OLPRESS - PACKAGE LEAFLET - LEAFLETS

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Olpress - Package Leaflet

Indications Contraindications Precautions for use Interactions Warnings Dosage and method of use Overdose Undesirable Effects Shelf life and Storage Composition and pharmaceutical form

Active ingredients: Olmesartan medoxomil

OLPRESS 10 mg, 20 mg, 40 mg film-coated tablets

Why is Olpress used? What is it for?

Olpress belongs to a group of medicines called angiotensin II receptor antagonists. They lower blood pressure by releasing blood vessels.

Olpress is used to treat high blood pressure (also called "high blood pressure"). High blood pressure can damage blood vessels in organs such as the heart, kidney, brain and eye. In some cases, this can lead to heart attacks, heart or kidney failure, stroke, or blindness. Usually, high blood pressure does not have symptoms. It is important to check your blood pressure to prevent damage.

High blood pressure can be controlled with medicines such as Olpress 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 Olpress should not be used

Do not take Olpress

if you are allergic to olmesartan medoxomil or any of the other ingredients of this medicine (listed in section 6).
if you have been pregnant for more than three months. (Olpress is also best avoided in early pregnancy - see "Pregnancy" section).
if you suffer from yellowing of the skin and eyes (jaundice) or from changes in the outflow of bile from the gallbladder (biliary obstruction, for example stones).
if you have diabetes or impaired kidney function and you are being treated with a blood pressure lowering medicine containing aliskiren.

Precautions for use What you need to know before taking Olpress

Talk to your doctor before taking Olpress.

Consult your doctor if you are taking any of the following medicines used to treat high blood pressure:

an "ACE inhibitor" (eg 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 Olpress"

Consult your doctor if you also have any of the following health problems:

Kidney problems.
Liver disease.
Heart failure or problems with your heart valves or heart muscle.
Severe vomiting, diarrhea, treatment with high doses of diuretics or if you are on a low-salt diet.
Increased levels of potassium in the blood.
Problems with the adrenal glands.

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.

As with any medicine that lowers blood pressure, too much blood pressure reduction 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.

You should tell your doctor if you think you are pregnant (or if there is a possibility of becoming pregnant). Olpress is not recommended in early pregnancy and must not be taken if you are more than three months pregnant, as it may cause serious harm to your baby if used at that stage (see "pregnancy" section).

Children and adolescents

Olpress is not recommended for children and adolescents under 18 years of age.

Interactions Which drugs or foods may change the effect of Olpress

Other medicines and Olpress

Tell your doctor or pharmacist if you are taking, have recently taken or might also take any of the following medicines:

Other medicines that lower blood pressure may increase the effect of Olpress 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 the heading: "Do not take Olpress" and "Warnings and precautions")
Potassium supplements, salt substitutes that contain potassium, diuretics or heparin (to thin the blood). The use of these medicines taken together with Olpress can increase the levels of potassium in the blood.
Lithium (a medicine used to treat mood swings and some types of depression) used together with Olpress can increase the toxicity of lithium. If you have to take lithium, your doctor will measure your lithium blood levels.
Non-steroidal anti-inflammatory drugs (NSAIDs, medicines used to decrease pain, swelling and other symptoms of inflammation, including arthritis) used together with Olpress may increase the risk of kidney failure and the effectiveness of Olpress may be reduced by NSAIDs .
Colesevelam hydrochloride, a medicine that lowers cholesterol levels in the blood, which may decrease the effect of Olpress.Your doctor may advise you to take Olpress at least 4 hours before colesevelam hydrochloride
Some antacids (used for indigestion) may slightly reduce the effectiveness of Olpress.

Older people

If you are over 65 years of age and your doctor decides to increase your olmesartan dose to 40 mg a day, your blood pressure should be regularly checked by your doctor to prevent it from falling too low.

Black patients

As with other similar medicines, the blood pressure lowering effect of Olpress is somewhat reduced in black patients.

Taking Olpress with food and drink

Olpress can be taken on a full or empty stomach.

Warnings It is important to know that:

Pregnancy

You should tell your doctor if you think you are pregnant (or if there is a possibility of becoming pregnant). Your doctor will usually advise you to stop taking Olpress before you become pregnant or as soon as you know you are pregnant and will advise you to take another medicine instead of Olpress. Olpress is not recommended for use at all. early pregnancy and must not be taken if you are more than three months pregnant as it may cause serious harm to your baby if taken after the third month of pregnancy.

Feeding time

Tell your doctor if you are breastfeeding or about to start breastfeeding. Olpress is not recommended for women who are breastfeeding, and your doctor may choose another treatment for you if you wish to breastfeed, especially if your baby is just born or premature birth Ask your doctor or pharmacist for advice before taking any medicine.

Driving and using machines

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

Olpress 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 Olpress: Posology

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

The recommended starting dose is one 10 mg tablet once a day. However, if your blood pressure is not controlled, your doctor may decide to increase the dose to 20 or 40 mg once a day, or he may prescribe other medicines. In patients with mild to moderate renal impairment, the dose should not exceed 20 mg once daily.

The tablets can be taken on a full or empty stomach. Swallow the tablets with a sufficient amount of water (for example a glass). If possible, take your daily dose at the same time each day, for example with breakfast.

Overdose What to do if you have taken too much Olpress

If you take more Olpress than you should

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

If you forget to take Olpress

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 tablet.

If you stop taking Olpress

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

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

Side Effects What are the side effects of Olpress

Like all medicines, this medicine can cause side effects, although not everybody gets them. If they do occur, they are mostly mild and do not require discontinuation of treatment.

Although they do not occur in all people, the following two side effects can be serious:

On rare occasions (which may affect up to one in 1000 people), the following allergic reactions that can affect the whole organism have been reported:

Swelling of the face, mouth and / or larynx (seat of the vocal cords) associated with itching and rash may occur during treatment with Olpress. If this happens, stop taking Olpress and contact your doctor immediately.

Rarely (but slightly more often in older people) Olpress can cause excessive reductions in blood pressure in sensitive individuals or as a result of an allergic reaction. This could cause severe dizziness or fainting. If this happens, stop taking Olpress, contact your doctor immediately and stay in a lying position.

These are the other side effects known to date with Olpress:

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

Dizziness, headache, nausea, indigestion, diarrhea, stomach pain, gastroenteritis, fatigue, throat irritation, nasal hypersecretion, bronchitis, flu-like symptoms, cough, pain, chest, back, bone or joint pain, infection urinary tract, swelling of ankles, feet, legs, hands or arms, blood in the urine.

Some changes in laboratory tests have also been observed, including the following: increased blood fat (hypertriglyceridaemia), increased blood uric acid (hyperuricaemia), increased blood urea, increased liver function tests and muscular.

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

Rapid allergic reactions which can affect the whole body and can cause breathing problems or rapid drop in blood pressure which can also lead to fainting (anaphylactic reactions), dizziness, vomiting, weakness, feeling sick, muscle pain, rash, rash allergic, itching, exanthema (rash), skin blisters (wheals), angina (pain or discomfort in the chest). A reduction in the number of a type of particles normally found in the blood, called platelets (thrombocytopenia), has been observed blood analysis.

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

Lack of energy, muscle cramps, decreased kidney function, kidney failure.

Some alterations in laboratory analyzes were also observed. These include increased potassium levels (hyperkalaemia) and increased levels of substances related to kidney function.

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.

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

This medicine does not require any special storage conditions.

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.

Composition and pharmaceutical form

What Olpress contains

The active ingredient is olmesartan medoxomil.

Each film-coated tablet contains 10 mg, 20 mg or 40 mg of olmesartan medoxomil.

The other ingredients are microcrystalline cellulose, lactose monohydrate, hydroxypropylcellulose, low-substituted hydroxypropylcellulose, magnesium stearate, titanium dioxide (E171), talc and hypromellose (see section 2 "Olpress contains lactose").

What Olpress looks like and contents of the pack

Olpress 10 mg white, round, film-coated tablets, engraved with C13 on one side;

Olpress 20 mg white, round, film-coated tablets with C14 debossed on one side;

Olpress 40 mg white, oval, film-coated tablets, debossed with C15 on one side.

Olpress 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 pre-cut single 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 Olpress 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 interaction 04.6 Pregnancy and lactation 04.7 Effects on ability to drive and use machines 04.8 Undesirable effects 04.9 Overdose 05.0 PHARMACOLOGICAL PROPERTIES 05.1 Pharmacodynamic properties 05.2 Pharmacokinetic properties 05.3 Preclinical safety data 06.0 PHARMACEUTICAL PARTICULARS 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 HOLDER 08.0 MARKETING AUTHORIZATION NUMBER O 09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION 10.0 DATE OF REVISION OF THE TEXT 11.0 FOR RADIO DRUGS, COMPLETE DATA ON INTERNAL RADIATION DOSIMETRY 12.0 FOR RADIO DRUGS, ADDITIONAL DETAILED INSTRUCTIONS AND QUALITY CONTROLS

01.0 NAME OF THE MEDICINAL PRODUCT

OLPRESS TABLETS COATED WITH FILM

02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION

Olmesartan medoxomil

Each film-coated tablet contains 10 mg olmesartan medoxomil.

Each film-coated tablet contains 20 mg olmesartan medoxomil.

Each film-coated tablet contains 40 mg olmesartan medoxomil.

Excipients with known effects:

Olpress 10 mg film-coated tablets: each film-coated tablet contains 61.6 mg lactose monohydrate.

Olpress 20 mg film-coated tablets: Each film-coated tablet contains 123.2 mg lactose monohydrate.

Olpress 40 mg film-coated tablets: each film-coated tablet contains 246.4 mg lactose monohydrate.

For the full list of excipients, see section 6.1.

03.0 PHARMACEUTICAL FORM

Film-coated tablet.

OLPRESS 10 mg and 20 mg: white, round, film-coated tablets engraved with C13 and C14 respectively on one side

OLPRESS 40 mg: White, oval-shaped film-coated tablets with C15 debossed on one side

04.0 CLINICAL INFORMATION

04.1 Therapeutic indications

Treatment of essential arterial hypertension.

04.2 Posology and method of administration

Dosage:

Adults

The recommended starting dose of olmesartan medoxomil is 10 mg once daily. In patients for whom this dosage does not ensure adequate blood pressure control, the dose of olmesartan medoxomil can be increased to 20 mg once daily as the optimal dose. If further reduction in blood pressure is required, the dose of olmesartan medoxomil can be further increased to a maximum of 40 mg per day or combined with hydrochlorothiazide therapy.

The antihypertensive effect of olmesartan medoxomil is substantially achieved within 2 weeks of initiation of therapy and reaches its maximum level within approximately 8 weeks of initiation of treatment. These data should be taken into account when planning dose adjustments for any patient.

Older people (65 years or older)

Dosage adjustments are generally not required in elderly people (see below for dosage recommendations in patients with impaired renal function). If administration of the maximum dose of 40 mg per day is required, blood pressure should be carefully monitored.

Altered kidney function

The maximum dosage in patients with mild or moderate renal impairment (creatinine clearance between 20 and 60 ml / min) is 20 mg olmesartan medoxomil once daily due to limited clinical experience with higher doses in this patient group. . The use of olmesartan medoxomil in patients with severe renal impairment (creatinine clearance less than 20 ml / min) is not recommended due to limited clinical experience in this patient group (see sections 4.4 and 5.2).

Altered liver function

No dosage adjustments are required for patients with mild hepatic impairment. 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. In patients with hepatic impairment taking diuretics and / or other antihypertensive drugs, careful monitoring of blood pressure and renal function is advised. There is no experience of the use of olmesartan medoxomil in patients with severe hepatic impairment, therefore use in this patient group is not recommended (see sections 4.4 and 5.2). Olmesartan medoxomil must not be used in patients with biliary obstruction (see section 4.3).

Pediatric population

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

Method of administration:

For better compliance, it is recommended that you take your Olpress tablets at approximately the same time each day, either on an empty stomach or on a full stomach, for example with breakfast. The tablets should be swallowed with a sufficient amount of liquid (eg a glass of water). The tablets should not be chewed.

04.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

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

Biliary obstruction (see section 5.2).

The concomitant use of Olpress with aliskiren-containing products is contraindicated in patients with diabetes mellitus or renal impairment (GFR 2) (see sections 4.5 and 5.1).

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 olmesartan medoxomil.

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

In patients whose vascular tone and renal function are primarily dependent on the activity of the renin-angiotensin-aldosterone system (eg, patients with severe congestive heart failure or with kidney disease, including renal artery stenosis), treatment with other drugs that affect this system it has been associated with acute hypotension, azotemia, oliguria or, in rare cases, acute renal failure. The possibility of similar effects cannot be excluded with angiotensin II receptor antagonists.

Renovascular hypertension:

In patients with bilateral renal artery stenosis, 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 severe hypotension and renal failure.

Altered kidney function and kidney transplant:

If olmesartan medoxomil is administered to patients with impaired renal function, periodic monitoring of serum potassium and creatinine levels is recommended. The use of olmesartan medoxomil is not recommended in patients with severe renal impairment (creatinine clearance less than 20 ml / min) (see sections 4.2, 5.2). There is no experience of the administration of olmesartan medoxomil in patients recently undergoing kidney transplantation or in patients with end stage renal insufficiency (creatinine clearance

Impaired liver function:

There is no experience in patients with severe hepatic impairment, and therefore the use of olmesartan medoxomil is not recommended in this patient group (see section 4.2 for dose adjustments in patients with mild or moderate hepatic impairment).

Hyperkalaemia:

The use of drugs that affect the renin-angiotensin-aldosterone system can lead to hyperkalaemia. The risk, which can be fatal, is increased in the elderly, in patients with renal insufficiency, in diabetics, in patients taking concomitant other drugs in able to increase blood potassium and / or in patients with intercurrent events.

Before considering concomitant use of drugs affecting the renin-angiotensin-aldosterone system, the benefit-risk ratio should be assessed and other options considered (see also section below "Dual blockade of the renin-angiotensin-aldosterone system. (RAAS) ".

The main risk factors to consider for hyperkalaemia are:

- Diabetes, renal impairment, age (> 70 years),

- Association with one or more drugs that affect the renin-angiotensin-aldosterone system and / or potassium supplements. Certain drugs or therapeutic classes of drugs can cause hyperkalaemia: potassium-containing salt substitutes, potassium-sparing diuretics, ACE inhibitors, angiotensin II receptor antagonists, non-steroidal anti-inflammatory drugs (including selective COX-2 inhibitors), heparin, immunosuppressants such as cyclosporine or tacrolimus, trimethoprim,

- Intercurrent events, in particular dehydration, acute heart failure, metabolic acidosis, worsening of renal function, sudden worsening of kidney conditions (e.g. infections), cell lysis (e.g. acute limb ischemia, rhabdomyolysis, extensive trauma).

In patients at risk, careful monitoring of serum potassium levels should be performed (see section 4.5).

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

There is evidence that 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 the 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 block therapy is considered absolutely necessary, this should only be done under the supervision of a specialist and with close and frequent monitoring of kidney function, electrolytes and blood pressure.

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

Lithium:

As with other angiotensin II antagonists, the combination of lithium and olmesartan medoxomil is not recommended (see section 4.5).

Stenosis of the aortic or mitral valve; obstructive hypertrophic myocardiopathy:

As with other vasodilators, special 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 drugs acting by inhibition of the renin-angiotensin system. Therefore, the use of olmesartan medoxomil is not recommended in the treatment of these patients.

Sprue-like enteropathy:

In very rare cases, chronic diarrhea with significant weight loss, possibly caused by a delayed localized hypersensitivity reaction, has been reported in patients receiving olmesartan for a few months or years. Intestinal biopsies from patients often revealed villous atrophy. If a patient experiences these symptoms during treatment with olmesartan other etiologies should be excluded. Discontinuation of olmesartan medoxomil should be considered in cases where no "other etiology is identified."

In cases where symptoms disappear and sprue-like enteroparia is confirmed by a biopsy, treatment with olmesartan medoxomil should not be restarted.

Ethnic differences:

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

Pregnancy:

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

Other:

As with any antihypertensive agent, an excessive decrease in blood pressure in patients with ischemic heart disease or ischemic cerebrovascular disease can cause myocardial infarction or stroke.

This drug contains lactose. Patients with rare hereditary problems of galactose intolerance, lactase deficiency or glucose-galactose malabsorption should not take this drug.

04.5 Interactions with other medicinal products and other forms of interaction

Interaction studies have only been performed in adults.

Effects of other medicinal products on olmesartan medoxomil

Other antihypertensive drugs:

The hypotensive effect caused by olmesartan medoxomil may be potentiated by the concomitant use of other antihypertensive drugs.

ACE inhibitors, angiotensin II receptor antagonists or aliskiren

Clinical trial data have 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 agent active on the RAAS system (see sections 4.3, 4.4 and 5.1).

Potassium supplements and potassium-sparing diuretics:

Clinical experience indicates that the use of other drugs that affect the renin-angiotensin system in combination with potassium-sparing diuretics, potassium supplements, potassium-containing salt substitutes or other drugs capable of increasing serum potassium levels (eg heparin) may cause an increase in serum potassium (see section 4.4). Such concomitant use is therefore not recommended.

Non-steroidal anti-inflammatory drugs (NSAIDs)

NSAIDs (including acetylsalicylic acid at doses> 3 g / day and COX-2 inhibitors) and angiotensin II receptor antagonists may act synergistically by reducing glomerular filtration. The risk of concomitant use of NSAIDs and angiotensin II antagonists is acute renal failure. It is recommended to monitor renal function at the start of treatment and to hydrate the patient regularly.

Furthermore, concomitant treatment may reduce the antihypertensive effect of angiotensin II receptor antagonists, leading to their partial loss of efficacy.

Colesevelam, bile acid sequestering agent

Concomitant administration of the bile acid sequestering colesevelam hydrochloride reduces the systemic exposure, maximum plasma concentration and t½ of olmesartan. Administration of olmesartan medoxomil at least 4 hours prior to colesevelam hydrochloride reduces the effect of this drug interaction. Administration of olmesartan medoxomil at least 4 hours prior to the colesevelam hydrochloride dose should be considered (see section 5.2).

Other drugs

After treatment with antacids (magnesium aluminum hydroxide), a modest reduction in the bioavailability of olmesartan was observed. Concomitant administration of warfarin and digoxin has no effect on the pharmacokinetics of olmesartan.

Effects of olmesartan medoxomil on other medicinal products

Lithium:

Reversible increases in serum lithium concentrations and its toxicity have been reported during administration of lithium in combination with angiotensin converting enzyme inhibitors and angiotensin II antagonists. Therefore, the use of olmesartan medoxomil and lithium in combination is not recommended (see section 4.4). If the use of this combination is deemed necessary, careful monitoring of serum lithium levels is recommended.

Other drugs:

Warfarin, digoxin, an antacid (magnesium aluminum hydroxide), hydrochlorothiazide and pravastatin were studied in specific clinical studies conducted in healthy volunteers. No relevant clinical interactions were observed and, in particular, olmesartan medoxomil had no significant effect on the pharmacokinetics or pharmacodynamics of warfarin or on the pharmacokinetics of digoxin.

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. Therefore, no in vivo interaction studies have been performed with known cytochrome P450 inhibitors and enzyme inducers, and clinically relevant interactions between olmesartan and drugs metabolised by the aforementioned cytochrome P450 enzymes are not expected.

04.6 Pregnancy and lactation

Pregnancy

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 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 receptor antagonists are not available, a similar risk may also exist for this class of medicinal products. Alternative antihypertensive treatments with a proven safety profile for use in pregnancy should be used for patients planning pregnancy unless continued angiotensin II receptor antagonist therapy is considered essential. 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 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) in women. ) (see also section 5.3 "Preclinical safety data").

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

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

Feeding time:

Olmesartan is excreted in the breast milk of rats, but it is not known whether the same occurs in human milk. As no data are available regarding the use of Olpress during breastfeeding, Olpress is not recommended and alternative treatments with a proven safety profile for use during breastfeeding are preferred, especially when breastfeeding a newborn or preterm infant.

04.7 Effects on ability to drive and use machines

Olpress has mild or moderate effects 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

Summary of the safety profile:

The most commonly reported adverse reactions during treatment with Olpress are headache (7.7%), flu-like symptoms (4.0%) and dizziness (3.7%).

In the placebo-controlled monotherapy studies, the only unequivocal adverse reaction related to treatment was dizziness (2.5% incidence with olmesartan medoxomil and 0.9% with placebo). The incidence was also somewhat higher with olmesartan medoxomil compared to placebo for hypertriglyceridaemia (2.0% versus 1.1%) and for the increase in creatine phosphokinase (1.3% versus 0, 7%).

Tabulated list of adverse reactions:

The following table summarizes the adverse reactions from Olpress observed in clinical studies, post-registration safety studies and spontaneously reported.

The following terminology has been used to classify the frequency of adverse reactions: very common (≥1 / 10); common (≥1 / 100,

MedDRA Classification for Organs and Systems Adverse reactions Frequency Disorders of the blood and lymphatic system Thrombocytopenia Uncommon Disorders of the immune system Anaphylactic reaction Uncommon Metabolism and nutrition disorders Hypertriglyceridemia common Hyperuricemia common Hyperkalaemia Rare Nervous system disorders Dizziness common Headache common Ear and labyrinth disorders Dizziness Uncommon Cardiac pathologies Angina pectoris Uncommon Vascular pathologies Hypotension Rare Respiratory, thoracic and mediastinal disorders Bronchitis common Pharyngitis common Cough common Rhinitis common Gastrointestinal disorders Gastroenteritis common Diarrhea common Abdominal pain common Nausea common Dyspepsia common He retched Uncommon Sprue-like enteropathy (see section 4.4) Very rare Skin and subcutaneous tissue disorders Rash Uncommon Allergic dermatitis Uncommon Urticaria Uncommon Rash Uncommon Itching Uncommon Angioedema Rare Musculoskeletal and connective tissue disorders Arthritis common Back pain common Skeletal pain common Myalgia Uncommon Muscle spasms Rare Renal and urinary disorders Hematuria common Urinary tract infections common Acute renal failure Rare Kidney failure Rare General disorders and administration site conditions Ache common Chest pain common Peripheral edema common Flu-like symptoms common Fatigue common Face edema Uncommon Asthenia Uncommon Malaise Uncommon Lethargy Rare Diagnostic tests Increased liver enzymes common Increased plasma urea common Increased creatine phosphokinase common Increased blood creatinine Rare

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

Additional information on special populations

In older people, the frequency of hypotension is slightly increased from rare to uncommon.

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions occurring after authorization of the medicinal product is important as it allows continuous monitoring of the benefit / risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system. "address: www.agenziafarmaco.gov.it/it/responsabili.

04.9 Overdose

Only limited data are available regarding overdose in humans. The most likely effect of overdose is hypotension. In the event of an overdose, the patient should be closely monitored and treatment should be symptomatic and supportive.

There are no data on the dialysability of olmesartan.

05.0 PHARMACOLOGICAL PROPERTIES

05.1 Pharmacodynamic properties

Pharmacotherapeutic group: angiotensin II antagonists.

ATC code: CO9CA08.

Mechanism of action / Pharmacodynamic effects

Olmesartan medoxomil is a potent orally effective selective angiotensin II receptor antagonist (type AT1). Its effect is to block all AT1 receptor-mediated angiotensin II activities, regardless of origin and route of synthesis. "angiotensin II. Selective angiotensin II receptor antagonism (AT1) produces an increase in plasma renin levels and angiotensin I and II concentrations and a decrease in plasma aldosterone concentrations.

Angiotensin II is the main vasoactive hormone of the renin-angiotensin-aldosterone system and plays a significant role in the pathophysiology of hypertension by means of the type 1 receptor (AT1).

Clinical efficacy and safety

In cases of hypertension, olmesartan medoxomil results in a dose-dependent, long-term reduction in blood pressure. There are no reports of hypotension after the first administration, of tachyphylaxis during prolonged treatments or of rebound hypertension on discontinuation of therapy.

The once-a-day administration of olmesartan medoxomil ensures an effective and constant reduction of blood pressure in the 24-hour interval between one dose and the next. With the same overall dosage, once-daily administration produced the same results in decreasing blood pressure. compared to administering the drug twice a day.

With continued treatment, the maximum reduction in blood pressure is achieved within 8 weeks after initiation of therapy, although a substantial decrease in blood pressure is already observed after 2 weeks of treatment.When used in combination with hydrochlorothiazide, there is a further decrease in blood pressure and co-administration is well tolerated.

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

The Randomized Olmesartan and Diabetes Microalbuminuria Prevention (ROADMAP) study, conducted in 4,447 patients with type 2 diabetes, normoalbuminuria and at least one additional cardiovascular risk factor, investigated whether treatment with olmesartan could delay the onset of microalbuminuria. During the median follow-up period of 3.2 years, patients received olmesartan or placebo plus other antihypertensive drugs excluding ACE inhibitors or sartans.

The study demonstrated a significant risk reduction in terms of increased time to onset of microalbuminuria (primary endpoint) in favor of olmesartan. After adjustment for blood pressure values, this risk reduction was no longer statistically significant. 8.2% (178 out of 2160) of the patients in the olmesartan group and 9.8% (210 out of 2139) in the placebo group experienced microalbuminuria.

Regarding the secondary endpoints, cardiovascular events occurred in 96 patients (4.3%) in the olmesartan group and in 94 patients (4.2%) in the placebo group. The incidence of cardiovascular mortality was higher in the olmesartan group than in the placebo group (15 patients [0.7%] vs. 3 patients [0.1%]), despite similar values 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 higher (26 patients [1.2%]) vs 15 patients [0.7%]) mainly due to a greater number of fatal cardiovascular events.

The Olmesartan Reducing Incidence of End-stage Renal Disease in Diabetic Nephropathy Trial (ORIENT) study evaluated the effects of olmesartan on renal and cardiovascular events in 577 Chinese and Japanese patients with type 2 diabetes and overt nephropathy. During the median follow-up period of 3.1 years, patients received olmesartan or placebo plus other antihypertensive drugs including ACE inhibitors.

The primary composite endpoint (time to first serum creatinine doubling event, end-stage nephropathy, death from all causes) occurred in 116 patients in the olmesartan group (41.1%) and 129 patients in the placebo group (45.4 %) (HR 0.97 [95% CI 0.75-1.24]; p = 0.791). The composite cardiovascular secondary 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 patients (3.5%) receiving olmesartan versus 3. patients (1.1%) receiving placebo, total mortality 19 (6.7%) vs 20 (7.%), non-fatal stroke 8 (2.8%) vs 11 (3.9%) and non-fatal myocardial infarction 3 (1.1%) vs 7 (2.5%), respectively.

Other information:

Two large randomized 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 antagonist of the angiotensin II receptor.

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

These studies did not demonstrate any significant beneficial effect on renal and / or cardiovascular outcomes and mortality, while an increased risk of hyperkalaemia, acute renal injury and / or hypotension was observed compared to monotherapy.

These results are also relevant for other ACE inhibitors and angiotensin II receptor antagonists, given their similar pharmacodynamic properties.

ACE inhibitors and angiotensin II receptor antagonists should therefore not be used simultaneously in patients with diabetic nephropathy.

ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints) was a study aimed at verifying the advantage of adding aliskiren to standard therapy of an ACE inhibitor or angiotensin II receptor antagonist in patients with diabetes mellitus. type 2 and chronic kidney disease, cardiovascular disease, or both. The study was terminated early due to an increased risk of adverse events. 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 reported more frequently in the aliskiren group than in the placebo group.

05.2 Pharmacokinetic properties

Absorption and distribution

Olmesartan medoxomil is a pro-drug rapidly converted to a pharmacologically active metabolite, 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 plasma 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 co-administered highly bound drugs is low (as confirmed by the "absence 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 administration is small (16-29 l).

Biotransformation and elimination

Total plasma clearance was 1.3 l / h (CV 19%), relatively low when compared to hepatic flow (approx. 90 l / h). Following a single oral dose of 14C-labeled olmesartan medoxomil, 10-16% of the administered radioactivity was excreted in the urine (largely within 24 hours following administration), while the remaining radioactivity was eliminated with the feces. 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 varies between 10 and 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. Clearance renal rate was approximately 0.5-0.7 L / h and was independent of the dose.

Pharmacokinetics in special patient groups

Older people (65 years or older):

In hypertensive patients, steady state AUC was approximately 35% higher in older people (65 to 75 years old) and about 44% higher in very old people (3 75 years old) than in younger patients This may be due, at least in part, to a mean decrease in renal function in this patient group.

Altered kidney function:

In cases of renal impairment, steady state AUC was 62%, 82% and 179% higher in patients with mild, moderate and severe renal impairment, respectively, compared to subjects with normal renal function (see sections 4.2, 4.4 ).

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. The unbound fraction of olmesartan two hours after dosing 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. The mean C values of olmesartan were similar in patients with impaired hepatic function and in the healthy subjects Olmesartan medoxomil has not been studied in patients with severe hepatic impairment (see sections 4.2, 4.4).

Drug interactions

Colesevelam, bile acid sequestering agent

Concomitant administration of 40 mg olmesartan medoxomil and 3750 mg colesevelam hydrochloride to healthy subjects resulted in a 28% reduction in Cmax and 39% in AUC of olmesartan. Minor effects, 4% and 15% reduction, respectively, in Cmax and AUC were observed when olmesartan medoxomil was administered 4 hours prior to colesevelam hydrochloride. The elimination half-life of olmesartan was reduced by 50-52% regardless of concomitant administration or 4 hours prior to colesevelam hydrochloride (see section 4.5).

05.3 Preclinical safety data

In chronic toxicity studies in rats and dogs, olmesartan medoxomil showed similar effects to other ACE inhibitors and AT1 receptor antagonists: increased urea nitrogen (BUN) and creatinine (due to functional changes in the kidney caused by receptor blockade AT1); weight reduction of the heart; reduction of erythocitrar parameters (erythrocytes, hemoglobin, hematocrit); histological indications of renal damage (regenerative lesions of the renal epithelium, thickening of the basement membrane, dilation of the tubules). These adverse effects caused by the pharmacological action of olmesartan medoxomil have also occurred during preclinical trials on other ACE inhibitors and AT1 receptor antagonists and can be reduced by the simultaneous administration of sodium chloride.

In both species, increased plasma renin activity and hypertrophy / hyperplasia of renal juxtaglomerular cells were observed. These changes, which represent a typical effect of the class of ACE inhibitors and other AT1 receptor antagonists, do not seem to be of relevance. clinic.

Like other AT1 receptor antagonists, olmesartan medoxomil causes an increased incidence of chromosomal breaks in in vitro cell cultures. No relevant effects have been observed in numerous in vivo studies in which olmesartan medoxomil was administered at very high oral doses up to 2000. mg / kg Overall data from genotoxicity tests suggest that olmesartan is very unlikely to exhibit genotoxic effects under conditions of clinical use.

Olmesartan medoxomil was not carcinogenic, neither in rats in 2-year studies nor in mice studied in two 6-month carcinogenicity studies using transgenic models.

In reproduction studies in rats, olmesartan medoxomil did not impair fertility and there was no indication of teratogenic effects. Like other angiotensin II antagonists, offspring survival was reduced following exposure to olmesartan medoxomil and dilation of the renal pelvis was observed following exposure of females during late pregnancy and during pregnancy. feeding time. As with other antihypertensive agents, olmesartan medoxomil showed a higher toxic potential in rabbits than in pregnant rats. However, no indications of foetotoxic effects were found.