg film-coated tablets, OLMEGAN 20 mg / 25 mg
OLMEGAN 40 mg / 12.5 mg film-coated tablets, OLMEGAN 40 mg / 25 mg

Why is Olmegan used? What is it for?

OLMEGAN contains two substances called olmesartan medoxomil and hydrochlorothiazide. Both are used to control high blood pressure (hypertension).

Olmesartan medoxomil belongs to a group of medicines called "angiotensin II receptor antagonists". It lowers blood pressure by releasing blood vessels.
Hydrochlorothiazide belongs to a group of substances called "thiazide diuretics." It lowers blood pressure by helping the body to eliminate excess fluid by making the kidneys produce more urine.

You will be given OLMEGAN if OLMETEC (olmesartan medoxomil) alone has not adequately controlled your blood pressure. When given together, the two active ingredients in Olmegan help lower blood pressure more than they do when given alone.

If you are already taking medicines to treat high blood pressure, your doctor may give you OLMEGAN to get a further reduction.

High blood pressure can be controlled with medicines such as OLMEGAN tablets. Your doctor has probably also recommended that you make some lifestyle changes to help lower your blood pressure (for example, lose weight, quit smoking, reduce alcohol intake, and reduce dietary salt intake). . Your doctor may also have advised you to exercise regularly, such as walking or swimming. It is important that you follow these advice from your doctor.

Contraindications When Olmegan should not be used

Do not take OLMEGAN

if you are allergic to olmesartan medoxomil or hydrochlorothiazide, or to any of the other ingredients of this medicine (listed in section 6) or to substances similar to hydrochlorothiazide (sulphonamides).
if you are more than three months pregnant (it is advisable to avoid the use of OLMEGAN even during the first months of pregnancy - see the "pregnancy and breastfeeding" section).
if you have diabetes or impaired kidney function and you are being treated with a blood pressure lowering medicine containing aliskiren.
if you have severe kidney problems.
If you have low potassium or sodium levels, or high calcium or uric acid levels (with symptoms of gout or kidney stones) in your blood which do not improve after treatment.
if you have severe liver problems or yellowing of the skin and eyes (jaundice) or problems with the flow of bile from the gallbladder (biliary obstruction, for example stones).

If you think any of these apply to you, or you are not sure, do not take the medicine. Contact your doctor and follow his advice.

Precautions for use What you need to know before taking Olmegan

Talk to your doctor before using Olmegan.

Before taking this medicine, consult 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), particularly if you have diabetes-related kidney problems
Aliskiren

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

See also information under the heading "Do not take Olmegan".

Before taking this medicine, consult your doctor if you have any of the following health problems:

Mild or moderate kidney problems, or if you have recently had a kidney transplant.
Diseases of the liver.
Heart failure or problems with your heart valves or heart muscle.
Vomiting or diarrhea that is severe or lasts for several days.
Treatment with high-dose diuretics or if you are on a low-salt diet.
Problems with the adrenal glands (for example primary aldosteronism).
Diabetes.
Lupus erythematosus (an autoimmune disease).
Allergies or asthma.

Your doctor may want to see you more often and order some tests if you have any of the previous conditions.

Tell your doctor if you experience severe and prolonged diarrhea with significant weight loss. Your doctor will evaluate your symptoms and decide whether to continue this antihypertensive treatment.

OLMEGAN can cause increased fat and uric acid in the blood (causing gout - painful swelling of the joints). Your doctor will probably want to have periodic blood tests to evaluate these conditions.

The levels of certain substances, called electrolytes, in the blood can change. Your doctor will likely want to have periodic blood tests to evaluate these conditions. Signs of electrolyte changes are: thirst, dry mouth, muscle pain or cramps, muscle fatigue, low blood pressure (hypotension), feeling of weakness, sluggishness, tiredness, sleepiness or lack of rest, nausea, vomiting, reduced need for urinating, rapid heart rate. Tell your doctor if these symptoms appear.

As with any medicine that lowers blood pressure, an excessive reduction in blood pressure in patients with circulatory disorders of the heart or brain could lead to a heart attack or stroke. Your doctor will then check your blood pressure carefully.

If you need to have parathyroid function tests, you should stop taking OLMEGAN before doing these tests.

If you play sports, this medicine can alter the results of an anti-doping test, making it positive.

You should tell your doctor if you think you are pregnant or becoming pregnant. OLMEGAN is not recommended in early pregnancy and must not be taken after the third month of pregnancy as it may cause serious harm to the baby if used during that period (see "pregnancy and lactation" section).

Children and adolescents

Olmegan is not recommended for children and adolescents below 18 years of age

Interactions Which drugs or foods can modify the effect of Olmegan

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines.

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

Other medicines that lower blood pressure (antihypertensives) may increase the effect of Olmegan. Your doctor may need to adjust your dose and / or take other precautions: If you are taking an ACE inhibitor or aliskiren (see also information under "Do not take Olmegan "and" Warnings and precautions ".
Medicines which can cause changes in blood potassium levels when used concomitantly with Olmegan. These include:
- potassium supplements (such as potassium-containing salt substitutes)
- diuretics
- heparin (to thin the blood)
- laxatives
- steroids
- adrenocorticotropic hormone (ACTH)
- carbenoxolone (a medicine used to treat mouth and stomach ulcers)
- penicillin G sodium (also called benzylpenicillin sodium, an antibiotic)
- some pain relievers such as aspirin or salicylates
Lithium (a medicine used to treat mood swings and some types of depression) used together with Olmegan can increase the toxicity of lithium. If you have to take lithium, your doctor will measure your lithium blood levels.
Non-steroidal anti-inflammatory medicines (NSAIDs, medicines used to decrease pain, swelling and other symptoms of inflammation, including "arthritis) used together with Olmegan may increase the risk of kidney failure. The efficacy of Olmegan may be reduced by NSAIDs. .
Sleeping pills, sedatives and antidepressants used together with Olmegan can cause a "sudden drop in blood pressure when standing up.
Some medicines such as baclofen and tubocurarine, used to relax muscles
Amifostine and some other medicines used to treat cancer, such as cyclophosphamide or methotrexate
Colestyramine and colestipol, medicines to reduce fat levels in the blood
Colesevelam hydrochloride, a medicine that lowers blood cholesterol levels, which may decrease the effect of Olmegan. Your doctor may advise you to take Olmegan at least 4 hours before colesevelam hydrochloride.
Anticholinergic medicines, such as atropine and biperiden
Medicines such as thioridazine, chlorpromazine, levomepromazine, trifluoperazine, ciamemazine, sulpiride, amisulpride, pimozide, sultopride, tiapride, droperidol or haloperidol, used to treat some psychiatric diseases
Certain medicines such as quinidine, hydroquinidine, disopyramide, amiodarone, sotalol or digitalis, used to treat heart disease
Medicines such as mizolastine, pentamidine, terfenadine, dofetilide, ibutilide or erythromycin injected, which can alter the heart rhythm
Oral antidiabetic medicines, such as metformin, or insulin, used to lower the level of glucose in the blood
Beta-blockers and diazoxide, medicines used to treat high blood pressure or low blood glucose, respectively, as Olmegan may increase their hyperglycemic effect
Methyldopa, a medicine used to treat high blood pressure
Medicines such as norepinephrine, used to increase blood pressure and slow heart rate
Difemanil, used to treat a slow heartbeat or reduce sweating
Medicines such as probenecid, sulfinpyrazone and allopurinol, used to treat gout
Calcium Supplements
Amantadine, an antiviral medicine
Ciclosporin, a medicine used to stop the rejection of transplanted organs
Certain antibiotics called tetracyclines or sparfloxacin
Amphotericin, a medicine used to treat fungal diseases
Some antacids, used for stomach acid, such as magnesium aluminum hydroxide, because they can slightly reduce the effectiveness of OLMEGAN.
Cisapride, used to increase the movement of food in the stomach and intestines
Halofantina, used for malaria

OLMEGAN with food and drink

OLMEGAN can be taken on a full or empty stomach.

Take care to drink alcohol while taking Olmegan, as some people may feel faint or dizzy. If this happens to you, do not drink any other alcohol, including wine, beer or flavored alcoholic drinks.

Warnings It is important to know that:

Patients of black ethnicity

As with other similar medicines, the blood pressure lowering effect of Olmegan may be somewhat reduced in black patients.

Pregnancy and breastfeeding

Pregnancy

You should tell your doctor if you think you are pregnant or if there is a possibility of becoming pregnant. As a rule, your doctor will advise you to stop taking OLMEGAN before you become pregnant or as soon as you know you are pregnant and will advise you to take another medicine instead of OLMEGAN. OLMEGAN is not recommended during pregnancy and it must not be taken after the third month of pregnancy as it may cause serious harm to the baby if taken after the third month of pregnancy.

Feeding time

Tell your doctor if you are breastfeeding or about to start breastfeeding. OLMEGAN is not recommended for mothers who are breastfeeding and your doctor may choose another treatment for you if you wish to breastfeed.

If you are pregnant or breast-feeding, think, suspect or are planning to become pregnant, ask your doctor or pharmacist for advice before taking any medicine.

Driving and using machines

You may feel sleepy or dizzy during a high blood pressure treatment. If this happens, do not drive or use machines until the symptoms have disappeared. Consult your doctor for advice.

OLMEGAN 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.

Dose, Method and Time of Administration How to use Olmegan: Posology

Always take this medicine exactly as your doctor has told you. If in doubt, consult your doctor or pharmacist.

The recommended dose is one OLMEGAN 20 mg / 12.5 mg tablet per day. However, if your blood pressure is not controlled, your doctor may decide to change your prescription to one Olmegan 20 mg / 25 mg tablet per day.

Swallow the tablets with some water. If possible, take your daily dose at the same time each day, for example with breakfast. It is important to keep taking Olmegan until your doctor tells you to stop.

If you forget to take Olmegan

If you forget to take a dose, just take your normal dose the next day. Do not take a double dose to make up for a forgotten dose.

If you stop using OLMEGAN

It is important to continue taking Olmegan unless your doctor tells you to stop.

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

Overdose What to do if you have taken too much Olmegan

If you take more tablets than you should or if a child accidentally swallows some, go to your doctor or nearest emergency department immediately and take the medicine pack with you.

Side Effects What are the side effects of Olmegan

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 which may affect the whole body with swelling of the face, mouth and / or larynx (location of the vocal cords), associated with itching and rash, may occur rarely. If this happens, stop taking Olmegan and contact your doctor immediately.
OLMEGAN can cause an excessive reduction in blood pressure in susceptible individuals or as a result of an allergic reaction. Dizziness or fainting are not very common. If this happens, stop taking OLMEGAN, contact your doctor immediately and lie down.

OLMEGAN is a combination of two active substances and the following information first mentions the other undesirable effects reported so far with the OLMEGAN combination (in addition to those already mentioned above) and then those known for the separate active substances.

Other possible side effects of OLMEGAN known so far

If these side effects occur, they are often mild and treatment with Olmegan should not be stopped.

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

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

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

Perception of heartbeat (palpitations), rash, eczema, dizziness, cough, indigestion, abdominal pain, nausea, vomiting, diarrhea, muscle pain and muscle cramps, joint pain, pain in arms and legs, back pain, difficulty moving erection in men, blood in urine. Some changes in laboratory tests have also been observed uncommonly including: increased blood lipid levels, increased blood urea or uric acid levels, increased creatinine, increased or decreased blood potassium levels, increase in blood calcium levels, increase in blood glucose, increase in liver function indices. Your doctor will learn about this from your blood tests and tell you whether to do something.

Rare side effects (may affect up to 1 in 1000 people):

Feeling unwell, disturbed consciousness, skin blisters (wheals), acute kidney failure.

Rarely, some changes in laboratory tests have also been observed, which include the following: increased blood urea nitrogen, decreased hemoglobin and hematocrit values. Your doctor will learn about this from your blood tests and tell you if anything should be done. .

Additional undesirable effects reported with the use of olmesartan medoxomil or hydrochlorothiazide alone, but not with OLMEGAN or more frequently:

Olmesartan medoxomil

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

Bronchitis, cough, nasal hypersecretion, dry throat, abdominal pain, indigestion, diarrhea, nausea, gastroenteritis, joint or bone pain, back pain, blood in urine, urinary tract infection, flu-like symptoms, pain.

Some laboratory abnormalities have also been observed commonly including: increased blood lipid levels, increased blood urea or uric acid levels, increased liver and muscle function indices.

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

Rapid allergic reactions which can affect the whole body and which can cause breathing problems or rapid drop in blood pressure leading to fainting (anaphylactic reactions), swelling of the face, angina (pain or uncomfortable feeling in the chest, known as angina pectoris), feeling malaise, allergic skin reaction, itching, rash (rash), skin blisters (wheals).

Some changes in laboratory tests have also been observed uncommonly, including: reduction in the number of certain blood cells called platelets (thrombocytopenia).

Rare side effects (may affect up to 1 in 1000 people):

Renal impairment, weakness.

Some changes in laboratory tests have also been observed rarely, including the following: increased potassium in the blood.

Hydrochlorothiazide

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

Changes in laboratory tests which include: increased levels of fat and uric acid in the blood.

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

Feeling confused, abdominal pain, stomach discomfort, bloating, diarrhea, nausea, vomiting, constipation, urine glucose elimination. Some laboratory abnormalities have also been observed, including: increased creatinine levels, urea, calcium and glucose in the blood, decrease in the levels of chloride, potassium, magnesium and sodium in the blood. Increase in serum amylase (hyperamylasemia).

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

Decrease or loss of appetite, severe breathing difficulties, skin anaphylactic reactions (hypersensitivity reactions), worsening of pre-existing myopia, erythema, skin reactions to light, itching, purple spots or spots on the skin due to small bleeding (purpura), skin blisters (wheals).

Rare side effects (may affect up to 1 in 1000 people):

Swollen and painful salivary glands, decreased white blood cell count, decreased platelet count, anemia, bone marrow damage, restlessness, feeling depressed, sleep disturbances, lack of interest (apathy), tingling and numbness, seizures , vision of yellow objects, blurred vision, dry eye, irregular heartbeat, inflammation of blood vessels, blood clots (thrombosis or embolism), lung inflammation, accumulation of fluid in the lungs, inflammation of the pancreas, jaundice, infection of the gallbladder, symptoms of lupus erythematosus such as rash, joint pain and cold hands and fingers, allergic skin reactions, skin peeling and blistering, non-infectious inflammation of the kidney (interstitial nephritis), fever, muscle weakness (sometimes causing motor limitations).

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

Electrolyte changes causing an "abnormal reduction of chloride in the blood (hypochloraemic alkalosis). Intestinal blockage (paralytic ileus).

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 national reporting system at: www.agenziafarmaco.gov.it/it/responsabili. By reporting side effects you can help provide more information on the safety of this medicine.

Expiry and Retention

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

This medicine does not require any special storage conditions.

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

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

Other information

What OLMEGAN contains

The active ingredients are:

OLMEGAN 20 mg / 12.5 mg: Each film-coated tablet contains 20 mg of olmesartan medoxomil and 12.5 mg of hydrochlorothiazide.
OLMEGAN 20 mg / 25 mg: Each film-coated tablet contains 20 mg of olmesartan medoxomil and 25 mg of hydrochlorothiazide.

The other ingredients are: Microcrystalline cellulose, lactose monohydrate *, low-substituted hyprolose, hyprolose, magnesium stearate, titanium dioxide (E171), talc, hypromellose, iron (III) oxide (E172).

* See section "OLMEGAN contains lactose" above.

Description of what OLMEGAN looks like and contents of the pack

OLMEGAN 20 mg / 12.5 mg reddish-yellow, round, 8.5 mm film-coated tablets, debossed with C22 on one side.

OLMEGAN 20 mg / 25 mg pink, round, 8.5 mm film-coated tablets, debossed with C24 on one side.

OLMEGAN is available in packs of 14, 28, 30, 56, 84, 90, 98, and 10x28 film-coated tablets, and in packs of 10, 50 and 500 film-coated tablets with perforated unit dose blisters.

Not all pack sizes may be marketed.

Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.

Further information on Olmegan can be found in the "Summary of Characteristics" tab. 01.0 NAME OF THE MEDICINAL PRODUCT 02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION 03.0 PHARMACEUTICAL FORM 04.0 CLINICAL PARTICULARS 04.1 Therapeutic indications 04.2 Posology and method of administration 04.3 Contraindications 04.4 Special warnings and appropriate precautions for use 04.5 Interactions with other medicinal products and other forms of interaction04.6 Pregnancy and lactation04.7 Effects on ability to drive and use machines04.8 Undesirable effects04.9 Overdose05.0 PHARMACOLOGICAL PROPERTIES05.1 Pharmacodynamic properties05.2 Pharmacokinetic properties05.3 Preclinical safety data06.0 INFORMATION PHARMACEUTICALS 06.1 Excipients 06.2 Incompatibilities 06.3 Shelf life 06.4 Special precautions for storage 06.5 Nature of the immediate packaging and contents of the package 06.6 Instructions for use and handling 07.0 MARKETING AUTHORIZATION HOLDER08 .0 MARKETING AUTHORIZATION NUMBER 09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION 10.0 DATE OF REVISION OF THE TEXT 11.0 FOR RADIOPharmaceuticals, FULL DATA ON INTERNAL RADIATION DOSIMETRY 12.0 FOR RADIO DRUGS, ADDITIONAL DETAILED INSTRUCTIONS ON ESTEMPORANEA PREPARATION AND CONTROL

01.0 NAME OF THE MEDICINAL PRODUCT

OLMEGAN

02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION

Olmegan 20 mg / 12.5 mg film-coated tablets:

each film-coated tablet contains 20 mg of olmesartan medoxomil and 12.5 mg of hydrochlorothiazide

Olmegan 20 mg / 25 mg film-coated tablets:

each film-coated tablet contains 20 mg of olmesartan medoxomil and 25 mg of hydrochlorothiazide

Excipients:

Olmegan 20 mg / 12.5 mg film-coated tablets: each film-coated tablet contains 110.7 mg lactose monohydrate

Olmegan 20 mg / 25 mg film-coated tablets: each film-coated tablet contains 98.2 mg lactose monohydrate

For the full list of excipients, see section 6.1

03.0 PHARMACEUTICAL FORM

Film-coated tablet.

Olmegan 20 mg / 12.5 mg film-coated tablets: reddish-yellow, round, film-coated tablets with C22 on one side.

Olmegan 20 mg / 25 mg film-coated tablets: Pink, round, film-coated tablets debossed with C24 on one side.

04.0 CLINICAL INFORMATION

04.1 Therapeutic indications

Treatment of essential arterial hypertension.

Olmegan, fixed combination, is indicated in adult patients whose blood pressure is not adequately controlled on olmesartan medoxomil alone.

04.2 Posology and method of administration

Adults

Olmegan is indicated in patients whose blood pressure is not adequately controlled by 20 mg olmesartan medoxomil monotherapy and should not be used as initial therapy. Olmegan is given once daily, either on an empty stomach or on a full stomach.

When clinically appropriate, a direct switch from 20 mg olmesartan medoxomil monotherapy to the fixed combination may be considered, considering that the antihypertensive effect of olmesartan medoxomil is maximal approximately 8 weeks after initiation of therapy (see section 5.1). a dose adjustment of the individual components.

The combination of 20 mg olmesartan medoxomil and 12.5 mg hydrochlorothiazide can be administered in those patients whose blood pressure is not adequately controlled by optimal monotherapy with 20 mg olmesartan medoxomil.

The combination of 20 mg olmesartan medoxomil and 25 mg hydrochlorothiazide can be administered in those patients whose blood pressure is not adequately controlled by the combination of 20 mg olmesartan medoxomil and 12.5 mg hydrochlorothiazide.

Senior citizens (65 or more years of age)

The same posology as the combination used in adults is recommended in elderly patients.

Altered kidney function

When administering Olmegan to patients with mild to moderate renal impairment (creatinine clearance between 30 and 60 ml / min) it is suggested that renal function be monitored periodically (see section 4.4). Olmegan is contraindicated in patients with severe renal impairment (creatinine clearance less than 30 ml / min) (see section 4.3).

Altered liver function

Olmegan 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, the recommended starting dose of olmesartan medoxomil is 10 mg once daily and the maximum dose should not exceed 20 mg once daily. Close monitoring of blood pressure and renal function is advised in patients with hepatic impairment taking diuretics and / or other antihypertensive medicinal products. There is no experience of the use of olmesartan medoxomil in patients with severe hepatic impairment. Olmegan must not be used in patients with severe hepatic impairment (see sections 4.3, 5.2), cholestasis and biliary obstruction (see section 4.3).

Pediatric population

The safety and efficacy of Olmegan in children and adolescents below 18 years of age have not been established. There are no data available.

Method of administration:

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

04.3 Contraindications

Hypersensitivity to the active substances, to any of the excipients (see section 6.1) or to other sulphonamide-derived substances (since hydrochlorothiazide is a sulphonamide-derived medicinal product).

Severe renal impairment (creatinine clearance less than 30 ml / min).

Refractory hypokalaemia, hypercalcemia, hyponatremia and symptomatic hyperuricemia.

Severe hepatic impairment, cholestasis and obstructive biliary disease.

Second and third trimester of pregnancy (see sections 4.4 and 4.6).

04.4 Special warnings and appropriate precautions for use

Intravascular volume depletion:

In patients with hypovolaemia and / or sodium depletion caused by high doses of diuretics, reduced dietary sodium intake, diarrhea or vomiting, symptomatic hypotension may occur, especially after the first dose. These conditions must be corrected before starting treatment with Olmegan.

Other conditions related to stimulation of the renin-angiotensin-aldosterone system:

In patients whose vascular tone and kidney function are primarily dependent on the activity of the renin-angiotensin-aldosterone system (eg, patients with severe congestive heart failure or kidney disease, including renal artery stenosis), treatment with medicinal products that affect this system has been associated with acute hypotension, azotaemia, oliguria or, in rare cases, acute renal failure.

Renovascular hypertension:

In patients with bilateral stenosis of the renal artery, or stenosis of the afferent artery to a single functioning kidney, treated with drugs that affect the renin-angiotensin-aldosterone system, there is an increased risk of hypotension and severe renal failure.

Altered kidney function and kidney transplant:

Olmegan must not be used in patients with severe renal impairment (creatinine clearance less than 30 ml / min) (see section 4.3). No dosage adjustments are required in patients with mild to moderate renal impairment (creatinine clearance ≥ 30 ml / min and serum potassium, creatinine and uric acid. Thiazide diuretics. If progressive renal impairment is evident, careful re-evaluation of therapy is required, considering discontinuation of the diuretic. There is no experience of Olmegan administration in patients who have recently undergone renal transplantation.

Impaired liver function:

There is currently no experience with olmesartan medoxomil in patients with severe hepatic impairment. Furthermore, slight alterations in the water-electrolyte balance during thiazide therapy can induce hepatic coma in patients with impaired liver function or progressive liver disease. Therefore, caution should be exercised in patients with mild to moderate hepatic impairment (see section 4.2). The use of Olmegan is contraindicated in patients with severe hepatic impairment, cholestasis or biliary obstruction (see sections 4.3, 5.2).

Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy:

As with other vasodilators, particular caution is recommended in patients with aortic or mitral valve stenosis or obstructive hypertrophic cardiomyopathy.

Primary aldosteronism:

Patients with primary aldosteronism generally do not respond to antihypertensive medicinal products acting by inhibition of the renin-angiotensin system. Therefore, the use of Olmegan is not recommended in these patients.

Metabolic and endocrine effects

Thiazide therapy can impair glucose tolerance. Dosage adjustments of insulin or oral hypoglycaemics may be required in diabetic patients (see section 4.5). Latent diabetes mellitus may become manifest during thiazide therapy.

Increased cholesterol and triglyceride levels are a known undesirable effect associated with thiazide diuretic therapy. Hyperuricaemia or gout may occur in some patients receiving thiazide therapy.

Electrolyte imbalance

As with all patients on diuretic therapy, periodic serum electrolyte measurements 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 dry mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pain or cramps, muscle fatigue, hypotension, oliguria, tachycardia and gastrointestinal disturbances such as nausea or vomiting (see section 4.8).

The risk of hypokalaemia is greater in patients with cirrhosis of the liver, in patients with rapid diuresis, in patients receiving inadequate oral intake of electrolytes and in patients receiving concomitant therapy with corticosteroids or ACTH (see section 4.5). Conversely, due to the angiotensin II (AT-1) receptor antagonism of olmesartan medoxomil contained in Olmegan, hyperkalaemia may occur, especially in the presence of impaired renal function and / or heart failure and diabetes mellitus. Adequate monitoring of serum potassium is recommended in patients at risk. Potassium-sparing diuretics, potassium supplements or potassium-containing salt substitutes and other medicinal products that can induce increases in serum potassium (such as heparin) should be administered with caution when taking Olmegan (see paragraph 4.5).

There is no evidence that olmesartan medoxomil reduces or prevents diuretic-induced hyponatraemia. Chloride deficiency is usually mild and usually does not require treatment.

Thiazides may reduce urinary calcium excretion and cause mild and intermittent increases in serum calcium in the absence of known disorders of calcium metabolism. Hypercalcaemia may be a manifestation of occult hyperparathyroidism. Thiazides must be discontinued before a " analysis for parathyroid function.

Thiazides have been shown to increase urinary excretion of magnesium, with possible hypomagnesaemia.

In oedematous patients, dilution hyponatremia may occur during exposure to high atmospheric temperatures.

Lithium:

As with other medicinal products containing angiotensin II receptor antagonists and thiazides in combination, the concomitant administration of lithium and Olmegan is not recommended (see section 4.5).

Ethnic differences:

As with all other angiotensin II antagonists, the antihypertensive effect of olmesartan medoxomil is somewhat less in black patients, possibly due to the higher prevalence of low renin levels in the black hypertensive population.

Doping test:

The hydrochlorothiazide contained in this medicinal product may cause positive doping tests.

Pregnancy:

Angiotensin II antagonist therapy should not be initiated during pregnancy. Alternative antihypertensive treatment with an established safety profile for use in pregnancy should be used for patients planning to become pregnant, unless Continuation of angiotensin II antagonist therapy is considered essential. When pregnancy is diagnosed, treatment with angiotensin II antagonists should be stopped immediately and, if appropriate, alternative therapy should be started (see sections 4.3 and 4.6).

Other:

In the presence of generalized atherosclerosis, and in patients with ischemic heart disease or ischemic cerebrovascular disease, there is always the risk that the excessive reduction in blood pressure may cause myocardial infarction or stroke.

Hypersensitivity reactions to hydrochlorothiazide may arise in patients with or without a history of allergy or bronchial asthma, but are more frequent with such anamnestic findings.

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 medicine.

04.5 Interactions with other medicinal products and other forms of interaction

Potential interactions with 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 antagonists. In addition, renal clearance of lithium is reduced. from thiazides and consequently the risk of lithium toxicity may be increased. Therefore, the use of Olmegan and lithium in combination is not recommended (see section 4.4). If concomitant use is deemed necessary, careful monitoring of serum lithium levels is recommended.

Concomitant use requiring caution

Baclofen

Potentiation of the antihypertensive effect may occur.

Non-steroidal anti-inflammatory drugs (NSAIDs)

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

In some patients with impaired renal function (eg dehydrated or elderly patients with impaired renal function), the concomitant administration of angiotensin II antagonists and cyclooxygenase inhibitors may lead to further deterioration of renal function, including possible acute renal failure. usually reversible. Therefore, this combination should be administered with caution, especially in elderly patients. Patients should be adequately hydrated and monitoring of renal function should be considered after initiation of concomitant treatment and periodically during it.

Concomitant use to be evaluated

Amifostina

Potentiation of the antihypertensive effect may occur.

Other antihypertensive medicines:

The hypotensive effect caused by Olmegan may be enhanced by the concomitant use of other antihypertensive medicinal products.

Alcohol, barbiturates, narcotics or antidepressants

Potentiation of orthostatic hypotension may occur.

Potential interactions with olmesartan medoxomil:

Concomitant use not recommended

Medicines that affect potassium levels:

Based on the experience of the use of other medicinal products that affect the renin-angiotensin system, the concomitant use of potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium or other medicinal products capable of causing increased serum potassium levels (e.g. heparin, ACE inhibitors) may cause an increase in serum potassium (see section 4.4). If medicinal products capable of affecting potassium levels are prescribed in combination with Olmegan, monitoring of plasma levels is advised of potassium.

Additional information

A modest reduction in the bioavailability of olmesartan was observed after treatment with antacids (aluminum magnesium hydroxide).

Olmesartan medoxomil has no significant effect on the pharmacokinetics or pharmacodynamics of warfarin or the pharmacokinetics of digoxin.

Concomitant administration of olmesartan medoxomil and pravastatin did not cause clinically relevant effects on the pharmacokinetics of the two substances in healthy subjects.

Olmesartan has no clinically relevant inhibitory effects on human cytochrome P450 enzymes 1A1 / 2, 2A6, 2C8 / 9, 2C19, 2D6, 2E1 and 3A4 in vitro, while induction effects on rat cytochrome P450 are minimal or absent. Clinically relevant interactions between olmesartan and medicinal products metabolised by the aforementioned cytochrome P450 enzymes are not to be expected.

Potential interactions with hydrochlorothiazide:

Concomitant use not recommended

Medicines that affect potassium levels:

The potassium-depleting effect of hydrochlorothiazide (see section 4.4) may be potentiated by concomitant administration of other medicinal products associated with potassium loss and hypokalaemia (eg other diuretics causing potassium, laxatives, corticosteroids, ACTH, amphotericin, carbenoxolone, penicillin G sodium or salicylic acid derivatives) Therefore, such concomitant use is not recommended.

Concomitant use requiring caution

Calcium salts

Thiazide diuretics can increase serum calcium levels by decreasing their excretion. If calcium supplements are to be prescribed, serum calcium levels should be monitored and the calcium dosage adjusted accordingly.

Colestyramine and colestipol resins

The absorption of hydrochlorothiazide is impaired in the presence of anion exchange resins.

Digitalis glycosides

Thiazide-induced hypokalaemia or hypomagnesaemia may favor digitalis-induced cardiac arrhythmias.

Medicines affected by changes in potassium

Periodic monitoring of serum potassium and ECG is recommended when Olmegan is concomitantly administered with medicinal products that are affected by potassium abnormalities (eg digitalis glycosides and antiarrhythmics), or with the following medicinal products (including some antiarrhythmics) which may induce torsades de pointes (ventricular tachycardia), as hypokalaemia is a predisposing factor for torsades de pointes (ventricular tachycardia):

- class Ia antiarrhythmics (e.g. quinidine, hydroquinidine, disopyramide)

- class III antiarrhythmics (e.g. amiodarone, sotalol, dofetilide, ibutilide)

- some antipsychotics (e.g. thioridazine, chlorpromazine, levomepromazine, trifluoperazine, ciamemazine, sulpiride, sultopride, amisulpride, thiapride, pimozide, haloperidol, droperidol)

- others (e.g. bepridil, cisapride, dihemanyl, iv erythromycin, halofantrine, mizolastine, pentamidine, sparfloxacin, terfenadine, iv vincamine).

Nondepolarizing muscle relaxants (e.g. tubocurarine)

The effect of non-depolarising muscle relaxants can be enhanced by hydrochlorothiazide.

Anticholinergic drugs (eg atropine, biperiden)

Increased bioavailability of thiazide diuretics due to decreased gastrointestinal motility and gastric emptying time.

Antidiabetic medicines (oral medicines and insulin)

Treatment with a thiazide diuretic can affect glucose tolerance. Dosage adjustments of antidiabetic medicinal products may be required (see section 4.4).

Metformin

Metformin should be used with caution due to 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 (noradrenaline)

The effect of pressor amines can be reduced.

Medicines used to treat gout (probenecid, sulfinpyrazone and allopurinol)

Dosage adjustment of uricosuric medicinal products may be required, as hydrochlorothiazide may increase the serum uric acid level. An increase in the dose of probenecid or sulfinpyrazone may be required. Concomitant administration of a thiazide diuretic may increase the incidence of hypersensitivity reactions to allopurinol.

Amantadina

Thiazides may increase the risk of adverse reactions from amantadine.

Cytotoxic drugs (e.g. cyclophosphamide, methotrexate)

Thiazides can reduce the renal excretion of cytotoxic drugs and potentiate their myelosuppressive effects.

Salicylates

In case of administration of high doses of salicylates, hydrochlorothiazide may increase the toxic effect of salicylates on the central nervous system.

Methyldopa

There have been isolated reports of haemolytic anemia after concomitant use of hydrochlorothiazide and methyldopa.

Cyclosporine

Concomitant treatment with cyclosporine may increase the risk of hyperuricaemia and gout-like complications.

Tetracyclines

Concomitant administration of tetracyclines and thiazides increases the risk of tetracycline-induced increase in urea levels. This interaction probably does not occur with doxycycline.

04.6 Pregnancy and breastfeeding

Pregnancy (see section 4.3):

Due to the effects of the active substances of this combination in pregnancy, the use of Olmegan is not recommended during the first trimester of pregnancy (see section 4.4). The use of Olmegan is contraindicated during the second and third trimester of pregnancy (see section 4.4). see sections 4.3 and 4.4).

Olmesartan medoxomil

The use of angiotensin II antagonists is not recommended during the first trimester of pregnancy (see section 4.4). The use of angiotensin II antagonists is contraindicated during the second and third trimesters of pregnancy (see sections 4.3 and 4.4).

Epidemiological evidence on 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. Although controlled epidemiological data on risk with angiotensin II antagonists are not available, a similar risk may also exist for this class of medicinal products. An alternative antihypertensive treatment with a proven safety profile should be used for patients planning pregnancy. for use in pregnancy, unless continued angiotensin II antagonist therapy is considered essential. When pregnancy is ascertained, treatment with angiotensin II antagonists should be discontinued immediately and, if appropriate, start alternative therapy.

Exposure to angiotensin II antagonists during the second and third trimesters is known to induce fetal toxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia). (see also section 5.3).

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

Neonates whose mothers have taken angiotensin II antagonists should be closely monitored for hypotension (see sections 4.3 and 4.4).

Hydrochlorothiazide

Experience with the use of hydrochlorothiazide during pregnancy, especially during the first trimester, is limited. Animal studies are insufficient.

Hydrochlorothiazide crosses the placenta. Based on the pharmacological mechanism of action of hydrochlorothiazide, its use during the second and third trimester of pregnancy can impair fetal-placental perfusion and cause fetal and neonatal effects such as jaundice, electrolyte disturbance. and thrombocytopenia.

Hydrochlorothiazide should not be used in gestational edema, pregnancy hypertension or preeclampsia due to the risk of plasma volume depletion and placental hypoperfusion, without favorable effects on the course of the disease.

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

Feeding time

Olmesartan medoxomil

Since no data are available regarding the use of Olmegan during lactation, the use of Olmegan is not recommended and alternative therapies with a proven safety profile should be preferred for use during lactation especially in the case of newborn or preterm infants.

Hydrochlorothiazide

Hydrochlorothiazide is excreted in human milk in small quantities. High doses of thiazides, resulting in intense diuresis, may inhibit milk production. The use of Olmegan is not recommended during breastfeeding. doses should be kept as low as possible.

04.7 Effects on ability to drive and use machines

Olmegan may have a slight or moderate influence on the ability to drive and use machines. Dizziness or symptoms of fatigue, which may impair the ability to react, may occasionally occur in patients on antihypertensive therapy.

04.8 Undesirable effects

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

Hydrochlorothiazide can cause or aggravate fluid depletion which can lead to electrolyte imbalance (see section 4.4).

In clinical trials involving 1155 patients who received the olmesartan medoxomil / hydrochlorothiazide combination at doses of 20 / 12.5 mg or 20/25 mg and 466 patients who received placebo for up to 21 months, the overall frequency of adverse reactions to the combination of olmesartan medoxomil / hydrochlorothiazide were similar to that related to placebo.Treatment discontinuations due to adverse reactions were also similar for olmesartan medoxomil / hydrochlorothiazide 20 / 12.5 mg - 20/25 mg (2%) and for placebo (3%). The frequency of adverse reactions in the olmesartan medoxomil / hydrochlorothiazide group in total compared to placebo did not appear to be related to age (

In addition, the tolerability of high dose olmegan was evaluated in clinical studies conducted in 3709 patients who received olmesartan medoxomil in combination with hydrochlorothiazide at doses of 40 mg / 12.5 mg and 40 mg / 25 mg.

Adverse reactions observed with Olmegan in clinical trials, post-authorization tolerability studies and spontaneous reports are presented in the table below, as are the adverse reactions induced by the individual components olmesartan medoxomil and hydrochlorothiazide based on the tolerability profile of these substances.

The following terminology was used to rank the frequency of adverse reactions: very common (≥1 / 10); common (≥1 / 100 y

MeDRA Class of Organs and Systems Adverse reactions Frequency Olmegan Olmesartan HCTZ Infections and infestations Get rid of it Rare Disorders of the blood and lymphatic system Aplastic anemia Rare Medullary depression Rare Hemolytic anemia Rare Leukopenia Rare Neutropenia / Agranulocytosis Rare Thrombocytopenia Uncommon Rare Disorders of the immune system Anaphylactic reactions Uncommon Uncommon Metabolism and nutrition disorders Anorexia Uncommon Glycosuria common Hypercalcemia common Hypercholesterolemia Uncommon Very common Hyperglycemia common Hyperkalaemia Rare Hypertriglyceridemia Uncommon common Very common Hyperuricemia Uncommon common Very common Hypochloremia common Hypochloraemic alkalosis Very rare Hypokalaemia common Hypomagnesemia common Hyponatremia common Hyperamylasemia common Psychiatric disorders Apathy Rare Depression Rare Restlessness Rare Sleep disorders Rare Nervous system disorders Confusional state common Convulsions Rare Disturbances of consciousness (such as loss of consciousness) Rare Dizziness / light-headedness common common common Headache common common Rare Loss of appetite Uncommon Paresthesias Rare Postural dizziness Uncommon Drowsiness Uncommon Syncope Uncommon Eye disorders Reduction of lacrimation Rare Transient blurred vision Rare Worsening of pre-existing myopia Uncommon Xanthopsia Rare Ear and labyrinth disorders Dizziness Uncommon Uncommon Rare Cardiac pathologies Angina pectoris Uncommon Cardiac arrhythmias Rare Palpitations Uncommon Vascular pathologies Embolism Rare Hypotension Uncommon Rare Necrotizing angiitis (vasculitis, cutaneous vasculitis) Rare Orthostatic hypotension Uncommon Uncommon Thrombosis Rare Respiratory, thoracic and mediastinal disorders Bronchitis common Cough Uncommon common Dyspnea Rare Interstitial pneumonia Rare Pharyngitis common Pulmonary edema Rare Respiratory distress Uncommon Rhinitis common Gastrointestinal disorders Abdominal pain Uncommon common common Constipation common Diarrhea Uncommon common common Dyspepsia Uncommon common Gastric irritation common Gastroenteritis common Meteorism common Nausea Uncommon common common Pancreatitis Rare Paralytic ileus Very rare He retched Uncommon Uncommon common Hepato-biliary disorders Acute cholecystitis Rare Jaundice (intrahepatic cholestatic jaundice) Rare Skin and subcutaneous tissue disorders Allergic dermatitis Uncommon Skin anaphylactic reactions Rare Angioneurotic edema Rare Rare Lupus erythematosus-like skin reactions Rare Eczema Uncommon Erythema Uncommon Rash Uncommon Reactions of photosensitivity Uncommon Itching Uncommon Uncommon Purple Uncommon Rash Uncommon Uncommon Uncommon Exacerbation of cutaneous lupus erythematosus Rare Toxic epidermal necrolysis Rare Urticaria Rare Uncommon Uncommon Musculoskeletal and connective tissue disorders Arthralgia Uncommon Arthritis common Backache Uncommon common Muscle spasms Uncommon Rare Muscle weakness Rare Myalgia Uncommon Uncommon Pain in the extremities Uncommon Paresis Rare Skeletal pains common Renal and urinary disorders Acute renal failure Rare Rare Hematuria Uncommon common Interstitial nephritis Rare Kidney failure Rare Renal dysfunction Rare Urinary infections common Diseases of the reproductive system and breast Erectile dysfunction Uncommon Uncommon General disorders and administration site conditions Asthenia common Uncommon Chest pain common common Facial edema Uncommon Tiredness common common Fever Rare Flu-like symptoms common Lethargy Rare Malaise Rare Uncommon Ache common Peripheral edema common common Weakness Uncommon Diagnostic tests Hyper alanine aminotransferase Uncommon Hyper aspartate aminotransferase Uncommon Hypercalcemia Uncommon Hypercreatininemia Uncommon Rare common Hyper creatine phosphokinase common Hyperglycemia Uncommon Reduction of hematocrit values Rare Reduction of hemoglobin values Rare Hyperlipidemia Uncommon Hypokalemia Uncommon Hyperkalaemia Uncommon Increased plasma urea Uncommon common common Hyperazotemia Rare Hyperuricemia Rare Hyper gamma glutamyl transferase Uncommon Increased liver enzymes common

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

04.9 Overdose

No specific information is available on the effects or treatment of Olmegan overdose. The patient should be carefully monitored and the treatment should be symptomatic and supportive. Management depends on the time since intake and the severity of symptoms. Suggested measures include induction of vomiting and / or gastric lavage. Activated charcoal can be useful in the treatment of overdose. Serum electrolytes and creatinine should be checked frequently. If hypotension occurs, the patient should be placed in the supine position, with rapid restoration of plasma volume and salts.

The most likely expected manifestations of olmesartan medoxomil overdose are hypotension and tachycardia; bradycardia may also occur. Hydrochlorothiazide overdose is associated with electrolyte depletion (hypokalaemia, hypochloraemia) and dehydration due to excessive diuresis. of overdose are nausea and somnolence. Hypokalaemia may result in severe muscle spasms and / or cardiac arrhythmias associated with the concomitant use of digitalis glycosides or certain antiarrhythmic drugs.

There are no data on the dialyzability of olmesartan or hydrochlorothiazide.

05.0 PHARMACOLOGICAL PROPERTIES

05.1 Pharmacodynamic properties

Pharmacotherapeutic group: Angiotensin II antagonists associated with diuretics,

ATC code: C09DA08.

Mechanism of action / Pharmacodynamic effects

Olmegan is a combination of an angiotensin II receptor antagonist, olmesartan medoxomil, and a thiazide diuretic, hydrochlorothiazide. The combination of these substances has an additive antihypertensive effect, reducing blood pressure to a greater degree than either component alone.

Once daily administration of Olmegan ensures an effective and gradual reduction of blood pressure in the 24 hours between two administrations.

Olmesartan medoxomil is an orally effective selective angiotensin II receptor antagonist (type AT1). Angiotensin II is the major vasoactive hormone of the renin-angiotensin-aldosterone system and plays a significant role in the pathophysiology of hypertension. angiotensin II include vasoconstriction, stimulation of aldosterone synthesis and release, cardiac stimulation and renal sodium reabsorption. Olmesartan blocks the vasoconstrictor and aldosterone-secretory 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 origin or route of synthesis of angiotensin II. The selective antagonism of olmesartan against the angiotensin II receptor (AT1) produces an increase plasma renin levels and angiotensin I and II concentrations and some decrease in plasma concentrations asthmatics of aldosterone.

In cases of hypertension, olmesartan medoxomil causes a dose-dependent, long-term reduction in blood pressure. sudden therapy.

Once-a-day administration of olmesartan medoxomil ensures an effective and constant reduction in blood pressure in the 24-hour interval between one dose and the next. For the same overall dosage, once-daily administration produced similar decreases in blood pressure compared to administration. of the medicine twice a day.

With continued treatment, maximum reduction in blood pressure is achieved within 8 weeks after initiation of therapy, although a substantial share of the blood pressure lowering effect is already observed after 2 weeks of treatment.

The effects of olmesartan on mortality and morbidity are currently unknown.

L "hydrochlorothiazide is a thiazide diuretic. The mechanism of the antihypertensive effect of thiazide diuretics is not fully understood. Thiazides act on the electrolyte reabsorption mechanisms of the renal tubule, directly increasing the excretion of sodium and chlorine in approximately equivalent amounts. The diuretic action of hydrochlorothiazide reduces plasma volume, increases plasma renin activity and increases aldosterone secretion, with consequent increase in the loss of bicarbonate and potassium in urine, and reduction in serum potassium. The renin-aldosterone link is mediated by angiotensin II and, therefore, the concomitant administration of an angiotensin II receptor antagonist tends to counteract the potassium loss associated with thiazide diuretics. With hydrochlorothiazide, the onset of diuresis occurs after about two hours and the peak of effect approximately four hours after administration, while effect persists for approximately 6-12 hours.

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

Clinical efficacy and safety

The combination of olmesartan medoxomil and hydrochlorothiazide results in an additive reduction in blood pressure which generally increases with increasing dose of each component. In the overall data of the placebo-controlled studies, the administration of the combination of olmesartan medoxomil / hydrochlorothiazide 20 / 12.5 mg and 20/25 mg resulted in a mean reduction (minus the reduction due to placebo) in systolic / diastolic blood pressure to the lowest value of 12/7 mmHg and 16/9 mmHg, respectively. Age and gender had no clinically relevant effect on response to treatment with the combination olmesartan medoxomil / hydrochlorothiazide.

The administration of 12.5 mg and 25 mg of hydrochlorothiazide in patients insufficiently controlled on therapy with 20 mg olmesartan medoxomil alone resulted in a "further reduction in 24-hour diastolic / systolic blood pressure, measured by ambulatory blood pressure monitoring, respectively. 7/5 mmHg and 12/7 mmHg, compared to baseline values after monotherapy with olmesartan medoxomil. The mean further reduction in systolic / diastolic blood pressure to the lowest value from baseline, measured conventionally, was 11/10 mmHg, respectively. and 16/11 mmHg.

The efficacy of the combination olmesartan medoxomil / hydrochlorothiazide was maintained over the course of long-term treatments (one year). Discontinuation of olmesartan medoxomil, with or without concomitant hydrochlorothiazide, did not result in rebound hypertension. The effects of the fixed combination olmesartan medoxomil / hydrochlorothiazide on cardiovascular morbidity and mortality are currently unknown.

05.2 Pharmacokinetic properties

Absorption and distribution

Olmesartan medoxomil:

Olmesartan medoxomil is a pro-drug rapidly converted to a pharmacologically active metabolic, olmesartan, by esterases in the intestinal mucosa and portal circulation during absorption from the gastrointestinal tract. There is no trace of intact olmesartan medoxomil or the intact medoxomil side chain in plasma or excreta. The mean absolute bioavailability of olmesartan, in the tablet formulation, was 25.6%.

The mean peak concentration (Cmax) of olmesartan is achieved on average within approximately 2 hours after oral administration of olmesartan medoxomil; Plasma concentrations of olmesartan increase approximately linearly as the single oral dose increases to approximately 80 mg.

Food administration has minimal effects on the bioavailability of olmesartan and, therefore, olmesartan medoxomil can be administered in the fasted or fed state.

No clinically relevant differences in the pharmacokinetics of olmesartan dependent on patient sex were observed.

Olmesartan is strongly bound to plasma proteins (99.7%), but the potential for clinically significant protein binding displacement interactions between olmesartan and other highly bound active substances administered concurrently is low (as confirmed by the "absence of a" interaction. clinically significant between olmesartan medoxomil and warfarin). The binding of olmesartan to blood cells is negligible. The mean volume of distribution after intravenous administration is small (16-29 L).

Hydrochlorothiazide:

After oral administration of combined olmesartan medoxomil and hydrochlorothiazide, the median time to peak plasma concentration of hydrochlorothiazide ranged from 1.5 to 2 hours post dose. Hydrochlorothiazide is 68% bound to plasma proteins and its apparent volume of distribution is 0.83-1.14 L / kg.

Metabolism and elimination

Olmesartan medoxomil:

Total plasma clearance of olmesartan was 1.3 L / h (CV 19%), relatively low when compared to hepatic flow (approx. 90 L / h). Following oral administration of a single dose of 14C-labeled olmesartan medoxomil, 10-16% of the administered radioactivity was eliminated in the urine (largely within 24 hours after dosing), while the remaining radioactivity was eliminated in the faeces. . Based on a systemic bioavailability of 25.6%, it can be estimated that absorbed olmesartan is eliminated by renal (approximately 40%) and hepatobiliary (approximately 60%) excretion. All recovered radioactivity was identified as olmesartan No other significant metabolites identified. The enterohepatic circulation of olmesartan is minimal. Since a large amount of olmesartan is eliminated via the biliary route, use in patients with biliary obstruction is contraindicated (see section 4.3).

The terminal elimination half-life of olmesartan ranges from 10 to 15 hours after repeated oral administration. Steady state was reached after the first few administrations and no further accumulation was detected after 14 days of repeated administration. Renal clearance is was approximately 0.5-0.7 L / h and was independent of the dose.

Hydrochlorothiazide:

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

Olmegan

Systemic availability of hydrochlorothiazide is reduced by approximately 20% when co-administered with olmesartan medoxomil, but this modest reduction is of no clinical relevance. The kinetics of olmesartan are not affected by concomitant administration of hydrochlorothiazide.

Pharmacokinetics in special patient groups

Elderly (65 years or older):

In hypertensive patients, the steady-state AUC of olmesartan was increased by approximately 35% in elderly patients (aged 65 to 75 years) and by approximately 44% in very elderly patients (≥ 75 years) compared to patients younger (see section 4.2). However limited data suggest that the systemic clearance of hydrochlorothiazide is reduced in the elderly, healthy or hypertensive, compared to young healthy volunteers..

Altered kidney function:

In cases of renal impairment, the steady-state AUC of olmesartan was 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.

Altered liver function:

After single oral administration, the AUC values of olmesartan were 6% and 65% higher, respectively, in patients with mild and moderate hepatic impairment compared to subjects with normal hepatic function. administration was 0.26% in healthy subjects, 0.34% in patients with mild hepatic impairment and 0.41% in those with moderate hepatic impairment. Following repeated dosing in patients with moderate hepatic impairment , the mean AUC of olmesartan was still approximately 65% higher than in healthy controls. Olmesartan mean Cmax values were similar in patients with impaired hepatic function and healthy subjects. Olmesartan medoxomil has not been studied in patients with severe hepatic impairment (see sections 4.2, 4.4). Hepatic impairment does not significantly affect the pharmacokinetics of hydrochlorothiazide.

05.3 Preclinical safety data

The potential toxicity of the combination olmesartan medoxomil / hydrochlorothiazide was evaluated in repeated dose oral toxicity studies of up to six months duration in rats and dogs.

As with both individual components and other medicinal products belonging to this class, the main toxicological target organ of the combination is the kidney. The combination of olmesartan medoxomil / hydrochlorothiazide induced alterations in renal function (increase in serum urea nitrogen and serum creatinine). High dosages caused tubular degeneration and regeneration in the kidneys of rats and dogs, possibly by alterations in renal haemodynamics (reduced renal perfusion due to hypotension with tubular hypoxia and tubular cell degeneration). Furthermore, the combination olmesartan medoxomil / hydrochlorothiazide caused reduction of erythrocyte parameters (erythrocyte count, hemoglobin, hematocrit) and weight reduction of the heart in rats. These effects have also been observed with the other AT1 receptor antagonists and with ACE inhibitors; they appear to have been induced by a pharmacological action of olmesartan medoxomil at high doses and do not appear to be relevant in humans at the recommended therapeutic doses.

Genotoxicity studies with olmesartan medoxomil and hydrochlorothiazide, in combination or used alone, did not reveal any signs of clinically relevant genotoxic activity.

The carcinogenic potential of the combination of olmesartan medoxomil and hydrochlorothiazide has not been studied as there is no evidence of relevant carcinogenic effects of the two individual components under conditions of clinical use.

There is no evidence of teratogenicity in mice or rats treated with the combination olmesartan medoxomil / hydrochlorothiazide. As expected for this class of drugs, fetal toxicity was observed in rats, evidenced by low fetal weight of mothers treated with olmesartan. medoxomil and hydrochlorothiazide during pregnancy (see sections 4.3, 4.6).