Candesartan and Hydrochlorothiazide - 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, Hydrochlorothiazide

CANDESARTAN and HYDROCHLOROTHIAZIDE DOC Generici 8 mg + 12.5 mg tablets
CANDESARTAN and HYDROCHLOROTHIAZIDE DOC Generici 16 mg + 12.5 mg tablets

Candesartan and Hydrochlorothiazide - Generic Drug package inserts are available for pack sizes:
  • CANDESARTAN and HYDROCHLOROTHIAZIDE DOC Generici 8 mg + 12.5 mg tablets, CANDESARTAN and HYDROCHLOROTHIAZIDE DOC Generici 16 mg + 12.5 mg tablets
  • CANDESARTAN and HYDROCHLOROTHIAZIDE DOC Generici 32 mg + 12.5 mg tablets, CANDESARTAN and HYDROCHLOROTHIAZIDE DOC Generici 32 mg + 25 mg tablets

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

The name of the medicine is CANDESARTAN and HYDROCHLOROTHIAZIDE DOC Generici 8 mg / 12.5 mg tablets and CANDESARTAN and HYDROCHLOROTHIAZIDE DOC Generici 16 mg / 12.5 mg tablets.

This medicine contains two active substances: candesartan cilexetil and hydrochlorothiazide.

These work together to lower blood pressure

  • Candesartan cilexetil belongs to a group of medicines called angiotensin II receptor antagonists. It works by causing the blood vessels to relax and widen. This helps to reduce blood pressure.
  • Hydrochlorothiazide belongs to a group of medicines called diuretics (which help you urinate). This helps the body eliminate water and salts such as sodium in the urine. This helps to reduce blood pressure.

Your doctor may prescribe Candesartan and Hydrochlorothiazide if your blood pressure has not been adequately controlled by candesartan cilexetil or hydrochlorothiazide alone.

Contraindications When Candesartan and Hydrochlorothiazide should not be used - Generic Drug

Do not use Candesartan and Hydrochlorothiazide DOC Generici:

  • if you are allergic to candesartan cilexetil or hydrochlorothiazide or any of the other ingredients of this medicine (listed in section 6)
  • if you are allergic to sulphonamide medicines. If you are not sure if this applies to you, consult your doctor.
  • if you are more than 3 months pregnant (it is better to avoid the use of Candesartan and Hydrochlorothiazide also in the early stages of pregnancy - see pregnancy section)
  • if you have severe kidney problems
  • if you have severe liver disease or biliary obstruction (a problem with the drainage of bile from the gallbladder)
  • if you have persistently low levels of potassium in your blood
  • if you have persistently high levels of calcium in your blood
  • if you have had gout
  • if you have diabetes or impaired kidney function and you are being treated with a blood pressure lowering medicine containing aliskiren.

If you are not sure if any of these apply to you, consult your doctor or pharmacist before taking Candesartan / Hydrochlorothiazide.

Precautions for use What you need to know before taking Candesartan and Hydrochlorothiazide - Generic Drug

Talk to your doctor or pharmacist before taking Candesartan / Hydrochlorothiazide:

  • If you have diabetes.
  • If you have heart, liver or kidney problems.
  • If you have recently had a kidney transplant.
  • If you are vomiting, you have recently had severe vomiting or diarrhea.
  • If you have an adrenal gland disease known as Conn's syndrome (also called primary aldosteronism).
  • If you have ever had a disease called systemic lupus erythematosus (SLE).
  • If you have thyroid or parathyroid problems.
  • If you have low blood pressure.
  • If you have ever had a stroke.
  • If you have had asthma or allergies.
  • Tell your doctor if you think you are pregnant (or if there is a possibility of becoming pregnant). Candesartan / Hydrochlorothiazide is not recommended in early pregnancy, and must not be taken if you are more than 3 months pregnant, as it may cause serious harm to your baby if used at that stage (see pregnancy section).
  • If you are taking any of the following medicines used to treat high blood pressure:
    • an "ACE inhibitor" (for example enalapril, lisinopril, ramipril), particularly if you have diabetes-related kidney problems
    • aliskiren

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

See also information under the heading "Do not use CANDESARTAN and HYDROCHLOROTHIAZIDE DOC Generici if".

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

CANDESARTAN and HYDROCHLOROTHIAZIDE DOC Generici can increase the sensitivity of the skin to the sun.

Children and adolescents

There is no experience with the use of Candesartan and Hydrochlorothiazide in children and adolescents (under 18 years of age). Therefore Candesartan and Hydrochlorothiazide should not be given to children and adolescents.

For those who play sports it is important to pay attention because the hydrochlorothiazide contained in this medicine can determine positive anti-doping tests.

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

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

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 angiotensin converting enzymes (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).
  • Supplements of calcium or vitamin D.
  • Medicines to lower cholesterol levels, such as colestipol or cholestyramine.
  • Medicines for diabetes (oral tablets or insulin).
  • Medicines to control the heartbeat (antiarrhythmic agents) such as digoxin and beta-blockers.
  • Medicines whose action can be affected by blood potassium levels, such as some antipsychotic medicines.
  • Heparin (a medicine to thin the blood).
  • Medicines that help you pass urine (diuretics).
  • Laxatives.
  • Penicillin (an antibiotic).
  • Amphotericin (to treat fungal infections)
  • Lithium (a medicine for mental health problems).
  • Steroids, such as prednisolone.
  • Pituitary hormone (ACTH).
  • Medicines to treat cancer.
  • Amantadine (to treat Parkinson's disease or for severe infections caused by viruses).
  • Barbiturates (a type of sedative also used to treat epilepsy).
  • Carbenoxolone (to treat esophageal disease or oral ulcers).
  • Anticholinergic agents such as atropine and biperidene.
  • Ciclosporin, a medicine used in organ transplants to prevent organ rejection.
  • Other medicines which may potentiate the antihypertensive effect, such as baclofen (a medicine to relieve spasticity), amifostine (used to treat cancer) and some antipsychotic medicines.
  • If you are taking an ACE inhibitor or aliskiren (see also information under "Do not use CANDESARTAN / HYDROCHLOROTHIAZIDE DOC Generici" and "Warnings and precautions").

CANDESARTAN and HYDROCHLOROTHIAZIDE DOC Generici with food and drink and alcohol

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

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). Your doctor will usually advise you to stop taking Candesartan and Hydrochlorothiazide before becoming pregnant or as soon as you know you are pregnant and will advise you to take another medicine instead of Candesartan and Hydrochlorothiazide. Generic Candesartan / Hydrochlorothiazide is not recommended in early pregnancy and should not be taken if you are more than 3 months pregnant as it may cause serious harm to your baby if taken after the third month of gestation.

Feeding time

Tell your doctor if you are breastfeeding or about to start breastfeeding. Candesartan / Hydrochlorothiazide is not recommended for women who are breastfeeding and your doctor may choose another treatment for you if you wish to breastfeed, especially if the baby is a newborn. or was born premature.

Driving and using machines

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

Candesartan and Hydrochlorothiazide DOC Generici contains lactose

CANDESARTAN / HYDROCHLOROTHIAZIDE DOC Generici contains lactose which is 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 medicinal product.

Dose, Method and Time of Administration How to use Candesartan and Hydrochlorothiazide - 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 continue taking Candesartan and Hydrochlorothiazide DOC Generici every day.

The recommended dose is one tablet a day.

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.

The score line is there to help you break the tablet if you have difficulty swallowing it whole.

If you forget to take Candesartan / Hydrochlorothiazide

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 / HYDROCHLOROTHIAZIDE DOC Generici

If you stop taking Candesartan / Hydrochlorothiazide, your blood pressure may rise again. Therefore do not stop taking Candesartan / Hydrochlorothiazide Actavis 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 an overdose of Candesartan and Hydrochlorothiazide - Generic Drug

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

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

Like all medicines, this medicine can cause side effects, although not everybody gets them. It is important that you are aware of what these side effects may be. Some of the side effects of Candesartan and Hydrochlorothiazide are caused by candesartan cilexetil and some are caused by hydrochlorothiazide.

Stop taking Candesartan / Hydrochlorothiazide Accord 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 the face, lips, tongue and / or throat, which may cause difficulty in swallowing
  • severe itching of the skin (with raised blisters).

CANDESARTAN / HYDROCHLOROTHIAZIDE DOC Generici can cause a reduction in the number of white blood cells in the blood. 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 whether Candesartan / Hydrochlorothiazide has had any effect on your blood (agranulocytosis).

Other possible side effects include:

Common (may affect up to 1 in 10 people)

  • Changes in blood test results:
    • A low amount of sodium in the blood. If the reduction is severe then you may notice weakness, lack of energy or muscle cramps.
    • An increased or decreased amount of potassium in your blood, especially if you already have kidney problems or heart failure. If this increase or decrease is severe, then you may notice tiredness, weakness, an irregular heartbeat or tingling.
    • An increased amount of cholesterol, sugar, or uric acid in the blood.
  • Sugar in the urine.
  • Feeling lightheaded / lightheaded or weak.
  • Headache.
  • Respiratory infection.

Uncommon (may affect up to 1 in 100 people)

  • Low blood pressure. This can make you feel faint or lightheaded.
  • Loss of appetite, diarrhea, constipation, stomach irritation.
  • Skin rash, lumpy rash (hives), skin rash caused by sensitivity to sunlight.

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

  • Jaundice (yellowing of the skin or the whites of the eye). If this happens to you, contact your doctor immediately.
  • Effects on how your kidneys work, especially if you already have kidney problems or heart failure.
  • Difficulty sleeping, depression, restlessness.
  • Tingling or tingling in the arms or legs.
  • Blurred vision for a short time.
  • Abnormal heartbeat.
  • Breathing difficulties (including lung inflammation and fluid in the lungs).
  • High temperature (fever).
  • Inflammation of the pancreas. This causes moderate to severe stomach.
  • Muscle cramps.
  • Damage to blood vessels causing red or purple spots to appear on the skin.
  • A reduction in red or white blood cells or platelets. You may notice tiredness, infection, fever, easy swelling (bruising).
  • Severe rash that develops rapidly, with blistering and peeling on the skin and sometimes in the mouth.
  • Worsening of existing lupus erythematosus-like reactions or appearance of unusual skin reactions.

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

  • Swelling of the face, lips, tongue and / or throat.
  • 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 fatigue, yellowing of the skin and whites of the eyes and flu-like symptoms.
  • Cough.
  • Nausea.

Reporting of side effects

If you get any side effects, talk to your doctor or via the national reporting system at www.agenziafarmaco.gov.it/it/responsabili. This includes any possible side effects not listed in this leaflet. By reporting side effects you can help. Provide more information on the safety of this medicine pharmacist You can also report side effects directly via the national reporting system at www.agenziafarmaco.gov.it/it/responsabili. By reporting side effects you can help provide more information on the safety of this medicine.

Expiry and Retention

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

This medicinal product does not require any special storage conditions.

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

Deadline "> Other information

What CANDESARTAN and HYDROCHLOROTHIAZIDE DOC Generici contains

The active ingredients are: candesartan cilexetil and hydrochlorothiazide. Each tablet contains 8/16 mg of Candesartan cilexetil and 12.5 mg of Hydrochlorothiazide.

The other ingredients are Lactose monohydrate, Maize starch, Hydroxypropylcellulose, Croscarmellose sodium, Magnesium stearate and Triethyl citrate.

What Candesartan / Hydrochlorothiazide DOC Generici looks like and contents of the pack

CANDESARTAN / HYDROCHLOROTHIAZIDE DOC Generici 8 mg + 12.5 mg is presented as white, biconvex tablets with a break line on one side and CH8 imprint on the same side.

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

CANDESARTAN / HYDROCHLOROTHIAZIDE DOC Generici 16 mg + 12.5 mg is presented as white, biconvex tablets with a break line on one side and CH16 imprint on the same side.

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 and Hydrochlorothiazide - 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 AND HYDROCHLOROTHIAZIDE DOC GENERICI TABLETS

02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION -

One tablet of Candesartan and HYDROCHLOROTHIAZIDE DOC Generici 8 mg + 12.5 mg tablets contains 8 mg of candesartan cilexetil and 12.5 mg of hydrochlorothiazide.

Excipient with known effect:

Each tablet contains 117.3 mg of lactose monohydrate.

One tablet of Candesartan and HYDROCHLOROTHIAZIDE DOC Generici 16 mg + 12.5 mg tablets contains 16 mg of candesartan cilexetil and 12.5 mg of hydrochlorothiazide.

Excipient with known effect:

Each tablet contains 109.30 mg of lactose monohydrate.

For the full list of excipients, see section 6.1.

03.0 PHARMACEUTICAL FORM -

Tablet.

CANDESARTAN / HYDROCHLOROTHIAZIDE DOC Generici 8 mg + 12.5 mg tablets are presented as white, biconvex tablets with a break line on one side and CH8 imprint on the same side.

Candesartan and HYDROCHLOROTHIAZIDE DOC Generici 16 mg + 12.5 mg tablets are presented as white, biconvex tablets with a break line on one side and CH16 imprint 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 and HYDROCHLOROTHIAZIDE DOC Generici is indicated for:

• Treatment of essential hypertension in adult patients with blood pressure inadequately controlled by monotherapy with candesartan cilexetil or hydrochlorothiazide.

04.2 Posology and method of administration -

Dosage

The recommended dose of Candesartan / Hydrochlorothiazide DOC Generici is one tablet once a day.

Dose titration with the individual components (candesartan cilexetil and hydrochlorothiazide) is recommended. If clinically appropriate, a direct switch from treatment with monotherapy to CANDESARTAN and HYDROCHLOROTHIAZIDE DOC Generici may be considered. Dose titration of candesartan cilexetil is recommended when switching from hydrochlorothiazide monotherapy. Candesartan / HYDROCHLOROTHIAZIDE DOC Generici can be administered to patients whose blood pressure is not adequately controlled by monotherapy with candesartan cilexetil or hydrochlorothiazide or Candesartan and hydrochlorothiazide at lower doses (see sections 4.3, 4.4, 4.5 and 5.1).

The maximum antihypertensive effect is usually achieved within 4 weeks of starting treatment.

Special populations

Elderly population

No dosage adjustment is necessary in elderly patients.

Intravascular volume depletion

In patients at risk of hypotension, such as patients with possible intravascular volume depletion, a progressive increase of candesartan cilexetil is recommended (a starting dose of 4 mg may be considered in these patients).

Kidney damage

In these patients it is preferable to administer loop diuretics rather than thiazides. Dose titration of candesartan cilexetil is recommended in patients with mild to moderate renal impairment (creatinine clearance is? 30 ml / min / 1.73 m² body surface area (BSA)) before switching to CANDESARTAN and HYDROCHLOROTHIAZIDE DOC Generici (the recommended starting dose of candesartan cilexetil in these patients is 4 mg). The use of Candesartan and Hydrochlorothiazide is contraindicated in patients with severe renal impairment (creatinine clearance

Hepatic impairment

Dose titration of candesartan cilexetil is recommended in patients with mild to moderate hepatic impairment prior to switching to CANDESARTAN / HYDROCHLOROTHIAZIDE DOC Generici (the recommended starting dose of candesartan cilexetil is 4 mg in these patients).

The use of Candesartan and Hydrochlorothiazide is contraindicated in patients with severe hepatic impairment and / or cholestasis (see section 4.3).

Pediatric population

The safety and efficacy of Candesartan / Hydrochlorothiazide in newborn children and up to 18 years of age have not been established. No data are available.

Method of administration

Oral use.

CANDESARTAN and HYDROCHLOROTHIAZIDE DOC Generici can be administered regardless of food intake.

The bioavailability of candesartan is not affected by food.

There is no clinically significant interaction between hydrochlorothiazide and food.

04.3 Contraindications -

• Hypersensitivity to the active substances, to sulfonamide derivatives or to any of the excipients listed in section 6.1. Hydrochlorothiazide is a sulfonamide derivative.

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

• Severe impairment of renal function (creatinine clearance

• Severe impairment of liver function and / or cholestasis.

• Refractory hypokalaemia and hypercalcemia.

• Gout.

The concomitant use of Candesartan and Hydrochlorothiazide 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 / kidney transplant

In these patients it is preferable to administer loop diuretics rather than thiazides. When CANDESARTAN / HYDROCHLOROTHIAZIDE DOC Generici is administered to patients with impaired renal function, it is recommended that potassium, creatinine and uric acid levels be monitored periodically.

The use of Candesartan and Hydrochlorothiazide in patients who have undergone a recent kidney transplant has not been tested.

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 single kidney.

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.

Intravascular volume depletion

Symptomatic hypotension may occur in patients with intravascular volume and / or sodium depletion, as described for other agents acting on the renin-angiotensin-aldosterone system. Therefore, the use of Candesartan and HYDROCHLOROTHIAZIDE DOC Generici is not recommended until this condition has been corrected.

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.

Altered liver function

Thiazides should be used with caution in patients with impaired hepatic function or progressive liver disease, as minimal changes in fluid and electrolyte balance can cause hepatic coma. There is no clinical experience with Candesartan and Hydrochlorothiazide in patients with impaired liver function.

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 drugs which work by inhibiting the renin-angiotensin-aldosterone system. Therefore the use of Candesartan and Hydrochlorothiazide DOC Generici is not recommended in this population.

Electrolyte imbalance

Periodic determination of serum electrolytes should be performed at appropriate intervals. Thiazides, including hydrochlorothiazide, can cause fluid or electrolyte imbalance (hypercalcaemia, hypokalaemia, hyponatremia, hypomagnesaemia and hypochloraemic alkalosis).

Thiazide diuretics may decrease urinary calcium excretion and cause intermittent and mild increases in serum calcium concentrations. Marked hypercalcaemia may be a sign of latent hyperparathyroidism. Thiazides must be discontinued before performing parathyroid function tests.

Hydrochlorothiazide dose-dependently increases urinary excretion of potassium which may induce hypokalaemia. This effect of hydrochlorothiazide seems less evident when combined with candesartan cilexetil. The risk of hypokalaemia may be increased in patients with cirrhosis of the liver, with rapid diuresis, in patients with inadequate oral intake of electrolytes and in patients on concomitant therapy with corticosteroids or adrenocorticotropic hormone (ACTH).

Treatment with candesartan cilexetil can cause hyperkalaemia, especially in the presence of heart failure and / or impaired renal function. Concomitant use of Candesartan and HYDROCHLOROTHIAZIDE DOC Generici and potassium-sparing diuretics, potassium supplements, potassium-containing salt substitutes or other drugs that may increase serum potassium levels (eg sodium heparin) may lead to increases in potassium.

Potassium monitoring should be performed as needed.

Thiazides increase urinary excretion of magnesium, which can induce hypomagnesaemia.

Metabolic and endocrine effects

Treatment with a thiazide diuretic can impair glucose tolerance. Dosage adjustment of antidiabetic drugs, including insulin, may be necessary. Latent diabetes mellitus may become manifest during thiazide therapy. Increases in cholesterol and triglyceride levels have been associated with thiazide diuretic therapy. At the doses contained in Candesartan and Hydrochlorothiazide DOC Generici only minimal effects have been reported. Thiazide diuretics increase uricaemia and can cause gout in predisposed patients.

Photosensitivity

Photosensitivity reactions have been reported during the use of thiazide diuretics (see section 4.8). In case of a photosensitivity reaction it is recommended to stop treatment. If it is necessary to restart treatment, it is recommended to protect the exposed parts of the body in sunlight or artificial UVA rays.

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 with other medicinal products affecting this system, including AIIRAs, has been associated with acute hypotension, BUN, oliguria or, rarely, acute renal failure. As with other antihypertensive drugs, excessive decrease in blood pressure in patients with ischemic heart disease or atherosclerotic cerebrovascular disease can lead to myocardial infarction or stroke.Hypersensitivity reactions to hydrochlorothiazide may occur, regardless of whether or not patients have a history of allergy or bronchial asthma, but are more likely in this type of patient. Exacerbation or activation has been reported with the use of thiazide diuretics. of systemic lupus erythematosus.

The antihypertensive effect of Candesartan and HYDROCHLOROTHIAZIDE DOC Generici may be enhanced by other antihypertensive agents.

This medicinal product contains lactose as an excipient, and therefore patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption syndrome should not take this medicinal product..

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 instituted (see sections 4.3 and 4.6).

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

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).

Compounds that have been tested in clinical pharmacokinetic studies include warfarin, digoxin, oral contraceptives (i.e. ethinyl estradiol / levonorgestrel), glibenclamide and nifedipine. No clinically relevant pharmacokinetic interactions were identified in these studies.

The potassium-depleting effect of hydrochlorothiazide could be potentiated by other drugs associated with potassium loss and hypokalaemia (eg, other kaliuretic diuretics, laxatives, amphotericin, carbenoxolone, penicillin sodium G, salicylic acid derivatives, steroids, ACTH) .

Concomitant use of Candesartan and HYDROCHLOROTHIAZIDE DOC Generici and potassium-sparing diuretics, potassium supplements or salt substitutes containing potassium or other medicinal products that may increase serum potassium levels (eg sodium heparin), may lead to increases in potassium Monitoring of potassium must be done in an appropriate manner in consideration (see section 4.4).

Diuretic-induced hypokalaemia and hypomagnesaemia predispose to the potential cardiotoxic effects of digitalis glycosides and antiarrhythmics. It is recommended that potassium levels be monitored periodically when CANDESARTAN / HYDROCHLOROTHIAZIDE DOC Generici is administered with these drugs and with the following drugs that can induce torsades de pointes:

• Class Ia antiarrhythmics (eg quinidine, hydroquinidine, disopyramide)

• Class III antiarrhythmics (eg amiodarone, sotalol, dofetilide, ibutilide)

• Some antipsychotics (eg thioridazine, chlorpromazine, levomepromazine, trifluoperazine, ciamemazine, sulpiride, sultopride, amisulpride, thiapride, pimozide, haloperidol, droperidol)

• Others (eg bepridil, cisapride, difemanil, iv erythromycin, halofantrine, cheetanserine, mizolastine, pentamidine, sparfloxacin, terfinadine, vincamine iv)

Reversible increases in serum lithium concentrations and toxic reactions have been reported during concomitant administration of lithium with Angiotensin Converting Enzyme (ACE) inhibitors or hydrochlorothiazide. A similar effect has been reported with AIIRAs. The use of candesartan and hydrochlorothiazide 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 pre-existing renal impairment. 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 periodically thereafter.

The diuretic, natriuretic and antihypertensive effect of hydrochlorothiazide is attenuated by non-steroidal anti-inflammatory drugs (NSAIDs).

Absorption of hydrochlorothiazide is reduced by colestipol or cholestyramine.

The effect of non-depolarising musculoskeletal relaxants (eg tubocurarine) can be enhanced by hydrochlorothiazide.

Thiazide diuretics can increase serum calcium levels due to decreased excretion. If calcium or vitamin D supplements are to be prescribed, serum calcium levels should be monitored and dosage adjusted accordingly.

The hyperglycemic effect of beta-blockers and diazoxide may be potentiated by thiazides.

Anticholinergic agents (e.g., atropine, biperidene) may increase the bioavailability of thiazide diuretics by reducing gastrointestinal motility and stomach emptying rate.

Thiazides may increase the risk of adverse events caused by amantadine.

Thiazides may reduce the renal excretion of cytotoxic drugs (eg, cyclophosphamide, methotrexate) and enhance their myelosuppressive effects.

Postural hypotension can be aggravated by the simultaneous intake of alcohol, barbiturates or anesthetics.

Treatment with thiazide diuretics can impair glucose tolerance. Dosage adjustments of antidiabetic drugs, including insulin, may be necessary. Metformin should be used with caution due to the risk of lactic acidosis which may result from "possible renal insufficiency linked to" hydrochlorothiazide.

Hydrochlorothiazide may cause a decrease in the arterial response to pressor amines (eg, adrenaline), but not such as to abolish the pressure effect.

Hydrochlorothiazide may increase the risk of acute renal failure, especially with high doses of iodinated contrast media.

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

Concomitant treatment with baclofen, amifostine, tricyclic or neuroleptic antidepressants may result in an increase in the antihypertensive effect and induce hypotension.

04.6 Pregnancy and breastfeeding -

Pregnancy

Angiotensin II Receptor Antagonists (AIIRA):

The use of Angiotensin II Receptor Antagonists (AIIRA) 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 no controlled epidemiological data on risk with angiotensin II receptor antagonists (AIIRAs) are available, a similar risk may also exist for this class of medicinal products. An alternative antihypertensive treatment should be used for patients planning pregnancy. with a 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 trimester of pregnancy 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).

Hydrochlorothiazide:

Experience with the use of hydrochlorothiazide during pregnancy is limited, especially during the first trimester. Animal studies are not enough.

Hydrochlorothiazide crosses the placenta. Considering the pharmacological mechanism of action of hydrochlorothiazide, its use during the second and third trimester of pregnancy can compromise fetal-placental perfusion and cause fetal and neonatal effects such as jaundice, disturbances in electrolyte balance and thrombocytopenia.

Hydrochlorothiazide should not be used for gestational edema, gestational hypertension or preeclampsia, due to the risk of decreased plasma volume and placental hypoperfusion, with no beneficial effect on the course of the disease.

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

Feeding time

Angiotensin II Receptor Antagonists (AIIRA):

Since no information is available on the use of Candesartan and Hydrochlorothiazide during breastfeeding, the use of Candesartan and Hydrochlorothiazide is not recommended and alternative treatments with a known better safety profile during breastfeeding are preferable, especially in the case of newborns or premature babies.

Hydrochlorothiazide:

Hydrochlorothiazide is excreted in human breast milk in minimal quantities. Thiazides, by causing intense diuresis in high doses, can inhibit milk production. The use of Candesartan and Hydrochlorothiazide during breastfeeding is not recommended.

04.7 Effects on ability to drive and use machines -

No studies on the ability to drive and use machines have been performed. When driving vehicles or using machines, it should be taken into account that occasionally dizziness or dizziness may occur with the use of Candesartan and Hydrochlorothiazide fatigue.

04.8 Undesirable effects -

In controlled clinical trials performed with candesartan cilexetil / hydrochlorothiazide, adverse events were mild and transient. Discontinuation of treatment due to adverse events was similar with candesartan cilexetil / hydrochlorothiazide (2.3-3.3%) and placebo (2.7-4.3%).

In clinical trials with candesartan cilexetil / hydrochlorothiazide adverse reactions were limited to those previously reported with candesartan cilexetil and / or hydrochlorothiazide.

The table below presents the adverse reactions reported with candesartan cilexetil in clinical studies and post marketing experience. From a comprehensive analysis of data from clinical trials in hypertensive patients, adverse reactions with candesartan cilexetil were defined on the basis of incidence. adverse events with candesartan cilexetil at least 1% higher than the incidence observed with placebo.

The frequencies used in the tables throughout section 4.8 are:

Very common (≥1 / 10), Common (≥1 / 100,

System and organ classification Frequency Undesirable effect Infections and infestations common Respiratory infections 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 Respiratory, thoracic and mediastinal disorders Very rare Cough 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 Renal impairment including renal failure in susceptible patients (see section 4.4)

The table below presents adverse reactions reported with hydrochlorothiazide alone, usually at doses of 25 mg or higher.

System and organ classification Frequency Undesirable effect Disorders of the blood and lymphatic system Rare Leukopenia, neutropenia / agranulocytosis, thrombocytopenia, aplastic anemia, bone marrow depression, haemolytic anemia Disorders of the immune system Rare Anaphylactic reactions Metabolism and nutrition disorders common Hyperglycaemia, hyperuricaemia, electrolyte imbalance (including hyponatremia and hypokalaemia) Psychiatric disorders Rare Sleep disturbances, depression, restlessness Nervous system disorders common Slight dizziness, dizziness Rare Paresthesia Eye disorders Rare Transient blurred vision Cardiac pathologies Rare Cardiac arrhythmias Vascular pathologies Uncommon Postural hypotension Rare Necrotizing angitis (vasculitis and cutaneous vasculitis) Respiratory, thoracic and mediastinal disorders Rare Breathing difficulty (including pneumonia and pulmonary edema) Gastrointestinal disorders Uncommon Anorexia, loss of appetite, gastric irritation, diarrhea, constipation Rare Pancreatitis Hepatobiliary disorders Rare Jaundice (intrahepatic cholestatic jaundice) Skin and subcutaneous tissue disorders Uncommon Rash, urticaria, photosensitivity reactions Rare Toxic epidermal necrolysis, lupus erythematosus-like reactions, reactivation of cutaneous lupus erythematosus Musculoskeletal and connective tissue disorders Rare Muscle spasm Renal and urinary disorders common Glycosuria Rare Renal dysfunction and interstitial nephritis General disorders and administration site conditions common Weakness Rare Fever Diagnostic tests common Increase in cholesterol and triglycerides Rare Increase in BUN and serum creatinine

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. at the address www.agenziafarmaco.gov.it/it/responsabili.

04.9 Overdose -

Symptoms

Based on pharmacological considerations, the main manifestations of an overdose of candesartan cilexetil are expected to be symptomatic hypotension and dizziness. In individual reports of overdose (up to 672 mg candesartan cilexetil), the patient recovered without consequences.

The main manifestation of hydrochlorothiazide overdose is acute loss of fluids and electrolytes. Symptoms such as dizziness, hypotension, thirst, tachycardia, ventricular arrhythmia, sedation / impaired consciousness and muscle cramps have also been observed.

Methods of intervention in case of overdose

No specific information is available in the treatment of overdose with Candesartan and Hydrochlorothiazide. In the event of an overdose it is however recommended to take the following measures.

When indicated, induction of vomiting or gastric lavage should be considered. If symptomatic hypotension occurs, symptomatic treatment should be instituted and vital functions monitored. The patient should be placed in a supine position with legs elevated. . If this is not sufficient, the plasma volume should be increased by infusion of isotonic saline. Serum electrolytes and acid-base balance should be monitored and corrected if necessary. Sympathomimetic drugs can be administered if the above measures were insufficient.

Candesartan cannot be removed by hemodialysis. The amount of hydrochlorothiazide that can be removed by hemodialysis is not known.

05.0 PHARMACOLOGICAL PROPERTIES -

05.1 "Pharmacodynamic properties -

Pharmacotherapeutic group: Angiotensin II antagonists + diuretics, ATC code C09D A06.

Angiotensin II is the main vasoactive hormone of the renin-angiotensin-aldosterone system and plays a role in the pathophysiology of hypertension and other cardiovascular diseases. It also plays a role in the pathogenesis of hypertrophy and organ damage. 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 which is rapidly converted to the active substance, candesartan, by ester hydrolysis during absorption from the gastrointestinal tract. Candesartan is AIIRA selective for AT1 receptors, with close binding and slow dissociation from the receptor. He has no competitive activity.

Candesartan does not affect ACE or other enzyme systems usually associated with the use of ACE inhibitors.Since there is no effect on the breakdown of kinins or the metabolism of other substances, such as substance P, angiotensin II receptor antagonists are unlikely to be associated with cough. In controlled clinical trials comparing candesartan cilexetil 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 cardiovascular regulation. L "AT1 receptor antagonism manifests itself in dose-related increases in plasma levels of renin, angiotensin I and angiotensin II, and in a decrease in plasma aldosterone concentrations.

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 with 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 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 1,000 patient-years in the candesartan group vs 30.0 events per 1,000 patient-years in the control group (relative risk 0.89, 95% CI 0.75 - 1.06, p = 0.19).

Hydrochlorothiazide inhibits the active reabsorption of sodium, mainly in the distal renal tubules and promotes the excretion of sodium, chloride and water. Renal excretion of potassium and magnesium increases in a dose-dependent manner, while calcium is reabsorbed to a greater extent. Hydrochlorothiazide decreases plasma volume and extracellular fluids and reduces cardiac output and blood pressure. During long-term therapy, the reduction of peripheral resistance contributes to the reduction of blood pressure.

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

Candesartan and hydrochlorothiazide have additive antihypertensive effects.

In hypertensive patients, candesartan cilexetil / hydrochlorothiazide causes a dose-dependent and long-lasting reduction in blood pressure without reflex increases in heart rate. No severe or excessive first dose hypotension or rebound effects were observed after discontinuation of treatment. Following a single dose administration of candesartan cilexetil / hydrochlorothiazide, the onset of the antihypertensive effect usually occurs within 2 hours. With continued treatment, the maximum antihypertensive effect on blood pressure is achieved within 4 weeks and is maintained during long-term treatment. Candesartan cilexetil / hydrochlorothiazide tablets administered once daily results in an effective and homogeneous reduction in blood pressure over 24 hours, with a small difference in the ratio between the peak and trough effects during the interval between doses. a randomized, double-blind study, candesartan cilexetil / hydrochlorothiazide 16 mg + 12.5 mg once daily reduced blood pressure significantly more and controlled more patients than the combination losartan / hydrochlorothiazide 50 mg / 12.5 mg once daily.

In double-blind, randomized studies, the incidence of adverse events, especially cough, was lower during treatment with candesartan cilexetil / hydrochlorothiazide compared to treatment with combinations of ACE inhibitors and hydrochlorothiazide.

Candesartan cilexetil / hydrochlorothiazide is equally effective in all patients regardless of age and gender.

There are currently no data on the use of candesartan cilexetil / hydrochlorothiazide in patients with renal disease / nephropathy, reduced left ventricular function / congestive heart failure and post-myocardial infarction.

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 -

Concomitant administration of candesartan cilexetil and hydrochlorothiazide did not produce a clinically significant effect on the pharmacokinetics of either of the components.

Absorption and distribution

Candesartan cilexetil

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 of candesartan cilexetil compared to the oral solution is approximately 34% with very little variability. Mean peak serum concentrations (Cmax) are achieved within 3-4 hours of tablet intake. 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) of serum concentration over time is not significantly affected by food.

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

Hydrochlorothiazide

Hydrochlorothiazide is rapidly absorbed from the gastrointestinal tract with an absolute bioavailability of approximately 70%. Concomitant administration with food increases absorption by approximately 15%. Bioavailability may decrease in patients with heart failure and pronounced edema.

Plasma protein binding of hydrochlorothiazide is approximately 60%. The apparent volume of distribution is approximately 0.8 l / kg.

Biotransformation and elimination

Candesartan cilexetil

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 in vitro data, no in vivo interactions are expected with drugs whose metabolism depends on cytochrome P450 isoenzymes CYP1A2, CYP2A6, CYP2C9, CYP2C19, CYP2D6, CYP2E1 or CYP3A4. The terminal half-life (t½) of candesartan is approximately 9 hours. No accumulation is observed following repeated dosing. The half-life of candesartan remains unchanged (approximately 9 hours) after administration of candesartan cilexetil in combination with hydrochlorothiazide. No additional accumulation of candesartan occurs after repeated administration of the combination compared to monotherapy.

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.

Hydrochlorothiazide

Hydrochlorothiazide is not metabolised and is excreted almost entirely as unchanged drug by glomerular filtration and active tubular secretion. The terminal half-life (t1 / 2) of hydrochlorothiazide is approximately 8 hours. Approximately 70% of an oral dose is eliminated. in urine within 48 hours. The half-life of hydrochlorothiazide remains unchanged (approximately 8 hours) after administration of hydrochlorothiazide in combination with candesartan cilexetil. There is no additional accumulation of hydrochlorothiazide after repeated administration of the combination compared to monotherapy.

Pharmacokinetics in special populations

Candesartan cilexetil

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 / hydrochlorothiazide in young and elderly patients (see section 4.2).

In patients with mild and moderate renal impairment, candesartan Cmax and AUC during repeated dosing increased by approximately 50% and 70%, respectively, but terminal t1 / 2 was not altered compared to patients with normal kidney function. Corresponding changes in patients with severe renal impairment were approximately 50% and 110%, respectively. The terminal t1 / 2 of candesartan was approximately doubled in patients with severe renal impairment. The pharmacokinetic profile in hemodialysis patients was similar to that of 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.

Hydrochlorothiazide

The terminal t1 / 2 of hydrochlorothiazide is prolonged in patients with impaired renal function.

05.3 Preclinical safety data -

No new toxic effects were observed with the combination compared to those observed with the individual components. 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 tubular regeneration, dilation and basophilicity; increased plasma concentrations of urea and creatinine) were induced by candesartan and may be secondary to the hypotensive effect resulting in impaired renal perfusion. The addition of hydrochlorothiazide potentiates the nephrotoxicity of candesartan. Furthermore, candesartan induced hyperplasia / hypertrophy of the juxtaglomerular cells. These changes can be considered as a consequence of the pharmacological action of candesartan and of little clinical relevance.

Foetotoxicity has been observed in advanced pregnancy with candesartan. The addition of hydrochlorothiazide did not significantly affect fetal development in rats, mice and rabbits (see section 4.6).

Candesartan and hydrochlorothiazide exhibit genotoxic activity at very high concentrations / doses. The genotoxicity data in vitro And in vivo indicate that candesartan and hydrochlorothiazide are unlikely to exert mutagenic or clastogenic activity under conditions of clinical use. No carcinogenic phenomena were observed with either compound.

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 medicine does not require any special storage conditions.

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

PVC-PVDC / Al blisters

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 -

No particular precautions.

07.0 HOLDER OF THE "MARKETING AUTHORIZATION" -

DOC Generici Srl, via Turati 40, 20121 Milan

08.0 MARKETING AUTHORIZATION NUMBER -

040508018 - 8 mg / 12.5 mg tablets - 7 tablets in PVC-PVDC / AL blister

040508020 - 8 mg / 12.5 mg tablets - 14 tablets in PVC-PVDC / AL blister

040508032 - 8 mg / 12.5 mg tablets - 28 tablets in PVC-PVDC / AL blister

040508044 - 8 mg / 12.5 mg tablets - 30 tablets in PVC-PVDC / AL blister

040508057 - 8 mg / 12.5 mg tablets - 56 tablets in PVC-PVDC / AL blister

040508069 - 8 mg / 12.5 mg tablets - 70 tablets in PVC-PVDC / AL blister

040508071 - 8 mg / 12.5 mg tablets - 90 tablets in PVC-PVDC / AL blister

040508083 - 8 mg / 12.5 mg tablets - 98 tablets in PVC-PVDC / AL blister

040508095 - 16 mg / 12.5 mg tablets - 7 tablets in PVC-PVDC / AL blister

040508107 - 16 mg / 12.5 mg tablets - 14 tablets in PVC-PVDC / AL blister

040508119 - 16 mg / 12.5 mg tablets - 28 tablets in PVC-PVDC / AL blister

040508121 - 16 mg / 12.5 mg tablets - 30 tablets in PVC-PVDC / AL blister

040508133 - 16 mg / 12.5 mg tablets - 56 tablets in PVC-PVDC / AL blister

040508145 - 16 mg / 12.5 mg tablets - 70 tablets in PVC-PVDC / AL blister

040508158 - 16 mg / 12.5 mg tablets - 90 tablets in PVC-PVDC / AL blister

040508160 - 16 mg / 12.5 mg tablets - 98 tablets in PVC-PVDC / AL blister

09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION -

July 2012

10.0 DATE OF REVISION OF THE TEXT -

July 2016

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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