Candesartan - Generic Drug - Package Leaflet

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

Active ingredients: Candesartan

Candesartan DOC Generici 4 mg tablets
Candesartan DOC Generici 8 mg tablets
Candesartan DOC Generici 16 mg tablets
Candesartan Accord 32 mg tablets

Why is Candesartan used - Generic Drug? What is it for?

The name of the medicine is Candesartan DOC Generici. The active ingredient is candesartancilexetil.

It belongs to a group of medicines called angiotensin II receptor antagonists. It works by causing blood vessels to relax and widen. This helps to lower blood pressure. It also makes the heart pump blood more easily around the world. body.

This medicine is used for:

  • treat high blood pressure (hypertension) in adult patients and in children and adolescents aged 6 to 18 years
  • Candesartan can be used to treat heart failure in adult patients with reduced heart muscle function when angiotensin converting enzyme (ACE) inhibitors cannot be used or in addition to ACE inhibitors when symptoms persist despite mineralocorticoid receptor antagonists (MRA) treatment and antagonists cannot be used. (ACE inhibitors and MRAs are medicines used to treat heart failure).

Contraindications When Candesartan - Generic Drug should not be used

Do not take Candesartan tablets if:

  • you are allergic (hypersensitive) to candesartancilexetil or any of the other ingredients of this medicine (listed in section 6)
  • if you are more than three months pregnant (it is also better to avoid Candesartan tablets in early pregnancy - see pregnancy section)
  • have severe liver disease or biliary obstruction (a problem with the drainage of bile from the gallbladder)
  • if the patient is a child under 1 year of age
  • 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 Candesartan - Generic Drug

Talk to your doctor or pharmacist before taking Candesartan tablets:

  • if you have heart, liver or kidney problems or are on dialysis
  • if you have recently had a kidney transplant
  • if you are vomiting, have recently had severe vomiting or have diarrhea
  • if you have a disease of the adrenal gland known as Conn's syndrome (also called primary aldosteronism)
  • if you have low blood pressure
  • if you have ever had a stroke
  • tell your doctor if you think you are pregnant (or if there is a possibility of becoming pregnant). Candesartan 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).
  • if you are taking any of the following medicines used to treat high blood pressure:
    • an "ACE inhibitor" (for example enalapril, lisinopril, ramipril), particularly if you have diabetes-related kidney problems
    • aliskiren
  • if you are taking an ACE inhibitor together with a medicine belonging to the class of medicines known as mineralocorticoid receptor antagonists (MRA). These medicines are used to treat 'heart failure (see' Other medicines and Candesartan tablets').

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 Candesartan tablets if"

Your doctor may need to see you more often and get tested if you have any of these conditions.

If you are about to have an operation, tell your doctor or dentist that you are taking Candesartan tablets. This is because Candesartan tablets, when combined with any anesthetics, can cause a drop in blood pressure.

Children and adolescents

Candesartan has been studied in children. For more information, talk to your doctor. CANDESARTAN DOC Generici cannot be given to children under 1 year of age due to the possible risk of kidney development.

Interactions Which drugs or foods can modify the effect of Candesartan - Generic Drug

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines. Candesartan tablets can affect the way some other medicines work, and some medicines can have an effect on candesartan tablets. If you are taking certain medicines, your doctor may need to have blood tests from time to time.

In particular, tell your doctor if you are taking any of the following medicines:

  • other medicines that help lower blood pressure, including beta blockers, diazoxide and ACE inhibitors such as enalapril, captopril, lisinopril or ramipril
  • non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen, naproxen, diclofenac, celecoxib, or etoricoxib (medicines to relieve pain and inflammation)
  • acetylsalicylic acid (if you are taking more than 3 g per day) (medicine to relieve pain and inflammation)
  • potassium supplements or potassium-containing salt substitutes (medicines that increase the level of potassium in the blood)
  • heparin (a blood thinning medicine) - tablets that help urinate (diuretics)
  • lithium (a medicine for mental health problems).

Your doctor may need to change your dose and / or take other precautions:

  • If you are taking an ACE inhibitor or aliskiren (see also information under the headings: "Do not take Candesartan if" and "Warnings and precautions")
  • If you are being treated with an ACE inhibitor together with other medicines used for heart failure, known as mineralocorticoid receptor antagonists (MRAs) (eg spironolactone, eplerenone)

Candesartan DOC Generici with food, drink and alcohol

  • You can take Candesartan with or without food
  • When prescribed Candesartan tablets, talk to your doctor before drinking alcohol. Alcohol can make you feel faint or lightheaded.

Warnings It is important to know that:

Pregnancy, breastfeeding and fertility

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 Candesartan before becoming pregnant or as soon as you know you are pregnant and will advise you to take another medicine instead of Candesartan. Generic is not recommended in early pregnancy, and should not be taken if more than three months pregnant, as it may cause serious harm to your baby if used after the third month of pregnancy.

Feeding time

Tell your doctor if you are breastfeeding or about to start breastfeeding. Candesartan 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 a newborn or was born premature.

Driving and using machines

Some people may feel tired or lightheaded when taking Candesartan. If this happens to you, do not drive or use any tools or machinery

Important information about some of the ingredients of Candesartan DOC Generici

Candesartan DOC Generici contains lactose which is a type of sugar. If you have been told by your doctor that you have "intolerance to some sugars, contact your doctor before taking this medicinal product.

Dose, Method and Time of Administration How to use Candesartan - Generic Drug: Posology

Always take this medicine exactly as your doctor has told you. If in doubt, consult your doctor or pharmacist. It is important to keep taking Candesartan DOC Generici every day. Candesartan can be taken with or without food. Swallow the tablet with a drink of water.

Try to take the tablet at the same time each day. This will help you remember to take it.

High blood pressure:

  • the usual dosage of Candesartan tablets is 8 mg once a day. Your doctor may increase this dose up to 16 mg once a day and further up to 32 mg once a day depending on your blood pressure response.
  • In some patients, such as those with liver problems, kidney problems or who have recently lost fluids due to for example: vomiting, diarrhea or taking tablets that help urinate, the doctor may prescribe a lower starting dosage.
  • Some black patients may respond poorly to this medicine when given as the only treatment and may need a higher dose.

Heart failure:

  • the usual starting dosage of Candesartan tablets is 4 mg once a day. Your doctor may increase this dosage by doubling the dose at intervals of at least 2 weeks to 32 mg once a day. Candesartan can be taken together with other medicines for heart failure, and your doctor will decide which treatment is best for you.

Use in children and adolescents with high blood pressure

Children between the ages of 6 and 18

The recommended starting dose is 4mg once a day.

For patients weighing less than 50 kg: In some patients whose blood pressure is not adequately controlled, the doctor may decide that the dose needs to be increased up to a maximum of 8 mg once a day.

For patients weighing 50 kg or more: In some patients whose blood pressure is not adequately controlled, the doctor may decide that the dose should be increased to 8 mg once daily and 16 mg once daily.

If you forget to take Candesartan

Do not take a double dose to make up for a forgotten tablet. Just take the next dose as usual.

If you stop taking Candesartan tablets

If you stop taking Candesartan tablets, your blood pressure may rise again. Therefore do not stop taking Candesartan tablets without first talking to your doctor. If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

Overdose What to do if you have taken too much Candesartan - Generic Drug

If you take more Candesartan tablets than prescribed by your doctor, contact a doctor or pharmacist immediately for advice.

Side Effects What are the side effects of Candesartan - Generic Drug

Like all medicines, Candesartan Accord can cause side effects, although not everybody gets them. It is important that you are aware of what these side effects may be.

Stop taking Candesartan tablets and seek medical help immediately if you experience any of the following allergic reactions:

  • difficulty in breathing, with or without swelling of the face, lips, tongue and / or throat
  • swelling of your face, lips, tongue and / or throat, which may cause you difficulty in swallowing
  • severe itchy skin (with raised blisters)

Candesartan tablets can cause a reduction in the number of white blood cells. Your resistance to infection may decrease and you may notice tiredness, infection or fever. If this happens, contact your doctor. Your doctor may occasionally perform blood tests to check if Candesartan Accord has had any effect on your blood (agranulocytosis).

Possible side effects include:

Common (affects 1 to 10 users in 100)

  • Feeling dizzy / lightheaded
  • Headache
  • Respiratory infection
  • Low blood pressure. This can make you feel faint or lightheaded.
  • Changes in blood test results:
    • An increased amount of potassium in the blood, especially if you already have kidney problems or heart failure. If this is severe then you may also notice tiredness, weakness, an irregular heartbeat or tingling.
  • Effects on how your kidneys work, especially if you already have kidney problems or heart failure. In very rare cases, kidney failure can occur.

Very rare (affects less than 1 user in 10,000)

  • Swelling of the face, lips, tongue and / or throat.
  • A reduction in red or white blood cells. You may notice tiredness, an infection or a fever.
  • Skin rash, swollen rash (hives).
  • Itching.
  • Back pain, pain in the joints and muscles.
  • Changes in the way the liver works, including inflammation of the liver (hepatitis). You may notice tiredness, yellowing of the skin and whites of the eyes and flu-like symptoms.
  • Nausea.
  • Changes in blood test results:
    • A low amount of sodium in the blood. If this is severe then you may also notice weakness, lack of energy or muscle cramps.
  • Cough

In children treated for high blood pressure, side effects appear similar to those seen in adults, but they occur more often. Sore throat is a very common side effect in children but not reported in adults and runny nose, fever and increased heart rate are common in children but not reported in adults.

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 or blister. The expiry date refers to the last day of the month.

The medicinal product does not require any particular storage temperatures. Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.

Deadline "> Other information

What Candesartan DOC Generici contains

The active ingredient is candesartancilexetil.

Each CANDESARTAN DOC Generici 4 mg tablet contains 4 mg of candesartancilexetil.

Each CANDESARTAN DOC Generici 8 mg tablet contains 8 mg of candesartancilexetil.

Each CANDESARTAN DOC Generici 16 mg tablet contains 16 mg of candesartancilexetil.

Each CANDESARTAN DOC Generici 32 mg tablet contains 32 mg of candesartancilexetil.

The other ingredients are lactose monohydrate, maize starch, hydroxypropylcellulose, croscarmellose sodium, magnesium stearate and triethyl citrate.

What Candesartan DOC Generici looks like and contents of the pack

Candesartan 4 mg tablets are white, biconvex tablets with a score line on one side and debossed with C4 on the same side.

CANDESARTAN DOC Generici 8 mg tablets are white, biconvex tablets with a score line on one side and debossed with C8 on the same side.

Candesartan tablets 16 mg tablets are white, biconvex tablets with a score line on one side and engraved with C16 on the same side.

Candesartan Accord 32 mg tablets are white, biconvex tablets with a score line on one side and debossed with C32 on the same side.

The score line on the tablet is to facilitate breaking for easier swallowing and not to divide into equal doses.

Pack sizes: 7, 14, 28, 30, 56, 70, 90, 98 tablets.

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.

More information about Candesartan - Generic Drug 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 the 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 Incompatibility "- 06.3 Shelf life" - 06.4 Special precautions for storage - 06.5 Nature of the primary packaging and contents of the package - 06.6 Instructions for use and handling - 07.0 AUTHORIZATION HOLDER ALL "PLACING ON THE MARKET - 08.0 MARKETING AUTHORIZATION NUMBER - 09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION - 10.0 DATE OF REVISION OF THE TEXT - 11.0 FOR RADIO DRUGS, COMPLETE DATA ON INTERNAL RADIATION DOSIMETRY - 12.0 INSTRUCTIONS FOR RADIOPHONES ON EXTEMPORARY PREPARATION AND QUALITY CONTROL -

01.0 NAME OF THE MEDICINAL PRODUCT -

CANDESARTAN DOC GENERICI TABLETS

02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION -

Each CANDESARTAN DOC Generici 4 mg tablet contains 4 mg of candesartan cilexetil.

Each CANDESARTAN DOC Generici 8 mg tablet contains 8 mg of candesartan cilexetil.

Each CANDESARTAN DOC Generici 16 mg tablet contains 16 mg of candesartan cilexetil.

Each CANDESARTAN DOC Generici 32 mg tablet contains 32 mg of candesartan cilexetil.

Each CANDESARTAN DOC Generici 4 mg tablet contains 133.8 mg of lactose monohydrate.

Each CANDESARTAN DOC Generici 8 mg tablet contains 129.8 mg of lactose monohydrate.

Each CANDESARTAN DOC Generici 16 mg tablet contains 121.8 mg of lactose monohydrate.

Each CANDESARTAN DOC Generici 32 mg tablet contains 243.6 mg of lactose monohydrate.

For the full list of excipients, see section 6.1.

03.0 PHARMACEUTICAL FORM -

Tablet.

Candesartan 4 mg tablets are white, biconvex tablets with a score line on one side and debossed with C4 on the same side.

CANDESARTAN DOC Generici 8 mg tablets are white, biconvex tablets with a score line on one side and debossed with C8 on the same side.

Candesartan tablets 16 mg tablets are white, biconvex tablets with a score line on one side and engraved with C16 on the same side.

Candesartan Accord 32 mg tablets are white, biconvex tablets with a score line on one side and debossed with C32 on the same side.

The score line on the tablet is to facilitate breaking for easier swallowing and not to divide into equal doses.

04.0 CLINICAL INFORMATION -

04.1 Therapeutic indications -

CANDESARTAN DOC Generici is indicated for:

• Treatment of essential hypertension in adults.

• Treatment of adult patients with heart failure and impaired left ventricular systolic function (left ventricular ejection fraction ≤ 40%) when ACE inhibitors are not tolerated or as add-on therapy to ACE inhibitors in patients with symptomatic heart failure, despite optimal therapy, when mineralocorticoid receptor antagonists are not tolerated (see sections 4.2, 4.3, 4.4, 4.5 and 5.1).

• Treatment of hypertension in children and adolescents aged between 6 and 18 years.

04.2 Posology and method of administration -

Dosage in hypertension

The recommended starting dose and the usual maintenance dose of Candesartan tablets is 8 mg once daily. Most of the antihypertensive effect is achieved within 4 weeks. In some patients whose blood pressure is not adequately controlled, the dose may be increased up to 16 mg once daily and up to a maximum of 32 mg once daily. day. Therapy should be adjusted based on blood pressure response. Candesartan can also be administered with other antihypertensive agents. "The addition of hydrochlorothiazide has shown an additional antihypertensive effect with various doses of Candesartan tablets" (see sections 4.3 , 4.4, 4.5 and 5.1) ".

Elderly population

No initial dosage adjustment is necessary in elderly patients.

Patients with intravascular volume depletion

In patients at risk of hypotension, such as patients with possible intravascular volume depletion, a starting dose of 4 mg may be considered (see also section 4.4).

Patients with impaired renal function

In patients with impaired renal function the starting dose is 4 mg, including patients on hemodialysis.

The dose should be titrated based on the response. Experience in patients with very severe or end-stage renal insufficiency (Clcreatinine

Patients with impaired hepatic function

A starting dose of 4 mg once daily is recommended in patients with mild and moderate hepatic impairment. The dose can be adjusted based on the response. CANDESARTAN DOC Generici is

contraindicated in patients with severe hepatic impairment and / or cholestasis (see sections 4.3 and 5.2).

Black patients

The antihypertensive effect of candesartan is less evident in black patients than in non-black patients. Therefore, an increase in CANDESARTAN DOC Generici dosages and the addition of concomitant therapy may be required more frequently for blood pressure control. in black patients versus non-blacks (see section 5.1).

Dosage in heart failure

The usual recommended starting dose of Candesartan is 4 mg once daily. Titration to the target dose of 32 mg once daily (maximum dose) or to the highest tolerated dose is done by doubling the dose at intervals of at least 2 weeks (see section 4.4). Evaluation of patients with heart failure should always include monitoring of renal function, including serum creatinine and potassium.

Candesartan can be given with other heart failure therapies, including ACE inhibitors, beta blockers, diuretics and digitalis or a combination of these medicines. Candesartan Accord can be administered concomitantly with an ACE inhibitor in patients with symptomatic heart failure, despite optimal standard therapy for heart failure when mineralocorticoid receptor antagonists are not tolerated.

The combination of an ACE inhibitor, a potassium-sparing diuretic and Candesartan is not recommended and should only be considered after careful consideration of the potential benefits and risks (see sections 4.4, 4.8 and 5.1).

Special patient populations

No initial dosage adjustment is necessary in elderly patients or in patients with intravascular volume depletion, renal impairment or mild to moderate hepatic impairment.

Pediatric population

The safety and efficacy of Candesartan tablets in children from birth to 18 years have not been established in the treatment of hypertension and heart failure. No data are available.

Pediatric population

Children and adolescents between the ages of 6 and 18:

The recommended starting dose is 4 mg once daily

- For patients weighing less than 50 kg: in patients whose blood pressure is not adequately controlled, the dose can be increased up to a maximum of 8 mg once a day.

- For patients weighing 50 kg or more: in patients whose blood pressure is not adequately controlled, the dose can be increased to 8 mg once a day and then to 16 mg a day if needed (see section 5.1)

Doses above 32 mg have not been studied in pediatric patients.

Most of the antihypertensive effect is achieved within 4 weeks

For children with possible intravascular volume depletion (e.g. patients treated with diuretics, particularly those with impaired renal function), Candesartan treatment should be started under close medical supervision and with a starting dose lower than the usual starting dose. as described above (see section 4.4)

Candesartan has not been studied in children with glomerular filtration rates below 30 mL / min / 1.73 m² (see section 4.4).

Black pediatric patients

The antihypertensive effect of candesartan is less pronounced in black patients than in non-black patients (see section 5.1).

Children aged 1 to 6 years

- The safety and efficacy in children aged 1 to 6 years have not been established. Currently available data are described in section 5.1 but no recommendation on posology can be made.

- Candesartan Accord is contraindicated in children less than 1 year of age (see section 4.3).

Method of administration

Oral use

Candesartan Accord should be administered once daily with or without food.

The bioavailability of candesartan is not affected by food.

04.3 Contraindications -

- Hypersensitivity to candesartan cilexetil or to any of the excipients listed in section 6.1

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

- Severe hepatic insufficiency and / or cholestasis.

- Children less than 1 year of age (see section 5.3)

-The concomitant use of Candesartan tablets with aliskiren-containing medicines is contraindicated in patients with diabetes mellitus or renal impairment (glomerular filtration rate GFR

04.4 Special warnings and appropriate precautions for use -

Altered kidney function

As with other agents that inhibit the renin-angiotensin-aldosterone system, changes in renal function can be expected in susceptible patients treated with Candesartan.

Periodic monitoring of serum potassium and creatinine levels is recommended when Candesartan is used in hypertensive patients with impaired renal function. Experience is limited in patients with very severe or end-stage renal impairment (Clcreatinine blood pressure monitoring.

Evaluation of patients with heart failure should include periodic assessments of renal function, particularly in elderly patients 75 years of age or older, and in patients with impaired renal function. During dose titration of Candesartan tablets, it is recommended to monitor serum creatinine and potassium concentrations. Clinical trials in heart failure did not include patients with serum creatinine concentrations> 265 μmol / L (> 3 mg / dL).

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.

Concomitant therapy with ACE inhibitors in heart failure

The risk of adverse reactions, particularly hypotension, hyperkalaemia and decreased renal function (including acute renal failure), and may be increased when CANDESARTAN DOC Generici is taken in combination with an ACE inhibitor.

The triple combination of an ACE inhibitor, a mineralocorticoid receptor antagonist and candesartan is also not recommended. The use of these combinations should be under the supervision of a specialist and with close and frequent monitoring of renal function, electrolytes and blood pressure. ACE inhibitors and angiotensin II receptor antagonists should not be used. simultaneously in patients with diabetic nephropathy.

Hemodialysis

During dialysis, blood pressure can be particularly sensitive to blockade of the AT1 receptor as a result of reduced plasma volume and activation of the renin-angiotensin-aldosterone system. Therefore Candesartan tablets should be carefully dosed by monitoring blood pressure in patients with hemodialysis.

Renal artery stenosis

Medicinal products that affect the renin-angiotensin-aldosterone system, including angiotensin II receptor antagonists (AIIRAs), may increase blood urea nitrogen and creatinine in patients with bilateral renal artery stenosis or renal artery stenosis in the presence of of single kidney.

Kidney transplant

There is no experience with the use of Candesartan in patients who have recently undergone a kidney transplant.

Hypotension

Hypotension may occur in patients with heart failure during treatment with Candesartan. This can also occur in hypertensive patients with intravascular volume depletion such as those taking high-dose diuretics. Caution should be used when initiating therapy and attempts should be made to correct hypovolaemia.

Anesthesia and surgery

Hypotension due to blockade of the renin-angiotensin system may occur during anesthesia and surgery in patients treated with angiotensin II antagonists. Very rarely, hypotension can be so severe as to justify the use of intravenous fluids and / or vasopressor substances.

Aortic and mitral stenosis (obstructive hypertrophic cardiomyopathy)

As with other vasodilators, special caution is recommended in patients with haemodynamically relevant aortic or mitral stenosis, or hypertrophic obstructive cardiomyopathy.

Primary hyperaldosteronism

Patients with primary aldosteronism generally do not respond to antihypertensive medicinal products which work by inhibiting the renin-angiotensin-aldosterone system. Therefore the use of Candesartan DOC Generici is not recommended in this population.

Hyperkalaemia

Concomitant use of Candesartan tablets with potassium-sparing diuretics, potassium supplements, potassium-containing salt substitutes or other medicinal products that may increase potassium (such as heparin) may cause serum potassium increases in hypertensive patients. Monitoring of serum potassium levels should be done where appropriate.

Hyperkalaemia may occur in patients with heart failure treated with Candesartan tablets. Periodic monitoring of serum potassium levels is recommended. The combination of an ACE inhibitor, a potassium-sparing diuretic (e.g. spironolactone) and Candesartan is not recommended and should only be considered after careful consideration of the potential benefits and risks.

General aspects

In patients whose vascular tone and renal function are predominantly dependent on the activity of the renin-angiotensin-aldosterone system (eg patients with severe congestive heart failure or with underlying renal disease including renal artery stenosis), treatment it has been associated with acute hypotension, azotaemia, oliguria or, rarely, acute renal failure with other medicinal products affecting this system. The possibility of similar effects cannot be excluded with the use of AIIRAs. As with other antihypertensive drugs, the excessive decrease in blood pressure in patients with ischemic heart disease or ischemic cerebrovascular disease can lead to myocardial infarction or stroke.

The antihypertensive effect of candesartan may be enhanced by other medicinal products with hypotensive properties, whether prescribed as antihypertensive or for other indications.

Pregnancy

Angiotensin II receptor antagonist therapy (AIIRAs) should not be initiated during pregnancy. Alternative antihypertensive treatments with a proven safety profile for use in pregnancy should be used for patients planning pregnancy. unless continued AIIRA therapy is considered essential. When pregnancy is diagnosed, treatment with AIIRAs should be stopped immediately, and, if appropriate, alternative therapy should be started (see sections 4.3 and 4.6).

In fertile patients, the possibility of pregnancy should be assessed on a regular basis. Adequate information must be provided and / or actions taken to prevent the risk of exposure during pregnancy (see sections 4.3 and 4.6).

Pediatric population

Use in pediatric patients, including those with impaired renal function

Candesartan has not been studied in children with glomerular filtration rate below 30ml / min / 1.73 m² (see section 4.2).

In children with possible intravascular volume depletion (e.g. patients treated with diuretics, particularly those with impaired renal function), Candesartan treatment should be initiated under close medical supervision and a lower starting dose should be considered (see section 4.2. ).

Candesartan DOC Generici contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption syndrome should not take this medicine.

04.5 Interactions with other medicinal products and other forms of interaction -

Compounds that have been tested in clinical pharmacokinetic studies include hydrochlorothiazide, warfarin, digoxin, oral contraceptives (e.g. ethinyl estradiol / levonorgestrel), glibenclamide, nifedipine and enalapril. No clinically relevant pharmacokinetic interactions with other medicinal products have been identified.

Concomitant use of potassium-sparing diuretics, potassium supplements, potassium-containing salt substitutes or other medicinal products (eg heparin) may increase potassium. If appropriate, monitoring of potassium may be considered (see paragraph 4.4).

Reversible increases in serum lithium concentrations and toxic reactions have been reported during concomitant administration of lithium with ACE inhibitors. A similar effect can occur with AIIRAs. The use of candesartan with lithium is not recommended. If the combination proves necessary, careful monitoring of serum lithium levels is recommended.

When AIIRAs are administered simultaneously with non-steroidal anti-inflammatory drugs (NSAIDs) (eg, selective COX-2 inhibitors, acetylsalicylic acid (> 3 g / day) and non-selective NSAIDs), "attenuation of the antihypertensive effect" may occur. .

As with ACE inhibitors, concomitant use of AIIRAs and NSAIDs may lead to an increased risk of worsening of renal function including possible acute renal failure and increased serum potassium levels, especially in patients with impaired pre-existing renal function. The combination should be administered with caution, especially in the elderly. Patients should be adequately hydrated and monitoring of renal function should be considered at the initiation of concomitant therapy and thereafter periodically.

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).

Pediatric population

Interaction studies have only been performed on adult patients.

04.6 Pregnancy and breastfeeding -

Pregnancy

The use of Angiotensin II Receptor Antagonists (AIIRAs) is not recommended during the first trimester of pregnancy (see section 4.4). The use of AIIRAs 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 the risk of Angiotensin II Receptor Antagonists (AIIRAs) are not available, a similar risk may also exist for this class of medicines. proven safety profile for use in pregnancy unless continued therapy with an AIIRA is considered essential. When pregnancy is diagnosed, treatment with AIIRAs should be stopped immediately and, if appropriate, alternative therapy should be started.

Exposure to AIIRAs 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 section 5.3). .

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

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

Feeding time

As no data are available regarding the use of Candesartan during breastfeeding, Candesartan is not recommended and alternative treatments with a proven safety profile for use during breastfeeding are preferred, especially if breastfeeding. newborns or premature babies.

04.7 Effects on ability to drive and use machines -

No studies on the effects of candesartan on the ability to drive and use machines have been performed. However, it should be taken into account that occasionally dizziness or dizziness may occur

fatigue during treatment with Candesartan tablets.

04.8 Undesirable effects -

Treatment of hypertension

In controlled clinical trials, adverse reactions were mild and transient. The total incidence of adverse events showed no correlation with dose or age. Discontinuation of treatment due to adverse events was similar with candesartan cilexetil (3.1%) and placebo (3.2%).

From a pooled analysis of data from clinical trials in hypertensive patients, adverse reactions with candesartan cilexetil were defined based on the incidence of adverse events with candesartan cilexetil at least 1% higher than the incidence observed with placebo. Based on this definition, the most commonly reported adverse reactions were dizziness / vertigo, headache and respiratory infections.

The table below presents adverse reactions reported from clinical studies and post-marketing experience.

Frequencies used in the tables throughout section 4.8 are: very common (≥ 1/10), common (≥ 1/100 a

System and organ classification Frequency Undesirable effect Infections and infestations common Respiratory infection Disorders of the blood and lymphatic system Very rare Leukopenia, neutropenia and agranulocytosis Metabolism and nutrition disorders Very rare Hyperkalaemia, hyponatremia Nervous system disorders common Dizziness / vertigo, headache Gastrointestinal disorders Very rare Nausea Hepatobiliary disorders Very rare Increased liver enzymes, impaired liver function or hepatitis Skin and subcutaneous tissue disorders Very rare Angioedema, skin rash, urticaria, pruritus Musculoskeletal and connective tissue disorders Very rare Back pain, arthralgia, myalgia Renal and urinary disorders Very rare Reduced renal function, including renal failure in susceptible patients (see section 4.4) Respiratory, thoracic and mediastinal disorders Very rare Cough

Laboratory tests

There was generally no clinically relevant influence of Candesartan on routine laboratory parameters. As with other inhibitors of the renin-angiotensin-aldosterone system, slight decreases in hemoglobin have been observed. No routine laboratory monitoring is usually necessary in patients treated with Candesartan tablets. However, in patients with impaired renal function, it is recommended that serum potassium and creatinine levels be checked periodically.

Treatment of heart failure

The tolerability profile of Candesartan tablets observed in patients with heart failure was consistent with the pharmacology of the drug and the health status of the patients. In the CHARM clinical program, which compared candesartan cilexetil at doses up to 32 mg (n = 3,803) with placebo (n = 3,796), 21.0% of the candesartan cilexetil group and 16.1% of the placebo discontinued treatment due to adverse events. The most commonly reported adverse reactions were hyperkalaemia, hypotension, renal impairment. These events were more common in patients over 70 years of age, diabetics or those who had received other medicinal products that affect the renin-angiotensin-aldosterone system, particularly an ACE inhibitor and / or spironolactone.

The table below presents adverse reactions reported from clinical studies and post-marketing experience.

System and organ classification Frequency Undesirable effect Disorders of the blood and lymphatic system Very rare Leukopenia, neutropenia and agranulocytosis Metabolism and nutrition disorders common Hyperkalaemia Very rare Hyponatremia Nervous system disorders Very rare Dizziness / vertigo, headache Vascular pathologies common Hypotension Gastrointestinal disorders Very rare Nausea Hepatobiliary disorders Very rare Increased liver enzymes, impaired liver function or hepatitis Skin and subcutaneous tissue disorders Very rare Angioedema, skin rash, urticaria, pruritus Musculoskeletal and connective tissue disorders Very rare Back pain, arthralgia, myalgia Renal and urinary disorders common Reduced renal function, including renal failure in susceptible patients (see section 4.4)

Laboratory tests

Hyperkalaemia and renal impairment are common in patients treated with Candesartan tablets for the indication of heart failure. Periodic monitoring of serum creatinine and potassium concentrations is recommended (see section 4.4).

Pediatric population

The safety of candesartan cilexetil was monitored in 255 hypertensive children and adolescents aged 6 to 18 years, in a 4-week clinical efficacy study and in a 1-year open label study (see section 5.1). In nearly all organ system classes, the frequency of adverse reactions in children is in the common / uncommon range. Although the nature and severity of adverse reactions are similar to those in adults (see table above), the frequency of all adverse reactions is higher in children and adolescents particularly in:

- Headache, dizziness, upper respiratory tract infections, are "very common" (≥1 / 10) in children and common (≥ 1/100 to

- Cough is "very common" (> 1/10) in children and very rare (

- Rash is "common" (≥1 / 100 y

- Hyperkalaemia, hyponatremia and hepatic impairment are uncommon (≥ 1 / 1,000 to

- Sinus arrhythmia, nasopharyngitis, pyrexia are "common" (≥1 / 100 a

The overall safety profile for candesartan cilexetil in pediatric patients does not differ significantly from the safety profile in adults.

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 -

Symptoms

Based on pharmacological considerations, the main manifestation of overdose should be symptomatic hypotension and dizziness. In individual reports of overdose (up to 672 mg candesartan cilexetil), patient recovery occurs without consequences.

Methods of intervention in case of overdose

Should symptomatic hypotension occur, symptomatic treatment should be instituted and vital functions monitored. The patient should be placed in the supine position with the legs raised. If this is not sufficient, the plasma volume should be increased by infusion, for example, of isotonic saline. Sympathomimetic medicinal products can be administered if the above measures are insufficient.

Candesartan is not removed by hemodialysis.

05.0 PHARMACOLOGICAL PROPERTIES -

05.1 "Pharmacodynamic properties -

Pharmaco-therapeutic category: Angiotensin II antagonists, unassociated.

ATC code: C09CA06.

Angiotensin II is the main vasoactive hormone of the renin-angiotensin-aldosterone system and plays a role in the pathophysiology of hypertension, heart failure and other cardiovascular diseases. It also plays a role in the pathogenesis of "hypertrophy and damage to" The major physiological effects of angiotensin II, such as vasoconstriction, stimulation of aldosterone, regulation of salt and water balance and stimulation of cell growth, are mediated through the type 1 receptor (AT1).

Candesartan cilexetil is a pro-drug for oral use. It is rapidly converted to the active substance, candesartan, by ester hydrolysis during absorption from the gastrointestinal tract. Candesartan is an AIIRA selective for AT1 receptors, with close binding affinity and slow dissociation from the receptor. He has no competitive activity.

Candesartan does not inhibit ACE, which converts angiotensin I to angiotensin II and degrades bradykinin. There is no effect on ACE and no potentiation of bradykinin or substance P. In controlled clinical trials comparing candesartan with ACE inhibitors, the incidence of cough was lower in patients treated with candesartan cilexetil. Candesartan does not bind or block other hormone receptors or ion channels that are important in regulating the cardiovascular system. Angiotensin II receptor (AT1) antagonism results in dose-related increases in plasma renin levels, angiotensin I levels and angiotensin II, and with a decrease in plasma aldosterone concentrations.

Hypertension

In hypertension, candesartan causes a dose-dependent, long-lasting reduction in blood pressure. The antihypertensive action is due to the decrease in peripheral systemic resistance, without reflex increases in heart rate. No severe or exaggerated effects of first dose hypotension or effect were observed "rebound" after stopping treatment.

After administration of a single dose of candesartan cilexetil, the onset of the antihypertensive effect usually occurs within 2 hours. Following continuous treatment, maximum reduction in blood pressure with any dosage is generally achieved within 4 weeks and is maintained during long-term treatment. According to a meta-analysis, increasing the dose from 16 mg to 32 mg once daily had, on average, a small additional effect. Taking into account the inter-individual variability, a greater effect of the dose may be expected in some patients. Candesartan cilexetil administered once daily causes an effective and homogeneous reduction in blood pressure over 24 hours with a small difference in trough-to-peak ratio during the interval between doses. The antihypertensive effect and tolerability of candesartan is losartan were compared in two randomized double-blind clinical trials involving a total of 1,268 patients with mild to moderate hypertension. The decrease in trough blood pressure (systolic / diastolic) was 13.1 / 10.5 mmHg with candesartan cilexetil 32 mg administered once daily and 10.0 / 8.7 mmHg with losartan potassium 100 mg administered once daily (difference in blood pressure reduction 3.1 / 1.8 mmHg, p

When candesartan cilexetil is combined with hydrochlorothiazide, there is an additive decrease in blood pressure. An increase in the antihypertensive effect is also observed when candesartan cilexetil is used in combination with amlodipine or felodipine.

Medicinal products that block the renin-angiotensin-aldosterone system have a less pronounced antihypertensive effect in black patients (usually low-renin population) than in non-black patients. This also occurs in the case of candesartan. In an open-label clinical study of 5,156 patients with diastolic hypertension, the reduction in blood pressure during treatment with candesartan was significantly less in black patients than in non-blacks (14.4 / 10.3 mmHg vs 19.0 / 12.7 mmHg, p

Candesartan increases renal flow and has no effect or increases glomerular filtration rate, while reducing renal vascular resistance and filtration fraction. In a 3-month clinical study in hypertensive patients with type 2 diabetes mellitus and microalbuminuria, antihypertensive treatment with candesartan cilexetil reduced urinary albumin excretion (mean reduction in albumin / creatinine ratio of 30%, 95% CI 15- 42%). There are currently no data on the effect of candesartan on progression to diabetic nephropathy.

The effects of candesartan cilexetil 8-16 mg (mean dose 12 mg), once daily, on cardiovascular morbidity and mortality were evaluated in a randomized clinical trial in 4,937 elderly patients (age 70-89 years; of which 21% aged 80 years or older) with mild to moderate hypertension followed for a mean of 3.7 years (Study on COgnition and Prognosis in the Elderly). Patients received candesartan cilexetil or placebo with other additional antihypertensive treatments as needed.Blood pressure was reduced from 166/90 to 145/80 mmHg in the candesartan group, and from 167/90 to 149/82 mmHg in the control group. There was no statistically significant difference in the primary end point, major cardiovascular events (cardiovascular mortality, non-fatal stroke and non-fatal myocardial infarction). There were 26.7 events per 1000 patient-years in the candesartan group vs 30.0 events per 1000 patient-years in the control group (relative risk 0.89, 95% CI 0.75 to 1.06, p = 0.19).

Heart failure

Treatment with candesartan cilexetil reduces mortality, reduces hospitalization due to heart failure and improves symptoms in patients with left ventricular systolic dysfunction as demonstrated in the Candesartan in Heart failure - Assessment of Reduction in Mortality and morbidity (CHARM) study.

This double-blind, placebo-controlled study program in patients with chronic heart failure (CHF) of NYHA functional class II to IV consisted of three separate studies: CHARM-Alternative (n = 2,028) in patients with ejection fraction left ventricular (LVEF) ≤ 40% not treated with ACE inhibitors due to intolerance (mainly due to cough, 72%), CHARM-Added (n = 2,548) in patients with LVEF ≤ 40% and treated with an ACE inhibitor , and CHARM-Preserved (n = 3,023) in patients with LVEF> 40%. Patients on optimal background therapy for heart failure (CHF) were randomized to placebo or candesartan cilexetil (titrated from 4 mg or 8 mg once daily up to 32 mg once daily or the highest tolerated dose. , mean dose 24 mg) and followed for a median of 37.7 months. After 6 months of treatment, 63% of patients still taking candesartan cilexetil (89%) had reached the target dose of 32 mg.

In the CHARM-Alternative study, the combined endpoint of cardiovascular mortality or first hospitalization for CHF was significantly reduced with candesartan compared to placebo, hazard ratio (HR) 0.77 (95% CI: 0.67 to 0 , 89, PCardiovascular or "hospitalization for treatment of heart failure. The combined end point of all-cause mortality or first hospitalization for CHF was also significantly reduced with candesartan HR 0.80 (95% CI: from 0 , 70 to 0.92, p = 0.001) Of candesartan-treated patients, 36.6% (95% CI: 33.7 to 39.7) and of placebo-treated patients, 42.7% ( 95% CI: 39.6 to 45.8) met this endpoint, absolute difference 6.0% (95% CI: 10.3 to 1.8). Both mortality and morbidity (hospitalization for CHF) both components of these combined endpoints contributed to the favorable effects of candesartan. Treatment with candesartan cilexetil resulted in an improvement in functional class. ale NYHA (p = 0.008).

In the CHARM-Added study, the combined endpoint of cardiovascular mortality or first hospitalization for CHF was significantly reduced with candesartan compared to placebo HR 0.85 (95% CI: 0.75 to 0.96, p = 0.011) This corresponds to a relative risk reduction of 15%. Of candesartan-treated patients, 37.9% (95% CI: 35.2 to 40.6) and of placebo-treated patients, 42.3% (95% CI: 39.6 to 45.1) met this endpoint, absolute difference 4.4% (95% CI: 8.2 to 0.6). Treatment required for the duration of the study 23 patients to prevent death from cardiovascular events in one patient or hospitalization for treatment of heart failure. The combined end point of all cause mortality or first hospitalization for CHF was also significantly reduced with candesartan HR 0.87, (95% CI: 0.78 to 0.98, p = 0.021). candesartan-treated patients, 42.2% (95% CI: 39.5 to 45.0) and of placebo-treated patients, 46.1% (95% CI: 43.4 to 48.9) achieved this endpoint, absolute difference 3.9% (95% CI: 7.8 to 0.1). Both mortality and morbidity, both components of these combined endpoints, contributed to the favorable effects of candesartan. with candesartan cilexetil produced an improvement in NYHA functional class (p = 0.020).

In the CHARM-Preserved study, no statistically significant reduction was obtained in the combined endpoint of cardiovascular mortality or first hospitalization for CHF, HR 0.89, (95% CI: 0.77 to 1.03, p = 0.118).

All cause mortality was not statistically significant when examined separately for each of the three CHARM studies. However, all-cause mortality was also assessed in pooled populations, in the CHARM-Alternative and CHARM-Added studies, HR 0.88, (95% CI: 0.79 to 0.98, p = 0.018) and in all three studies, HR 0.91 (95% CI: 0.83 to 1.00, p = 0.055).

The beneficial effects of candesartan were consistent regardless of age, gender and concomitant medications. Candesartan was also effective in patients taking both beta-blockers and ACE inhibitors at the same time, and the benefit was obtained whether or not patients took ACE inhibitors at the target dose recommended by the treatment guidelines.

In patients with CHF and impaired left ventricular systolic function (left ventricular ejection fraction, LVEF ≤ 40%), candesartan decreases systemic vascular resistance and pulmonary capillary wedge pressure, increases plasma renin activity and blood concentration. angiotensin II, and reduces aldosterone levels.

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.

Pediatric population - hypertension

The antihypertensive effect of candesartan was evaluated in hypertensive children aged 1 to 6 years and 6 to 17 years in two 4-week multicentre double-blind randomized variable dose studies.

In children aged 1 to 6 years, 93 patients, 74% of whom had kidney disease, were randomized to receive an oral suspension dose 0.05, 0.20, 0.40 mg / kg candesartan cilexetil once daily.

The primary method of analysis was the slope of the change in systolic pressure (SBP) as a function of dose. SBP and diastolic blood pressure (DBP) decreased from 6.0 / 5.2 to 12.0 / 11.1 mmHg from baseline of the three candesartan cilexetil doses. However, since there was no placebo group, the true magnitude of the blood pressure effect remains uncertain, making a conclusive assessment of the benefit / risk ratio in this age group difficult.

In children aged 6-17 years, 240 patients were randomized to receive either placebo or low, medium or high doses of candesartan cilexetil in the ratio 1: 2: 2: 2. For children weighing less than 50 kg, the doses of candesartan cilexetil were 2, 8 or 16 mg once daily. For children weighing more than 50 kg, the doses of candesartan cilexetil were 4, 16 or 32 mg once daily. Candesartan at pooled doses reduced SiSBP by 10.22 mmHg (In comparison to placebo, all individual doses of candesartan (and all doses overall) were significantly superior to placebo. The maximal response in blood pressure reduction in children above and below the 50 kg was achieved at doses of 8 mg and 16 mg, respectively, and the effect plateaued after that point.

Of those enrolled in the study, 47% were black patients and 29% were women: the "mean age +/- SD was 12.9 +/- 2.6 years. In children aged 6-17 years, there was a tendency to have a lower effect on blood pressure in black patients than in non-black patients.

05.2 "Pharmacokinetic properties -

Absorption and distribution

Following oral administration, candesartan cilexetil is converted to the active substance candesartan. The absolute bioavailability of candesartan is approximately 40% after administration of an oral solution of candesartan cilexetil. The relative bioavailability of the tablet formulation compared to the same oral solution is approximately 34% with very little variability. The estimated absolute bioavailability of the tablet is therefore 14%. Mean peak concentration values ​​(Cmax) are reached within 3-4 hours after dosing. Serum concentrations of candesartan increase linearly with increasing doses in the therapeutic range. No differences in candesartan pharmacokinetics were observed in either sex. The area under the curve (AUC) is not significantly affected by food.

Candesartan is highly bound to plasma proteins (more than 99%). The apparent volume of distribution of candesartan is 0.1 L / kg.

The bioavailability of candesartan is not affected by food.

Biotransformation and elimination

Candesartan is eliminated almost entirely unchanged via the urinary and biliary routes and only to a lesser extent via hepatic metabolism (CYP2C9). Available interaction studies indicate no effect on CYP2C9 and CYP3A4. Based on data in vitro, no interaction is expected to occur in vivo with drugs whose metabolism depends on cytochrome P450, CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1 or CYP3A4 isoenzymes. The terminal half-life is approximately 9 hours. No accumulation is observed following repeated dosing.

Total plasma clearance of candesartan is approximately 0.37 mL / min / kg, with a renal clearance of approximately 0.19 mL / min / kg. Renal excretion occurs by both glomerular filtration and active tubular secretion. Following an oral dose of 14C-labeled candesartan cilexetil, approximately 26% of the dose is excreted in the urine as candesartan and 7% as an inactive metabolite, while approximately 56 % of the dose is found in the faeces as candesartan and 10% as the inactive metabolite.

Pharmacokinetics in special populations

In the elderly (over 65 years of age) both Cmax and AUC of candesartan are increased by approximately 50% and 80%, respectively, compared to young subjects. However, the blood pressure response and the incidence of adverse events are similar after administration of the same dose of Candesartan in young and elderly patients (see section 4.2).

In patients with mild and moderate renal impairment, the Cmax and AUC of candesartan during repeated administration increased by approximately 50% and 70%, respectively, but the t½ was not altered compared to patients with normal renal function. Corresponding changes in patients with severe renal insufficiency were approximately 50% and 110%. The terminal t½ of candesartan was approximately doubled in patients with severe renal impairment. The AUC of candesartan in hemodialysis patients was similar to that in patients with severe renal impairment.

In two studies, both in patients with mild to moderate hepatic impairment there was an increase in mean AUC of candesartan of approximately 20% in one study and 80% in the other study (see section 4.2). experience in patients with severe hepatic impairment.

Pediatric population

The pharmacokinetic properties of candesartan were evaluated in hypertensive children aged 1 to 6 years and 6 to 17 years in two single dose pharmacokinetic studies.

In children aged 1 to 6 years, 10 children weighing 10 to 25 kg received a single dose of 02.mg / kg oral suspension. There was no correlation between Cmax and AUC with age or weight. No clearance data was collected; therefore the possibility of a correlation between clearance and weight / age in this population is unknown.

In children aged 6-17 years, 22 children received a single-dose 16 mg tablet. There was no correlation between Cmax and AUC with age. However, weight appears to be significantly correlated with Cmax (p = 0.012) and AUC (p = 0.011). No clearance data was collected, therefore the possibility of a correlation between clearance and weight / age in this population is unknown.

Children over 6 years of age showed similar exposure to adults at the same dose.

The pharmacokinetics of candesartan cilexetil have not been studied in pediatric patients less than 1 year of age.

05.3 Preclinical safety data -

In preclinical studies in neonatal and juvenile rats, candesartan caused a reduction in body weight and heart weight. As in adult animals, these effects are considered to be the result of the pharmacological action of candesartan. At the lowest dose of 10 mg / kg the exposure to candesartan was between 12 and 78 times the levels found in children aged between 1 and 6 years who received candesartan cilexetil at a dose of 0.2 mg / kg and between 7 and 54 times the levels found in children aged 6 to 17 years who received candesartan cilexetil at a dose of 16 mg. Since an effective level was not shown in these studies, the safety margin for effects on heart weight and the clinical relevance of the result is unknown.

The renin-angiotensin-aldosterone system plays a critical role in the development of the kidneys in the uterus.

Blockade of the renin-angiotensin-aldosterone system has been shown to lead to abnormal kidney development in very young mice. The administration of drugs that act directly on the renin-angiotensin-aldosterone system can alter the regular development of the kidneys. Therefore, children less than 1 year of age should not receive Candesartan tablets (see section 4.3).

No abnormal systemic or target organ toxicity was observed at clinically relevant doses. In preclinical safety studies candesartan had effects on kidney and red cell parameters at high doses in mice, rats, dogs and monkeys. Candesartan caused a reduction in red blood cell parameters (erythrocytes, hemoglobin, hematocrit). Effects on the kidneys (such as interstitial nephritis, tubular distension, tubular basophilia; increased plasma concentrations of BUN and creatinine) were induced by candesartan and may be secondary to the hypotensive effect resulting in impaired renal perfusion. Furthermore, candesartan induced hyperplasia / hypertrophy of juxtaglomerular cells These changes were considered to be caused by the pharmacological action of candesartan. With therapeutic doses of candesartan in humans, hyperplasia / hypertrophy of the juxtaglomerular cells does not appear to have any relevance.

Foetotoxicity has been observed in late pregnancy (see section 4.6).

The data of mutagenesis in vitro and in vivo indicate that candesartan does not exert mutagenic or clastogenic activity under conditions of clinical use. No carcinogenic phenomena were observed.

06.0 PHARMACEUTICAL INFORMATION -

06.1 Excipients -

Lactose monohydrate

Cornstarch

Hydroxypropylcellulose

Croscarmellose sodium

Magnesium stearate

Triethyl citrate

06.2 Incompatibility "-

Not relevant.

06.3 Period of validity "-

3 years.

06.4 Special precautions for storage -

This medicinal product does not require any special storage conditions.

06.5 Nature of the immediate packaging and contents of the package -

PVC-PVDC / Alu blister.

Pack sizes: 7, 14, 28, 30, 56, 70, 90, 98 tablets.

Not all pack sizes may be marketed.

06.6 Instructions for use and handling -

The unused product and the waste derived from this medicinal product must be disposed of in accordance with local regulations.

07.0 HOLDER OF THE "MARKETING AUTHORIZATION" -

DOC Generici S.r.l.

Via Turati 40

20121 Milan

Italy

08.0 MARKETING AUTHORIZATION NUMBER -

041341013 - 4 mg tablets - 7 tablets in PVC / PVDC / AL blister

041341025 - 4 mg tablets - 14 tablets in PVC / PVDC / AL blister

041341037 - 4 mg tablets - 28 tablets in PVC / PVDC / AL blister

041341049 - 4 mg tablets - 30 tablets in PVC / PVDC / AL blister

041341052 - 4 mg tablets - 56 tablets in PVC / PVDC / AL blister

041341064 - 4 mg tablets - 70 tablets in PVC / PVDC / AL blister

041341076 -4 mg tablets - 90 tablets in PVC / PVDC / AL blister

041341088 - 4 mg tablets - 98 tablets in PVC / PVDC / AL blister

041341090 - 8 mg tablets - 7 tablets in PVC / PVDC / AL blister

041341102 - 8 mg tablets - 14 tablets in PVC / PVDC / AL blister

041341114 - 8 mg tablets - 28 tablets in PVC / PVDC / AL blister

041341126 - 8 mg tablets - 30 tablets in PVC / PVDC / AL blister

041341138 - 8 mg tablets - 56 tablets in PVC / PVDC / AL blister

041341140 - 8 mg tablets - 70 tablets in PVC / PVDC / AL blister

041341153 - 8 mg tablets -90 tablets in PVC / PVDC / AL blister

041341165 - 8 mg tablets - 98 tablets in PVC / PVDC / AL blister

041341177 - 16 mg tablets - 7 tablets in PVC / PVDC / AL blister

041341189 - 16 mg tablets - 14 tablets in PVC / PVDC / AL blister

041341191 - 16 mg tablets -28 tablets in PVC / PVDC / AL blister

041341203 - 16 mg tablets -30 tablets in PVC / PVDC / AL blister

041341215 - 16 mg tablets -56 tablets in PVC / PVDC / AL blister

041341227 - 16 mg tablets - 70 tablets in PVC / PVDC / AL blister

041341239 - 16 mg tablets - 90 tablets in PVC / PVDC / AL blister

041341241 - 16 mg tablets - 98 tablets in PVC / PVDC / AL blister

041341254 - 32 mg tablets - 7 tablets in PVC / PVDC / AL blister

041341266 - 32 mg tablets - 14 tablets in PVC / PVDC / AL blister

041341278 - 32 mg tablets - 28 tablets in PVC / PVDC / AL blister

041341280 - 32 mg tablets - 30 tablets in PVC / PVDC / AL blister

041341292 - 32 mg tablets -56 tablets in PVC / PVDC / AL blister

041341304 - 32 mg tablets -70 tablets in PVC / PVDC / AL blister

041341316 - 32 mg tablets - 90 tablets in PVC / PVDC / AL blister

041341328 - 32 mg tablets - 98 tablets in PVC / PVDC / AL blister

09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION -

April 2012

10.0 DATE OF REVISION OF THE TEXT -

January 2015

11.0 FOR RADIO DRUGS, COMPLETE DATA ON THE INTERNAL RADIATION DOSIMETRY -

12.0 FOR RADIO DRUGS, FURTHER DETAILED INSTRUCTIONS ON EXEMPORARY PREPARATION AND QUALITY CONTROL -

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