Active ingredients: Olmesartan medoxomil, Hydrochlorothiazide
PLAUNAZIDE 40 mg / 12.5 mg film-coated tablets
PLAUNAZIDE 40 mg / 25 mg film-coated tablets
Plaunazide package inserts are available for pack sizes: - PLAUNAZIDE 40 mg / 12.5 mg film-coated tablets, PLAUNAZIDE 40 mg / 25 mg film-coated tablets
- PLAUNAZIDE 20 mg / 12.5 mg film-coated tablets, PLAUNAZIDE 20 mg / 25 mg film-coated tablets
Why is Plaunazide used? What is it for?
Plaunazide contains two active substances called olmesartan medoxomil and hydrochlorothiazide, which are used to treat high blood pressure (hypertension).
- Olmesartan medoxomil belongs to a group of medicines called 'angiotensin II receptor antagonists'. It lowers blood pressure by releasing the blood vessels.
- Hydrochlorothiazide belongs to a group of medicines called 'diuretics'. It lowers blood pressure by helping the body to eliminate excess fluid by making the kidneys produce more urine.
You will be given Plaunazide if Plaunac (olmesartan medoxomil) alone has not adequately controlled your blood pressure. When given together, the two active substances in Plaunazide help lower blood pressure more than they do when given alone.
You may already be taking medicines to treat high blood pressure, but your doctor may give you Plaunazide to get a further reduction.
High blood pressure can be controlled with medicines such as Plaunazide 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 Plaunazide should not be used
Do not take Plaunazide
- if you are allergic to olmesartan medoxomil or hydrochlorothiazide, or any of the other ingredients of this medicine or substances similar to hydrochlorothiazide (sulphonamides).
- if you are more than three months pregnant (it is advisable to avoid the use of Plaunazide even during the first months of pregnancy - see the "pregnancy" section).
- if you have kidney problems.
- if you have diabetes or impaired kidney function and you are being treated with a blood pressure lowering medicine containing aliskiren
- if you have low levels of potassium or sodium, or if you have high levels of calcium or uric acid (with symptoms of gout or kidney stones) in your blood which do not improve following treatment.
- if you have moderate or 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 you take Plaunazide
Talk to your doctor before using PLAUNAZIDE.
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" (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 Plaunazide"
Before taking this medicine, consult your doctor if you also have any of the following health problems:
- Kidney transplant.
- Liver disease.
- 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
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.
Your doctor may want to see you more often and do some tests if you have any of the previous conditions.
Plaunazide can cause increased levels of fat and uric acid (causing gout - painful swelling of the joints) in the blood. Your doctor will probably want to have periodic blood tests to evaluate these conditions.
It can alter the levels of certain substances, called electrolytes, in the blood. Your doctor will likely want to do 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, apathy, tiredness, sleepiness or restlessness, nausea, vomiting, reduced need to urinate, accelerated heart rate. Tell your doctor if these symptoms appear.
As with any medicine that lowers blood pressure, too much blood pressure reduction in patients with blood flow 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 have to have parathyroid function tests, you must stop taking Plaunazide before doing these tests.
If you play sports, this drug can alter the results of a doping test, making it positive.
You should tell your doctor if you think you are pregnant or becoming pregnant. Plaunazide 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
Plaunazide is not recommended for children and adolescents under 18 years of age.
Interactions Which drugs or foods can modify the effect of Plaunazide
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 Plaunazide. 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 Plaunazide "and" Warnings and precautions ")
- Medicines which can cause changes in blood potassium levels when used concomitantly with Plaunazide. These include: o potassium supplements (such as potassium-containing salt substitutes) o diuretics o heparin (to thin the blood) o laxatives o steroids o adrenocorticotropic hormone (ACTH) o carbenoxolone (a medicine used to treat mouth and stomach ulcers) o penicillin G sodium (also called benzylpenicillin sodium, an antibiotic) o some pain relievers such as aspirin or salicylates
- Lithium (a medicine used to treat mood swings and some types of depression) used together with Plaunazide 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 Plaunazide may increase the risk of kidney failure. The efficacy of Plaunazide may be reduced by NSAIDs. .
- Sleeping pills, sedatives and antidepressants used together with Plaunazide 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 drugs used to treat cancer, such as cyclophosphamide or methotrexate
- Colestyramine and colestipol, medicines to reduce fat in the blood
- Colesevelam hydrochloride, a medicine that lowers blood cholesterol levels, which may decrease the effect of Plaunazide. Your doctor may advise you to take Plaunazide at least 4 hours before colesevelam hydrochloride.
- Anticholinergic drugs, such as atropine and biperidene
- Drugs such as thioridazine, chlorpromazine, levomepromazine, trifluoperazine, ciamemazine, sulpiride, amisulpride, pimozide, sultopride, thiapride, droperidol or haloperidol, used to treat some psychiatric diseases
- Some 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 blood glucose levels
- Beta-blockers and diazoxide, medicines used to treat high blood pressure or low blood sugar, respectively, as Plaunazide may increase their hypotensive and 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 drug
- Ciclosporin, a medicine used to stop the rejection of transplanted organs
- Certain antibiotics called tetracyclines or sparfloxacin
- Amphotericin, a medicine used to treat fungal infections
- Some antacids, used for stomach acid, such as magnesium aluminum hydroxide, may slightly reduce the effectiveness of Plaunazide.
- Cisapride, used to increase the movement of food in the stomach and intestines
- Halofantine, used for malaria
Plaunazide with food and drink
Plaunazide can be taken with or without food. Take care to drink alcohol while taking Plaunazide, as some people may feel faint or dizzy. If this happens to you, do not drink any other alcohol, including wine, beer or carbonated alcoholic drinks.
Black patients
As with other similar medicines, the blood pressure lowering effect of Plaunazide may be somewhat reduced in black patients.
Warnings It is important to know that:
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 Plaunazide before you become pregnant or as soon as you know you are pregnant and will advise you to take another medicine instead of Plaunazide. Plaunazide is not recommended during pregnancy and is not recommended. must 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. Plaunazide 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 breastfeeding, think you may be pregnant or are planning to become pregnant, ask your doctor or pharmacist for advice before taking this medicine.
Driving and using machines
You may feel sleepy or dizzy while being treated for high blood pressure. If this happens, do not drive or use machines until the symptoms have disappeared. Consult your doctor for advice.
Plaunazide 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 Plaunazide: Posology
Always take this medicine exactly as your doctor has told you. If you are unsure, consult your doctor or pharmacist.
The recommended dose is one Plaunazide 40 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 Plaunazide 40 mg / 25 mg tablet per day.
Swallow the tablets with some water. If possible, take your dose at the same time each day, for example with breakfast. It is important to keep taking Plaunazide until your doctor tells you to stop.
Overdose What to do if you have taken too much Plaunazide
If you take more Plaunazide than you should
If you take more tablets than you should or if a child accidentally swallows one or more tablets, go to your doctor or the nearest emergency department immediately and take the medicine pack with you.
If you forget to take Plaunazide
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 taking Plaunazide
It is important to continue taking Plaunazide unless your doctor tells you to stop.
If you have any further questions on the use of this medicine, ask your doctor or pharmacist.
Side Effects What are the side effects of Plaunazide
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 Plaunazide and contact your doctor immediately.
- Plaunazide can cause an excessive reduction in blood pressure in susceptible individuals or as a result of an allergic reaction. Dizziness or fainting may occur uncommonly. If this happens, stop taking Plaunazide, contact your doctor immediately and lie down.
Plaunazide is a combination of two active substances and the following information first mentions the other side effects reported so far with the combination Plaunazide (in addition to those already mentioned above) and then those known for the separate active substances.
Other known side effects of Plaunazide so far:
If these side effects occur, they are often mild and treatment with Plaunazide should not be stopped.
Common side effects (may affect up to 1 in 10 people):
Dizziness, weakness, headache, tiredness, chest pain, swelling of the 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 cramps, muscle pain, joint pain, arm and leg pain, back pain, difficulty moving erection in men, blood in urine. Some changes in laboratory tests have also been observed uncommonly including: increased levels of fat in the blood, increased levels of urea or uric acid in the blood, increased creatinine, increased or decrease in blood potassium levels, increase in blood calcium levels, increase in blood glucose, increase in liver function indices Your doctor will find out from your blood tests and tell you if anything needs to be done.
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: increase in blood urea nitrogen, decrease in hemoglobin and hematocrit values. Your doctor will learn about this from your blood tests and will tell you if necessary. do something.
Additional undesirable effects reported with the use of olmesartan medoxomil or hydrochlorothiazide alone, but not with Plaunazide or with a higher frequency
Olmesartan medoxomil
Common side effects (may affect up to 1 in 10 people):
Bronchitis, cough, runny or stuffy nose, sore throat, abdominal pain, indigestion, diarrhea, nausea, gastroenteritis, joint or bone pain, back pain, blood in urine, urinary tract infection, flu-like symptoms , ache.
Some changes in laboratory tests have also been observed commonly including: increased blood fat 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):
Immediate allergic reactions which can affect the whole body and which can cause breathing problems or a rapid drop in blood pressure which can also lead to fainting (anaphylactic reactions), swelling of the face, angina (pain or uncomfortable feeling in the chest, known as angina pectoris), feeling sick, allergic skin reaction, itching, exanthema (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 increases in blood potassium.
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):
Decreased 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):
Painful and swollen 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 in blood chloride levels (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 "https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse". 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.
What Plaunazide contains
The active ingredients are:
Plaunazide 40 mg / 12.5 mg: Each film-coated tablet contains 40 mg of olmesartan medoxomil and 12.5 mg of hydrochlorothiazide.
Plaunazide 40 mg / 25 mg: Each film-coated tablet contains 40 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 "Plaunazide contains lactose" above.
What Plaunazide looks like and contents of the pack
Plaunazide 40 mg / 12.5 mg, film-coated, oval, 15x7 mm, yellowish-red tablets, debossed with "C23" on one side;
Plaunazide 40 mg / 25 mg, oval, 15x7 mm, pink film-coated tablets, debossed with "C25" on one side.
Plaunazide is available in packs of 14, 28, 30, 56, 84, 90, 98, 10x28, 10x30 film-coated tablets, and in packs of 10, 50 and 500 film-coated tablets with pre-cut 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.
01.0 NAME OF THE MEDICINAL PRODUCT
PLAUNAZIDE TABLETS COATED WITH FILM
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
Plaunazide 40 mg / 12.5 mg film-coated tablets:
each film-coated tablet contains 40 mg of olmesartan medoxomil and 12.5 mg of hydrochlorothiazide
Plaunazide 40 mg / 25 mg film-coated tablets:
each film-coated tablet contains 40 mg of olmesartan medoxomil and 25 mg of hydrochlorothiazide
Excipients with known effects:
Plaunazide 40 mg / 12.5 mg film-coated tablets: each film-coated tablet contains 233.9 mg of lactose monohydrate
Plaunazide 40 mg / 25 mg film-coated tablets: each film-coated tablet contains 221.4 mg of lactose monohydrate
For the full list of excipients, see section 6.1
03.0 PHARMACEUTICAL FORM
Film-coated tablet.
Plaunazide 40 mg / 12.5 mg film-coated tablets: reddish-yellow, oval-shaped, 15x7 mm film-coated tablets, debossed with C23 on one side
Plaunazide 40 mg / 25 mg film-coated tablets: Pink, oval-shaped, 15x7 mm film-coated tablets, debossed on one side with the initials C25
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Treatment of essential arterial hypertension.
Plaunazide 40 mg / 12.5 mg and 40 mg / 25 mg, fixed combinations, are indicated in adult patients whose blood pressure is not adequately controlled by olmesartan medoxomil 40 mg alone.
04.2 Posology and method of administration
Dosage
Adults
The recommended dose of Plaunazide 40 mg / 12.5 mg or 40 mg / 25 mg is one tablet per day.
Plaunazide 40 mg / 12.5 mg can be administered in patients whose blood pressure is not adequately controlled by olmesartan medoxomil 40 mg alone.
Plaunazide 40 mg / 25 mg can be administered in patients whose blood pressure is not adequately controlled by Plaunazide 40 mg / 12.5 mg fixed combination.
For ease of use, patients receiving olmesartan medoxomil and hydrochlorothiazide as separate tablets can switch to treatment with Plaunazide 40 mg / 12.5 mg or 40 mg / 25 mg tablets, containing the same amounts of active substances.
Plaunazide 40 mg / 12.5 mg and 40 mg / 25 mg can be taken either fasted or fed.
Elderly patients (aged 65 and over)
The same posology as the combination used in adults is recommended in elderly patients. Blood pressure should be carefully monitored.
Renal impairment
Plaunazide is contraindicated in patients with severe renal impairment (creatinine clearance less than 30 ml / min). The maximum dose of olmesartan medoxomil in patients with mild to moderate renal impairment (creatinine clearance 30-60 ml / min) is 20 mg olmesartan medoxomil once daily due to limited experience with higher doses in this group. of patients, and periodic monitoring is recommended. Therefore, Plaunazide 40 mg / 12.5 mg and 40 mg / 25 mg are contraindicated in all stages of renal impairment (see sections 4.3, 4.4, 5.2).
Hepatic impairment
Plaunazide 40 mg / 12.5 mg and 40 mg / 25 mg should be used with caution in patients with mild hepatic impairment (see sections 4.4, 5.2). Close monitoring of blood pressure and renal function is advised in patients with impaired hepatic function taking diuretics and / or other antihypertensive drugs. 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. There is no experience on the use of olmesartan medoxomil in patients with severe hepatic impairment. Plaunazide 40 mg / 12.5 mg and 40 mg / 25 mg should therefore not be used in patients with moderate and severe hepatic impairment (see sections 4.3 , 5.2), as well as in patients with cholestasis and biliary obstruction (see section 4.3).
Pediatric population
The safety and efficacy of Plaunazide 40 mg / 12.5 mg and 40 mg / 25 mg in children and adolescents below 18 years of age have not been established. 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 or to any of the excipients (listed in section 6.1) or to other sulphonamide-derived substances (since hydrochlorothiazide is a sulphonamide-derived drug).
Renal impairment (see sections 4.4 and 5.2).
Refractory hypokalaemia, hypercalcemia, hyponatremia and symptomatic hyperuricemia.
Moderate and severe hepatic impairment, cholestasis and obstructive biliary disorders (see section 5.2).
Second and third trimester of pregnancy (see sections 4.4 and 4.6).
The concomitant use of Plaunazide 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 Plaunazide.
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 it has been associated with acute hypotension, azotaemia, oliguria or, in rare cases, acute renal failure with medicinal products affecting this system.
Renovascular hypertension:
In patients with bilateral renal artery stenosis, or stenosis of the afferent artery to a single functioning kidney, treated with medicinal products that affect the renin-angiotensin-aldosterone system, there is an increased risk of severe hypotension and renal failure.
Renal impairment and renal transplant:
Plaunazide should not be used in patients with severe renal impairment (creatinine clearance less than 30 ml / min). The maximum dose of olmesartan medoxomil in patients with mild to moderate renal impairment (creatinine clearance 30-60 ml / min) is 20 mg olmesartan medoxomil once daily. However, in these patients Plaunazide 20 mg / 12.5 mg and 20 mg / 25 mg should be administered with caution and periodic monitoring of serum potassium, creatinine and uric acid is recommended. Azotaemia associated with the use of thiazide diuretics may occur in patients with impaired renal function. If progressive renal impairment occurs, careful re-evaluation of therapy is required, considering discontinuation of the diuretic. Therefore, Plaunazide 40 mg / 12, 5 mg and 40 mg / 25 mg are contraindicated in all stages of renal impairment (see section 4.3).
There is no experience with the administration of Plaunazide in patients who have recently undergone kidney transplantation.
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.
Hepatic impairment:
There is currently no experience with olmesartan medoxomil in patients with severe hepatic impairment. In patients with moderate hepatic impairment, the maximum dose of olmesartan medoxomil is 20 mg once daily. In addition, slight changes in the water and electrolyte balance during thiazide therapy can induce hepatic coma in patients with impaired hepatic function or progressive liver disease. The use of Plaunazide 40 mg / 12.5 mg and 40 mg / 25 mg is therefore contraindicated in patients with moderate to severe hepatic impairment, cholestasis and biliary obstruction (see sections 4.3, 5.2). Caution should be exercised in patients with mild hepatic impairment (see section 4.2).
Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy:
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 Plaunazide 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, 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 Plaunazide, 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 may induce increases in serum potassium (such as heparin) should be administered with caution when taking Plaunazide (see section 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 excretion of calcium 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 should be discontinued prior to examination. parathyroid function.
Thiazides have been shown to increase urinary excretion of magnesium, with possible hypomagnesaemia.
In oedematous patients, exposed to high atmospheric temperatures, dilution hyponatremia may occur.
Lithium:
As with other angiotensin II receptor antagonists, concomitant administration of lithium and Plaunazide is not recommended (see section 4.5).
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 medicines containing angiotensin II receptor antagonists, the antihypertensive effect of Plaunazide 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 could cause positive doping tests.
Pregnancy:
Angiotensin II receptor 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 pregnancy, unless Continuation of angiotensin II receptor antagonist therapy is not 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 all antihypertensives, in patients with ischemic heart disease or ischemic cerebrovascular disease, excessive reduction in blood pressure can 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 likely 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, 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 the Plaunazide association
Concomitant use not recommended
Lithium:
Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with angiotensin converting enzyme inhibitors and, rarely, with angiotensin II receptor antagonists. In addition, renal clearance of lithium it is reduced by thiazides and, consequently, the risk of lithium toxicity may be increased. Therefore, the use of Plaunazide 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 receptor antagonists.
In some patients with impaired renal function (e.g. dehydrated patients or elderly patients with impaired renal function), the concomitant administration of angiotensin II receptor antagonists and cyclooxygenase inhibitors may lead to further deterioration of renal function, including possible failure. acute renal function, 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 this.
Concomitant use to be considered
Amifostina
Potentiation of the antihypertensive effect may occur.
Other antihypertensive drugs:
The hypotensive effect caused by Plaunazide may be increased 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
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).
Medicines that affect potassium levels:
Based on the experience of the use of other medicinal products affecting the renin-angiotensin system, the concomitant use of potassium-sparing diuretics, potassium supplements, potassium-containing salt substitutes 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 Plaunazide, level control is advised plasma potassium.
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).
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 drugs 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 induced by 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 derivatives of salicylic acid). Therefore, such concomitant use is not recommended.
Concomitant use requiring caution
Calcium salts
Thiazide diuretics can increase serum calcium levels by decreasing its elimination. 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 alterations in potassium
Periodic monitoring of serum potassium and ECG is recommended when Plaunazide is concomitantly administered with medicinal products 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. bepridyl, 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 rate.
Antidiabetic medicines (oral medications 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 hyperglycemic effect of beta blockers and diazoxide may be enhanced by thiazides.
Pressor amines (e.g. norepinephrine)
The effect of pressor amines can be reduced.
Medicines used to treat gout (e.g. probenecid, sulfinpyrazone and allopurinol)
Dosage adjustment of uricosuric medicinal products may be necessary, 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 with the 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 lactation
Pregnancy:
Due to the effects of the active substances of this combination in pregnancy, the use of Plaunazide is not recommended during the first trimester of pregnancy (see section 4.4). The use of Plaunazide 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 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 exist for this class of medicinal products. safety for use in pregnancy, unless continued angiotensin II receptor antagonist therapy is considered essential. When pregnancy is ascertained, treatment with angiotensin II receptor antagonists should be discontinued immediately and, if appropriate, alternative therapy should be initiated.
Exposure to angiotensin II receptor antagonists during the second and third trimesters induces fetal toxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia). (See also paragraph 5.3 "Preclinical safety data").
Should exposure to angiotensin II receptor 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 receptor 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 may 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, in pregnancy hypertension or pre-eclampsia 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 Plaunazide during lactation, Plaunazide is not recommended and alternative therapies with a better proven safety profile should be preferred for use during lactation especially when breastfeeding newborn or preterm infants. .
Hydrochlorothiazide
Hydrochlorothiazide is excreted in human milk in small quantities. High doses of thiazides, which cause intense diuresis, can inhibit milk production. The use of Plaunazide is not recommended during breastfeeding. If you use Plaunazide while breastfeeding. doses should be kept as low as possible.
04.7 Effects on ability to drive and use machines
Plaunazide 40 mg / 12.5 mg and 40 mg / 25 mg has a slight or moderate influence on the ability to drive and use machines. Dizziness or fatigue, which can impair the ability to react, may occur occasionally in patients following antihypertensive therapy.
04.8 Undesirable effects
The most commonly reported adverse reactions during treatment with Plaunazide 40 mg / 12.5 mg and 40 mg / 25 mg 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).
The safety of Plaunazide 40 mg / 12.5 mg and 40 mg / 25 mg were studied in clinical trials involving 3709 patients who received olmesartan medoxomil in combination with hydrochlorothiazide.
Additional adverse reactions reported with the fixed combination of olmesartan medoxomil and hydrochlorothiazide at lower doses of 20 mg / 12.5 mg and 20 mg / 25 mg may be potential adverse reactions to Plaunazide 40 mg / 12.5 mg and 40 mg / 25 mg.
Adverse reactions observed with Plaunazide in clinical trials, post-authorization safety studies and spontaneous reports are presented in the table below, as are the adverse reactions induced by the individual active substances olmesartan medoxomil and hydrochlorothiazide based on the known safety profile of these substances. . The following terminology was used to classify the frequency of adverse reactions: very common (≥ 1/10); common (≥1 / 100 y
Single cases of rhabdomyolysis have been reported in temporal association with the intake of angiotensin II receptor blockers.
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
No specific information is available on the effects or treatment of Plaunazide overdose. The patient should be closely monitored and 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 monitored 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
Plaunazide is a combination of an angiotensin II receptor antagonist, olmesartan medoxomil, and a thiazide diuretic, hydrochlorothiazide. The combination of these active ingredients has an additive antihypertensive effect, reducing blood pressure to a greater degree than either component alone.
Once daily administration of Plaunazide ensures an effective and gradual reduction of blood pressure in the 24 hours between two administrations.
Olmesartan medoxomil is a selective antagonist of the orally active angiotensin II receptor (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 aldosterone matics.
In cases of hypertension, "olmesartan medoxomil causes a dose-dependent, long-term reduction in blood pressure. There have been no reports of hypotension after the first administration, of tachyphylaxis during prolonged treatments or of rebound hypertension. sudden interruption of therapy.
Once-a-day administration of olmesartan medoxomil ensures an effective and regular reduction in blood pressure in the 24-hour interval between one dose and the next. For the same overall daily dosage, once-daily administration produced similar decreases in blood pressure compared to administration of the drug 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.
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.
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 the effect is approximately four hours after administration, while the 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 it causes an additive reduction in blood pressure which generally increases as the dose of each component increases.
In the overall data from the placebo-controlled studies, administration of the combination olmesartan medoxomil / hydrochlorothiazide 20 mg / 12.5 mg and 20 mg / 25 mg resulted in a mean reduction (less the reduction due to placebo) in systolic / diastolic blood pressure at the lowest value, respectively, of 12/7 mmHg and 16/9 mmHg.
Administration of 12.5 mg and 25 mg hydrochlorothiazide in patients insufficiently controlled on 20 mg olmesartan medoxomil alone resulted in a "further reduction in 24-hour systolic / diastolic blood pressure, measured by ambulatory blood pressure monitoring, respectively. 7/5 mmHg and 12/7 mmHg, compared to values after olmesartan medoxomil monotherapy. The mean further reduction in systolic / diastolic blood pressure to the lowest value from baseline was 11/10 mmHg and 16/11 mmHg, respectively .
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 40 mg / 12.5 mg and 40 mg / 25 mg were studied in three clinical studies involving 1482 hypertensive patients.
A double-blind study in essential hypertension evaluated the efficacy of combination therapy with Plaunazide 40 mg / 12.5 mg versus monotherapy with olmesartan medoxomil (Plaunac) 40 mg, taking blood pressure reduction as the primary efficacy parameter. arterial blood pressure in a sitting position. After eight weeks of treatment, systolic / diastolic blood pressure was reduced by 31.9 / 18.9 mmHg in the group that received the combination and by 26.5 / 15.8 in the group that had received monotherapy (p
In the second phase of that study, double-blind, but uncontrolled, titration of non-responders from olmesartan medoxomil (Plaunac) 40 mg monotherapy to Plaunazide 40 mg / 12.5 mg, as well as titration of non-responders from Plaunazide 40 mg / 12.5 mg to Plaunazide 40 mg / 25 mg, determined a "further significant reduction in systolic / diastolic blood pressure, thus confirming that this titration is a valid strategy to improve blood pressure control.
A second randomized, double-blind, placebo-controlled study evaluated the efficacy of adding hydrochlorothiazide to the treatment of inadequately controlled patients after eight weeks of treatment with Plaunac 40 mg. Patients continued to take Plaunac 40 mg or received an additional 12.5 mg or 25 mg hydrochlorothiazide, respectively, for an additional eight weeks. A fourth group was randomized to receive Plaunazide 20 mg / 12.5 mg.
The addition of hydrochlorothiazide 12, 5 mg or 25 mg resulted in a further reduction in systolic / diastolic blood pressure of 5.2 / 3.4 mmHg, respectively (p
A comparison between the patients who received Plaunazide 20 mg / 12.5 mg and those who received 40 mg / 12.5 mg showed a statistically significant difference in the reduction in systolic blood pressure of 2.6 mmHg in favor of the combination with more high dosage (p = 0.0255), while, as regards the reduction in diastolic pressure, a difference of 0.9 mmHg was observed. Ambulatory blood pressure (ABPM) monitoring, based on mean changes in 24-hour day and night systolic and diastolic pressure data, confirmed the results obtained with conventional blood pressure measurements.
Another randomized double-blind study compared the efficacy of one treatment with the combination Plaunazide 20 mg / 25 mg to the combination Plaunazide 40 mg / 25 mg in patients with inadequate blood pressure control after eight weeks of treatment with Plaunac 40. mg.
After eight weeks of combination therapy, systolic / diastolic blood pressure was significantly reduced from baseline by 17.1 / 10.5 mmHg in the Plaunazide 20 mg / 25 mg group and by 17.4 / 11.2 mmHg in the Plaunazide 40 mg / 25 mg group. The differences between the two treatment groups were not statistically significant when using conventional blood pressure measurement, which could be explained by the known flat pattern of the dose response curve of the antagonists of the blood pressure receptor. "angiotensin II, such as olmesartan medoxomil.
However, a statistically and clinically significant difference in favor of Plaunazide 40 mg / 25 mg versus Plaunazide 20 mg / 25 mg was observed for 24-hour mean systolic and diastolic blood pressure (ABPM), day and night.
The antihypertensive effect of Plaunazide was not influenced by age, gender or the presence of diabetes.
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:
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 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.
Biotransformation 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 administration), 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.
Plaunazide
The 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 patients (aged 65 and over):
In hypertensive patients, the steady-state AUC of olmesartan was increased by approximately 35% in elderly patients (65 to 75 years) and by approximately 44% in very elderly patients (≥ 75 years) compared to patients younger (see section 4.2).
Limited data suggest that the systemic clearance of hydrochlorothiazide is reduced in the elderly, healthy or hypertensive, compared to young healthy volunteers..
Renal impairment:
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, 4.3, 4.4). The maximum dose of olmesartan medoxomil in patients with mild to moderate renal impairment (creatinine clearance of 30-60 mL / min) is 20 mg olmesartan medoxomil once daily. The use of olmesartan medoxomil in patients with severe renal impairment (creatinine clearance
The half-life of hydrochlorothiazide is prolonged in patients with impaired renal function.
Hepatic impairment:
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 AUC mean of olmesartan was still approximately 65% higher than in healthy controls. Olmesartan mean Cmax values were similar in patients with hepatic impairment and healthy subjects. In patients with moderate hepatic impairment, a starting dose of olmesartan medoxomil 10 mg once daily is recommended and the maximum dose should not exceed 20 mg once daily. Olmesartan medoxomil has not been studied in patients with severe hepatic impairment (see sections 4.2, 4.3, 4.4). Hepatic impairment does not significantly affect the pharmacokinetics of hydrochlorothiazide.
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
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 toxic 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 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 a significant reduction in fetal weight from treated mothers. with olmesartan medoxomil and hydrochlorothiazide during pregnancy (see sections 4.3, 4.6).
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Core of the tablet
Microcrystalline cellulose
Hyprolose with low substitution
Lactose monohydrate
Hyprolose
Magnesium stearate
Tablet coating
Talc
Hypromellose
Titanium dioxide (E 171)
Iron (III) oxide yellow (E 172)
Red iron (III) oxide (E 172)
06.2 Incompatibility
Not relevant.
06.3 Period of validity
5 years.
06.4 Special precautions for storage
This drug does not require any special storage conditions.
06.5 Nature of the immediate packaging and contents of the package
Laminated polyamide / aluminum / polyvinyl chloride / aluminum blister.
Packs contain 14, 28, 30, 56, 84, 90, 98, 10x28 and 10x30 film-coated tablets. The pre-cut unit dose blister packs contain 10, 50 and 500 film-coated tablets.
Not all pack sizes may be marketed.
06.6 Instructions for use and handling
No special instructions.
07.0 MARKETING AUTHORIZATION HOLDER
Menarini International Operations Luxembourg S.A.
1, Avenue de la Gare, L-1611 - Luxembourg
08.0 MARKETING AUTHORIZATION NUMBER
"40 / 12.5 mg film-coated tablets" 14 tablets in blister packs PA / AL / PVC / AL - AIC 037108230
"40 / 12.5 mg film-coated tablets" 28 tablets in blister packs PA / AL / PVC / AL - AIC 037108242
"40 / 12.5 mg film-coated tablets" 30 tablets in blister packs PA / AL / PVC / AL - AIC 037108255
"40 / 12.5 mg film-coated tablets" 56 tablets in blister packs PA / AL / PVC / AL - AIC 037108267
"40 / 12.5 mg film-coated tablets" 84 tablets in blister packs PA / AL / PVC / AL - AIC 037108279
"40 / 12.5 mg film-coated tablets" 90 tablets in blister packs PA / AL / PVC / AL - AIC 037108281
"40 / 12.5 mg film-coated tablets" 98 tablets in blister packs PA / AL / PVC / AL - AIC 037108293
"40 / 12.5 mg film-coated tablets" 10X28 tablets in blister packs PA / AL / PVC / AL - AIC 037108305
"40 / 12.5 mg film-coated tablets" 10X30 tablets in blister packs PA / AL / PVC / AL - AIC 037108317
"40 / 12.5 mg film-coated tablets" 10 tablets in blister PA / AL / PVC / AL - AIC 037108329
"40 / 12.5 mg film-coated tablets" 50 tablets in blister packs PA / AL / PVC / AL - AIC 037108331
"40 / 12.5 mg film-coated tablets" 500 tablets in blister packs PA / AL / PVC / AL - AIC 037108343
"40/25 mg film-coated tablets" 14 tablets in blister packs PA / AL / PVC / AL - AIC 037108356
"40/25 mg film-coated tablets" 28 tablets in blister PA / AL / PVC / AL - AIC 037108368
"40/25 mg film-coated tablets" 30 tablets in blister PA / AL / PVC / AL - AIC 037108370
"40/25 mg film-coated tablets" 56 tablets in blister packs PA / AL / PVC / AL - AIC 037108382
"40/25 mg film-coated tablets" 84 tablets in blister packs PA / AL / PVC / AL - AIC 037108394
"40/25 mg film-coated tablets" 90 tablets in blister packs PA / AL / PVC / AL - AIC 037108406
"40/25 mg film-coated tablets" 98 tablets in blister packs PA / AL / PVC / AL - AIC 037108418
"40/25 mg film-coated tablets" 10X28 tablets in blister packs PA / AL / PVC / AL - AIC 037108420
"40/25 mg film-coated tablets" 10X30 tablets in blister packs PA / AL / PVC / AL - AIC 037108432
"40/25 mg film-coated tablets" 10 tablets in blister PA / AL / PVC / AL - AIC 037108444
"40/25 mg film-coated tablets" 50 tablets in blister packs PA / AL / PVC / AL - AIC 037108457
"40/25 mg film-coated tablets" 500 tablets in blister packs PA / AL / PVC / AL - AIC 037108469
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
Date of first authorization: 20 February 2012
10.0 DATE OF REVISION OF THE TEXT
April 2015
