Combisartan - 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: Valsartan, Hydrochlorothiazide

Combisartan 80 mg / 12.5 mg film-coated tablets
Combisartan 160 mg / 12.5 mg film-coated tablets
Combisartan 160 mg / 25 mg film-coated tablets
Combisartan 320 mg / 12.5 mg film-coated tablets
Combisartan 320 mg / 25 mg film-coated tablets

Indications Why is Combisartan used? What is it for?

Combisartan film-coated tablets contain two active substances called valsartan and hydrochlorothiazide. Both of these substances help control high blood pressure (hypertension).

  • Valsartan belongs to a class of medicines known as "angiotensin II receptor antagonists", which help control high blood pressure. Angiotensin II is a substance in the body that causes blood vessels to narrow, thereby leading to the increase in pressure. Valsartan works by blocking the effect of angiotensin II. The result is that the blood vessels relax and the blood pressure drops.
  • Hydrochlorothiazide belongs to a group of medicines called thiazide diuretics.
  • Hydrochlorothiazide increases the amount of urine eliminated and, in so doing, reduces blood pressure.

Combisartan is used to treat high blood pressure when blood pressure is not sufficiently controlled by a single medicine.

When blood pressure is high, the workload on the heart and arteries increases. If left untreated it can damage the blood vessels of the brain, heart and kidneys and can lead to stroke, heart failure or kidney failure. High blood pressure increases the risk of heart attack. Bringing blood pressure back to normal reduces the risk of developing these conditions.

Contraindications When Combisartan should not be used

Do not take Combisartan:

  • if you are allergic (hypersensitive) to valsartan, hydrochlorothiazide, sulphonamide derivatives (substances chemically related to hydrochlorothiazide) or any of the other ingredients of Combisartan (listed in section 6)
  • if you are more than 3 months pregnant (it is also better to avoid Combisartan in early pregnancy - see pregnancy section)
  • if you have severe liver problems, destruction of the small bile channels in the liver (biliary cirrhosis) leading to the accumulation of bile in the liver (cholestasis)
  • if you have severe kidney problems
  • if you cannot urinate (anuria)
  • if you are being treated with an artificial kidney
  • if your blood potassium or sodium levels are lower than normal or if your blood calcium levels are higher than normal despite treatment
  • if you have gout
  • if you have diabetes or impaired kidney function and you are being treated with a blood pressure lowering medicine containing aliskiren.

If any of these apply to you, do not take this medicine and contact your doctor.

Precautions for use What you need to know before taking Combisartan

Take special care with Combisartan

  • if you are taking potassium-sparing medicines, potassium supplements, salt substitutes containing potassium or other medicines that increase potassium levels in the blood, such as heparin. Your doctor may need to check your potassium level in the blood at regular intervals. blood
  • if your blood potassium levels are low
  • if you have diarrhea or severe vomiting
  • if you are taking high doses of medicines that increase the elimination of fluids (diuretics)
  • if you have severe heart problems
  • if you have heart failure or have had a heart attack. Carefully follow your doctor's instructions on the starting dose of therapy. Your doctor will also check your kidney function.
  • if you suffer from a narrowing of the renal artery
  • if you have recently received a new kidney
  • if you suffer from hyperaldosteronism, a disease in which the adrenal glands produce too much aldosterone hormone. If this applies to you, the use of Combisartan is not recommended
  • if you have liver or kidney disease
  • if you have ever had swelling of the tongue and face caused by an allergic reaction called angioedema when taking other medicines (including ACE inhibitors), please tell your doctor. If these symptoms occur when taking Combisartan, stop taking Combisartan immediately and never take it again. See section 4, "Possible side effects"
  • if you have fever, rash and joint pain, which may be signs of systemic lupus erythematosus (SLE, a so-called autoimmune disease)
  • if you have diabetes, gout, high cholesterol or triglyceride levels in the blood
  • if you have had allergic reactions to the use of other blood pressure lowering medicines of the same class (angiotensin II receptor antagonists) or if you suffer from allergy or asthma.
  • if you experience decreased vision or eye pain. These may be symptoms of "increased intraocular pressure and can occur a few hours to a week after taking Combisartan. If left untreated, this can lead to permanent vision loss. If you have previously had an allergy to penicillins or sulphonamides. an increased risk of developing this disorder
  • it can cause the skin to be more sensitive to the sun
  • if you are taking any of the following medicines used to treat high blood pressure: - an "ACE inhibitor" (for example enalapril, lisinopril, ramipril), in particular if you have diabetes-related kidney problems. - aliskiren
  • if you are being treated with an ACE inhibitor together with other medicines used to treat heart failure, known as mineralocorticoid receptor antagonists (MRAs) (eg spironolactone, eplerenone) or beta blockers (eg metoprolol).

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

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

If any of these apply to you, please contact your doctor.

Combisartan is not recommended for use in children and adolescents (below 18 years of age).

You should tell your doctor if you think you are pregnant (or if there is a possibility of becoming pregnant). Combisartan 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).

Interactions Which drugs or foods may modify the effect of Combisartan

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines, including medicines obtained without a prescription.

The effect of the treatment can be influenced if Combisartan is taken with certain other medicines.

It may be necessary to change the dose, to take other precautions or, in some cases, to stop taking one of the medicines. This applies in particular to the following medicines:

  • lithium, a medicine used to treat some types of psychiatric disorders
  • medicines or substances that can increase the amount of potassium in your blood. These include potassium supplements or potassium-containing salt substitutes, potassium-sparing medicines and heparin
  • medicines that can decrease the amount of potassium in the blood, such as diuretics (medicines that increase the elimination of fluids), corticosteroids, laxatives, carboxolone, amphotericin or penicillin G.
  • some antibiotics (rifampicin group), a drug used against transplant rejection (cyclosporine) and an antiretroviral drug used to treat HIV / AIDS infections (ritonavir). These drugs may increase the effect of Combisartan
  • medicines that can induce torsades de pointes (irregular heartbeat), such as antiarrhythmics (medicines used to treat heart disorders) and some antipsychotics.
  • medicines that can reduce the amount of sodium in the blood, such as antidepressants, antipsychotics, antiepileptics
  • medicines for the treatment of gout, such as allopurinol, probenecid, sulfinpyrazone
  • therapeutic vitamin D and calcium supplements,
  • medicines used to treat diabetes (for oral use such as metformin or insulins)
  • other blood pressure lowering medicines, including methyldopa, ACE inhibitors (such as enalapril, lisinopril, etc.) or aliskiren (see also information under the headings: "Do not take Combisartan" and "Take special care with Combisartan").
  • medicines that increase blood pressure, such as norepinephrine and adrenaline
  • digoxin or other digitalis glycosides (medicines used to treat heart problems)
  • medicines that can increase blood sugar levels, such as diazoxide or beta blockers
  • cytotoxic medicines (used to treat cancer), such as methotrexate or cyclophosphamide
  • pain relievers such as non-steroidal anti-inflammatory drugs (NSAIDs), including selective cyclooxygenase-2 (Cox-2) inhibitors and acetylsalicylic acid> 3 g
  • muscle relaxing medicines, such as tubocurarine
  • anti-cholinergic medicines, (medicines used to treat various ailments such as gastrointestinal cramps, bladder spasm, asthma, motion sickness, muscle spasms, Parkinson's disease and to facilitate anesthesia)
  • amantadine (medicine used to treat Parkinson's disease and also to treat or prevent certain diseases caused by viruses)
  • cholestyramine and colestipol (medicines used mainly to treat high levels of lipids in the blood)
  • ciclosporin, a medicine used in organ transplantation to prevent organ rejection
  • alcohol, sleeping pills and anesthetics (medicines with narcotic or pain-relieving effect used for example during surgery)
  • iodinated contrast media (used for radiological examinations)

Taking Combisartan with food and drink

Combisartan can be taken with or without food. Avoid drinking alcohol unless you have talked to your doctor first. Alcohol can further reduce blood pressure and / or increase the risk of dizziness or fainting.

Warnings It is important to know that:

Pregnancy and breastfeeding

Ask your doctor or pharmacist for advice before taking any medicine.

  • You should tell your doctor if you think you are pregnant (or if there is a possibility of becoming pregnant). Your doctor will normally advise you to stop taking Combisartan before you become pregnant or as soon as you start to know that you are pregnant and will advise you to take another medicine instead of Combisartan. Combisartan is not recommended in early pregnancy and must not be taken if you are more than 3 months pregnant as it can cause serious harm to the baby if taken after the third month of pregnancy.
  • Tell your doctor if you are breastfeeding or about to start breastfeeding Combisartan 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 newborn or was born prematurely. .

Driving and using machines

Before you drive a vehicle, operate machinery or perform other activities that require concentration, you should know your reaction to Combisartan. Like many other medicines used to treat high blood pressure, Combisartan can in rare cases cause dizziness and affect your ability to concentrate.

For those who carry out sporting activities: the use of the drug without therapeutic necessity constitutes doping and can in any case determine positive anti-doping tests.

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

Always take Combisartan exactly as your doctor has told you. This will help you get better results and reduce the risk of side effects. If you are unsure, consult your doctor or pharmacist.

Those with high blood pressure often don't notice any signs of this problem, and many feel as good as usual. For this reason it is very important that you keep regular appointments with your doctor, even when you are feeling well.

Your doctor will tell you exactly how many Combisartan tablets to take. Based on your response to treatment, your doctor may suggest a higher or lower dose.

  • The usual dose of Combisartan is one tablet per day.
  • Do not change your dose or stop taking the tablets without first checking with your doctor.
  • This medicine should be taken at the same time each day, usually in the morning.
  • You can take Combisartan with or without food.
  • Swallow the tablet with a glass of water.

If you forget to take Combisartan

If you forget to take a dose, take it as soon as you remember it. However, if it is almost time for your next dose, skip the missed dose.

Do not take a double dose to make up for a forgotten dose.

If you stop taking Combisartan

Stopping treatment with Combisartan may cause your high blood pressure to get worse.

Do not stop using your medicine unless your doctor tells you to.

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

Overdose What to do if you have taken an overdose of Combisartan

In case of severe dizziness and / or fainting, it is best to lie down and contact your doctor immediately.

If you have inadvertently taken too many tablets, contact your doctor, pharmacist or hospital.

Side Effects What are the side effects of Combisartan

Like all medicines, Combisartan can cause side effects, although not everybody gets them.

These side effects can occur with certain frequencies, defined as follows:

  • very common: affects more than one user in 10
  • common: affects 1 to 10 users in 100
  • uncommon: affects 1 to 10 users in 1,000
  • rare: affects 1 to 10 users in 10,000
  • very rare: affects less than 1 user in 10,000
  • not known: frequency cannot be estimated from the available data.

Some side effects can be serious and require immediate medical attention.

See your doctor right away if you have symptoms of angioedema, such as:

  • swelling of the face, tongue or pharynx
  • difficulty swallowing
  • hives and difficulty in breathing

If you experience any of these symptoms, stop taking Combisartan and contact your doctor immediately (see also section 2 "Take special care with Combisartan").

Other side effects are:

Uncommon

  • cough
  • low pressure
  • light-headedness
  • dehydration (with symptoms such as thirst, dry mouth and tongue, infrequent urine, dark urine, dry skin)
  • muscular pain
  • tiredness
  • tingling or numbness
  • blurred vision
  • noises in the ears (e.g. ringing, hissing)

Very rare

  • dizziness
  • diarrhea
  • joint pain

Not known

  • difficulty in breathing
  • noticeable decrease in the amount of urine
  • low level of sodium in the blood (which can cause tiredness, confusion, muscle twitching and / or convulsions in severe cases)
  • low level of potassium in the blood (sometimes with muscle weakness, muscle spasms, abnormal heart rhythm)
  • low level of white blood cells (with symptoms such as fever, skin infections, sore throat or mouth ulcers due to infections, weakness)
  • increased level of bilirubin in the blood (which can, in severe cases, cause yellow skin and eyes)
  • increase in blood urea nitrogen and creatinine levels (which may indicate kidney failure)
  • increase in the level of uric acid in the blood (which can, in severe cases, cause gout)
  • syncope (fainting)

The following side effects have been reported with medicines containing valsartan or hydrochlorothiazide alone:

Valsartan

Uncommon

  • feeling of lightheadedness
  • abdominal pain

Not known

  • blistering of the skin (sign of bullous dermatitis)
  • rash with or without itching along with some of the following signs or symptoms: fever, joint pain, muscle pain, swollen lymph nodes and / or flu-like symptoms
  • rash, red-purple spots, fever, itching (symptoms of inflammation of the blood vessels)
  • low level of platelets in the blood (sometimes with unusual bleeding or bruising)
  • increased level of potassium in the blood (sometimes with muscle spasms, abnormal heart rhythm)
  • allergic reactions (with symptoms such as rash, itching, hives, difficulty breathing or swallowing, dizziness)
  • swelling mainly of the face and throat, rash, itching
  • increase in liver function values
  • decrease in hemoglobin levels and the percentage of red blood cells in the blood (which, in severe cases, can both lead to anemia)
  • kidney failure
  • low level of sodium in the blood (which can cause tiredness, confusion, muscle twitching and / or convulsions in severe cases)

Hydrochlorothiazide

Very common

  • low level of potassium in the blood
  • increased blood lipids

common

  • low level of sodium in the blood
  • low level of magnesium in the blood
  • high level of uric acid in the blood
  • itchy skin rashes or other types of rashes
  • decreased appetite
  • mild nausea and vomiting
  • dizziness, fainting when standing upright
  • inability to achieve or maintain an erection

Rare

  • swelling and blistering of the skin (due to "increased sensitivity to the sun)
  • high level of calcium in the blood
  • high blood sugar level
  • sugar in the urine
  • worsening of the metabolic state of diabetes
  • constipation, diarrhea, upset stomach or intestines, liver disorders which may occur with yellow skin or eyes
  • irregular heartbeat
  • headache
  • sleep disorders
  • sadness (depression)
  • low level of blood platelets (sometimes with bleeding or bruising under the skin)
  • dizziness
  • tingling or numbness
  • vision disturbances

Very rare

  • inflammation of blood vessels with symptoms such as skin rash, purplish red spots, fever (vasculitis)
  • rash, itching, hives, difficulty breathing or swallowing, dizziness (hypersensitivity reactions)
  • severe skin conditions causing rash, redness of the skin, blistering of the lips, eyes or mouth, peeling of the skin, fever (toxic epidermal necrolysis)
  • facial rashes, joint pain, muscle disorders, fever (lupus erythematosus)
  • severe upper stomach pain (pancreatitis)
  • difficulty in breathing with fever, cough, wheezing, shortness of breath (difficulty in breathing, including pneumonia and pulmonary edema)
  • fever, sore throat, frequent infections (agranulocytosis)
  • pale skin, tiredness, shortness of breath, dark urine (haemolytic anemia)
  • fever, sore throat or mouth ulcers due to infections (leukopenia)
  • confusion, tiredness, muscle tremor or spasm, shortness of breath (hypochloraemic alkalosis)

Not known

  • tiredness, bruising and frequent infections (aplastic anemia)
  • severe decrease in the amount of urine (possible sign of a kidney disorder or kidney failure)
  • decreased vision or pain in the eye due to high pressure in the eye (possible sign of acute narrow-angle glaucoma)
  • rash, redness of the skin, blistering of the lips, eyes or mouth, peeling of the skin, fever (possible signs of erythema multiforme)
  • muscle spasm
  • fever (pyrexia)
  • weakness (asthenia)

If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your doctor or pharmacist.

Expiry and Retention

  • Keep Combisartan out of the reach and sight of children.
  • Do not use Combisartan after the expiry date which is stated on the label. The expiry date refers to the last day of that month.
  • Do not store above 30 ° C. Store in the original package to protect from moisture.
  • Do not use Combisartan if you notice that the pack is damaged or shows signs of tampering.
  • 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 Combisartan contains

  • The active ingredients are valsartan and hydrochlorothiazide. Each film-coated tablet contains 80 mg, 160 mg or 320 mg of valsartan and 12.5 mg or 25 mg of hydrochlorothiazide, respectively.
  • The tablet core contains microcrystalline cellulose, crospovidone, anhydrous colloidal silica, magnesium stearate.
  • The tablet coating contains hypromellose, macrogol 8000 (80 mg / 12.5 mg and 160 mg / 12.5 mg only), macrogol 4000 (160 mg / 25 mg, 320 mg / 12.5 mg and 320 mg / 25 only) mg), talc, red iron oxide (E172, except 320 mg / 25 mg), yellow iron oxide (E172, only 80 mg / 12.5 mg, 160 mg / 12.5 mg and 320 mg / 12.5 mg) mg), black iron oxide (E172, only 160 mg / 25 mg and 320 mg / 12.5 mg), titanium dioxide (E171).

Description of what Combisartan looks like and contents of the pack

  • Combisartan 80 mg / 12.5 mg film-coated tablets are light orange, ovaloid, debossed "HGH" on one side and "CG" on the other side or "HGH" on one side only.
  • Combisartan 160 mg / 12.5 mg film-coated tablets are dark red, ovaloid, debossed "HHH" on one side and "CG" on the other side or "HHH" on one side only.
  • Combisartan 160 mg / 25 mg film-coated tablets are brown, ovaloid, debossed "HXH" on one side and "NVR" on the other side or "HXH" on one side only.
  • Combisartan 320 mg / 12.5 mg film-coated tablets are pink, ovaloid, bevelled edge, debossed "NVR" on one side and "HIL" on the other side or "HIL" on one side only.
  • Combisartan 320 mg / 25 mg film-coated tablets are yellow, ovaloid, debossed "CTI" on one side and "NVR" on the other side or "CTI" debossed on one side only.

Combisartan 80 mg / 12.5 mg tablets are available in calendar blisters, in packs of 14 or 28 tablets.

Combisartan 160 mg / 12.5 mg, 160 mg / 25 mg, 320 mg / 12.5 mg and 320 mg / 25 mg tablets are available in calendar blisters, in packs of 7 (320 mg / 12.5 mg only and 320 mg / 25 mg), 14, 28, 56, 98 or 280 tablets.

Divisible unit dose blisters are also available, in packs of 56x1 (only 320 mg / 12.5 and 320 mg / 25 mg), 98x1 (except 80 mg / 12.5) or 280x1 (only 320 mg / 12.5 and 320 mg / 25 mg) 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.

Further information on Combisartan 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 -

COMBISARTAN 160 MG / 12.5 MG TABLETS COATED WITH FILM

02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION -

Each tablet contains 160 mg of valsartan and 12.5 mg of hydrochlorothiazide.

For the full list of excipients, see section 6.1.

03.0 PHARMACEUTICAL FORM -

Film-coated tablet.

Dark red, ovaloid tablet engraved with the letters "HHH" on one side and "CG" on the other or engraved with the letters "HHH" on one side only.

04.0 CLINICAL INFORMATION -

04.1 Therapeutic indications -

Treatment of essential arterial hypertension in adults.

Combisartan is a fixed combination indicated in patients whose blood pressure is not adequately controlled by monotherapy with valsartan or hydrochlorothiazide.

04.2 Posology and method of administration -

Dosage

The recommended dose of Combisartan 160 mg / 12.5 mg is one film-coated tablet once daily. Dose titration with the individual components is recommended. In each case, titration of the individual components to the next dose should be taken in order to reduce the risk of hypotension and other adverse events.

If clinically appropriate, in patients whose blood pressure is not adequately controlled by valsartan or hydrochlorothiazide monotherapy, a direct switch from monotherapy to fixed combination may be considered, provided the recommended dose titration sequence for the individual components is followed.

Clinical response to Combisartan should be assessed after initiation of therapy and if blood pressure remains uncontrolled the dose of either component may be increased up to a maximum dose of Combisartan 320 mg / 25 mg.

The antihypertensive effect is substantially present within 2 weeks.

In the majority of patients, the maximum effect is seen within 4 weeks. However, 4-8 weeks of treatment may be required for some patients. This should be taken into account during dose titration.

Method of administration

Combisartan can be taken with or without food and must be administered with water.

Special populations

Kidney damage

No dose adjustment is required in patients with mild to moderate renal impairment (glomerular filtration rate ≥30 mL / min). Due to the hydrochlorothiazide component, Combisartan is contraindicated in patients with severe renal impairment (glomerular filtration rate anuria (see sections 4.3, 4.4 and 5.2).

Hepatic insufficiency

In patients with mild or moderate hepatic impairment without cholestasis, the dose of valsartan should not exceed 80 mg (see section 4.4). No dose adjustment of hydrochlorothiazide is required in patients with mild to moderate hepatic impairment. Due to the valsartan component, Combisartan is contraindicated in patients with severe hepatic impairment or with biliary cirrhosis and cholestasis (see sections 4.3, 4.4 and 5.2).

Senior citizens

No dose adjustment is required in elderly patients.

Pediatric patients

Combisartan is not recommended for use in children below 18 years due to a lack of data on safety and efficacy.

04.3 Contraindications -

• Hypersensitivity to valsartan, hydrochlorothiazide, other medicinal products containing sulphonamide derivatives or to any of the excipients.

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

• Severe hepatic impairment, biliary cirrhosis and cholestasis.

• Severe kidney damage (creatinine clearance

• Refractory hypokalaemia, hyponatremia, hypercalcemia and symptomatic hyperuricemia.

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

04.4 Special warnings and appropriate precautions for use -

Changes in serum electrolytes

Valsartan

Concomitant use of potassium supplements, potassium-sparing diuretics, potassium-containing salt substitutes, or other substances that may increase potassium levels (heparin, etc.) is not recommended. Blood potassium levels should be appropriately controlled. .

Hydrochlorothiazide

Hypokalaemia has been reported during treatment with thiazide diuretics, including hydrochlorothiazide. Frequent monitoring of serum potassium is recommended.

Therapy with thiazide diuretics, including hydrochlorothiazide, has been associated with hyponatremia and hypochloraemic alkalosis. Thiazides, including hydrochlorothiazide, increase urinary excretion of magnesium and therefore hypomagnesaemia may occur. reduced by thiazide diuretics and this can cause hypercalcaemia.

As with all patients on diuretic therapy, periodic monitoring of serum electrolytes should be performed at appropriate intervals.

Sodium and / or volume depleted patients

Patients taking thiazide diuretics, including hydrochlorothiazide, should be observed for clinical signs of fluid or electrolyte imbalance.

In highly sodium and / or volume depleted patients, such as those receiving high doses of diuretics, symptomatic hypotension may, in rare cases, occur after initiation of Combisartan therapy. Sodium and / or volume depletion should be corrected first. to start treatment with Combisartan.

Patients with severe chronic heart failure or other conditions that stimulate the renin-angiotensin-aldosterone system

In patients whose renal function may be dependent on the activity of the renin-angiotensin-aldosterone system (eg patients with severe congestive heart failure), treatment with angiotensin converting enzyme inhibitors has been associated with oliguria and / or progressive azotemia and, in rare cases, acute renal failure and / or death. Evaluation of patients with heart failure or post-myocardial infarction should always include examination of renal function. The use of Combisartan in patients with severe chronic heart failure has not been established. Therefore it cannot be excluded that, due to the inhibition of the renin-angiotensin-aldosterone system, the administration of Combisartan may also be associated with impaired renal function. . Combisartan should not be used in these patients.

Renal artery stenosis

Combisartan should not be used as an antihypertensive in patients with unilateral or bilateral renal artery stenosis or single kidney artery stenosis because BUN and serum creatinine may increase in these patients.

Primary hyperaldosteronism

Patients with primary aldosteronism should not be treated with Combisartan as their renin-angiotensin system is not active.

Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy

As with all other vasodilators, particular caution is required in patients suffering from aortic or mitral stenosis or obstructive hypertrophic cardiomyopathy.

Renal impairment

No dosage adjustment is required in patients with renal impairment with creatinine clearance ≥30 ml / min (see section 4.2). Periodic monitoring of serum potassium, creatinine and uric acid levels is recommended when Combisartan is used in patients with renal impairment.

Kidney transplant

There is currently no experience on the safe use of Combisartan in patients who have recently undergone kidney transplantation.

Hepatic impairment

In patients with mild or moderate hepatic impairment without cholestasis, Combisartan should be used with caution (see sections 4.2 and 5.2). Thiazide diuretics should be used with caution in patients with impaired liver function or progressive liver disease, as minimal changes in fluid and electrolyte balance can cause hepatic coma.

Previous episodes of angioedema

Episodes of angioedema, with enlargement of the larynx and glottis, resulting in airway obstruction and / or swelling of the face, lips, pharynx and / or tongue, have been reported in patients treated with valsartan; some of these patients had had previous episodes of angioedema with other medicines, including ACE inhibitors. In patients who develop angioedema, treatment with Combisartan should be stopped immediately and not restarted (see section 4.8).

Systemic lupus erythematosus

Thiazide diuretics, including hydrochlorothiazide, have been shown to exacerbate or activate systemic lupus erythematosus.

Other metabolic disorders

Thiazide diuretics, including hydrochlorothiazide, can impair glucose tolerance and raise serum cholesterol, triglyceride and uric acid levels. In diabetic patients, dosage adjustment of insulin or oral hypoglycemic agents may be necessary.

Thiazides may reduce urinary calcium excretion and cause a mild and intermittent rise in serum calcium in the absence of known disorders of calcium metabolism. Marked hypercalcaemia may be evidence of underlying hyperparathyroidism. Before performing parathyroid function tests. treatment with thiazides should be discontinued.

Photosensitivity

Cases of photosensitivity reactions have been reported during treatment with thiazide diuretics (see section 4.8). If photosensitivity reactions occur, it is recommended that treatment be discontinued. If it is considered necessary to resume administration of the diuretic, it is recommended to protect the parts exposed to the sun or artificial UVA rays.

Pregnancy

Angiotensin II receptor antagonist therapy (AIIRA) should not be initiated during pregnancy. An alternative antihypertensive treatment with an established safety profile for use in pregnancy should be used for patients planning 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 (see sections 4.3 and 4.6).

General

Particular caution is needed in patients who have had previous hypersensitivity reactions to other angiotensin II receptor antagonists. Hypersensitivity reactions to hydrochlorothiazide are more likely in patients with allergy and asthma.

Acute angle-closure glaucoma

Hydrochlorothiazide, a sulfonamide, has been associated with an idiosyncratic reaction, resulting in severe transient myopia and acute narrow-angle glaucoma. Symptoms include acute onset of reduced visual acuity or eye pain and usually appear within hours to one week after starting treatment. If left untreated, acute angle-closure glaucoma can cause permanent vision loss.

Primary treatment is to "discontinue administration of hydrochlorothiazide as quickly as possible. Prompt medical or surgical intervention may be necessary if intraocular pressure remains uncontrolled. Risk factors for developing acute narrow-angle glaucoma may include a history allergy to sulfonamide or penicillin.

Double 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.

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

Interactions related to both valsartan and hydrochlorothiazide

Concomitant use not recommended

Lithium

Reversible increases in serum concentrations and toxicity of lithium have been reported when lithium was co-administered with ACE inhibitors, angiotensin II receptor antagonists or thiazides, including hydrochlorothiazide. Since the renal clearance of lithium is reduced by thiazides, the risk of lithium toxicity may presumably further increase with the use of Combisartan. Should the use of the combination prove necessary, careful monitoring of serum lithium levels is recommended.

Concomitant use requiring caution

Other antihypertensive agents

Combisartan may enhance the effects of other agents with antihypertensive properties (eg guanethidine, methyldopa, vasodilators, ACE inhibitors, angiotensin receptor antagonists, beta-blockers, calcium channel blockers and renin inhibitors).

Pressor amines (e.g. adrenaline, noradrenaline)

A decrease in the response to pressor amines is possible. The clinical significance of this effect is uncertain and is not sufficient to preclude their use.

Non-steroidal anti-inflammatory drugs (NSAIDs), including selective COX-2 inhibitors, acetylsalicylic acid (> 3 g / day) and non-selective NSAIDs

When administered concomitantly, NSAIDs may attenuate the antihypertensive effect of both angiotensin II antagonists and hydrochlorothiazide. Furthermore, concomitant use of Combisartan and NSAIDs may lead to worsening of renal function and an increase in serum potassium. At the beginning of the treatment it is therefore recommended to check the renal function, as well as an adequate hydration of the patient.

Interactions related to valsartan

Double blockade of the renin-angiotensin-aldosterone system (RAAS) with ARB, ACEI, or aliskiren

Clinical trial data have shown that dual blockade of the renin-angiotensin-aldosterone system (RAAS) through the combined use of ACE inhibitors, angiotensin II receptor blockers or aliskiren is associated with a higher frequency of adverse events. such as hypotension, hyperkalaemia and decreased renal function (including acute renal failure) compared to the use of a single agent active on the RAAS system (see sections 4.3, 4.4 and 5.1).

Concomitant use not recommended

Potassium-sparing diuretics, potassium supplements, potassium-containing table salt substitutes and other substances that may increase potassium levels.

If the use of the combination of valsartan with a medicinal product that alters potassium levels is necessary, it is recommended that plasma potassium levels be monitored.

Conveyors

Data in vitro indicate that valsartan is a substrate of the hepatic uptake transporters OATP1B1 / OATP1B3 and the hepatic efflux transporter MRP2. The clinical relevance of this observation is unknown. Co-administration of uptake transporter inhibitors (eg rifampicin, cyclosporine) or efflux transporter (eg ritonavir) may increase systemic exposure to valsartan. Particular care should be taken when initiating or terminating concomitant treatment with these drugs.

No interaction

In interaction studies with valsartan, no interactions of clinical relevance were found with valsartan or with any of the following medicinal products: cimetidine, warfarin, furosemide, digoxin, atenolol, indomethacin, hydrochlorothiazide, amlodipine, glibenclamide. Digoxin and indomethacin may interact with the hydrochlorothiazide component of Combisartan (see interactions related to hydrochlorothiazide).

Interactions related to hydrochlorothiazide

Concomitant use requiring caution

Medicinal products affecting the serum potassium level.

The hypokalemic effect of hydrochlorothiazide can be increased by the concomitant administration of kaliuretic diuretics, corticosteroids, laxatives, ACTH, amphotericin, carbenoxolone, penicillin G, salicylic acid and its derivatives.

If these medicinal products are to be prescribed with the combination valsartan-hydrochlorothiazide monitoring of plasma potassium levels is advised (see section 4.4).

Medicines that can induce torsades de pointes

Due to the risk of hypokalaemia, hydrochlorothiazide should be administered with caution when combined with medicinal products that may induce torsades de pointes, particularly class Ia and class III antiarrhythmics and some antipsychotics.

Medicinal products affecting the serum sodium level

The hyponatremic effect of diuretics may be intensified by the concomitant administration of certain drugs such as antidepressants, antipsychotics, antiepileptics, etc. Caution is advised in the long-term administration of these drugs.

Digitalis glycosides

Thiazide-induced hypokalaemia or hypomagnesaemia may occur as undesirable effects, favoring the onset of digitalis-induced cardiac arrhythmias (see section 4.4).

Salts of calcium and vitamin D.

Administration of thiazide diuretics, including hydrochlorothiazide, with vitamin D or with calcium salts may potentiate the increase in serum calcium. The concomitant use of thiazide diuretics and calcium salts may cause hypercalcaemia in patients predisposed to hypercalcaemia (eg hyperparathyroidism, neoplasms or conditions mediated by vitamin D) by increasing tubular reabsorption of calcium.

Antidiabetic medicines (insulin and oral antidiabetics)

Thiazide diuretics can impair glucose tolerance. The dose of antidiabetic medicines may need to be adjusted.

Metformin should be used with caution due to the risk of lactic acidosis induced by possible renal failure associated with hydrochlorothiazide.

Beta blockers and diazoxide

The concomitant use of thiazide diuretics, including hydrochlorothiazide, and beta-blockers may increase the risk of hyperglycaemia. Thiazide diuretics, including hydrochlorothiazide, may enhance the hyperglycemic effect of diazoxide.

Medicines used in the treatment of gout (probenecid, sulfinpyrazone and allopurinol)

The dose of uricosuric medicinal products may need to be adjusted as hydrochlorothiazide may increase serum uric acid levels. The dosage of probenecid or sulfinpyrazone may need to be increased. Concomitant administration of thiazide diuretics, including hydrochlorothiazide, may increase the dose. incidence of hypersensitivity reactions to allopurinol.

Anticholinergics and other drugs affecting gastric motility

The bioavailability of thiazide-type diuretics may be increased by anticholinergic drugs (e.g. atropine, biperiden), apparently due to a decrease in gastrointestinal motility and stomach emptying rate.Conversely, it is assumed that prokinetic drugs such as cisapride may decrease the bioavailability of thiazide diuretics.

Amantadina

Thiazides, including hydrochlorothiazide, may increase the risk of adverse reactions caused by amantadine.

Ion exchange resins

Absorption of thiazide diuretics, including hydrochlorothiazide, is decreased by cholestyramine or colestipol. This could result in sub-therapeutic effects of thiazide diuretics. However, by distributing the dosage of the hydrochlorothiazide and the resin so that the hydrochlorothiazide is administered at least 4 hours before or 4-6 hours after the administration of the resins, the interaction could potentially be minimized.

Cytotoxic agents

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

Non-depolarizing skeletal muscle relaxants (e.g. tubocurarine)

Thiazides, including hydrochlorothiazide, enhance the action of skeletal muscle relaxants, such as curare derivatives.

Cyclosporine

Co-administration of cyclosporine may increase the risk of hyperuricaemia and gout-type complications.

Alcohol, barbiturates and narcotics

The concomitant use of thiazide diuretics with other substances which also have a blood pressure lowering effect (eg substances which decrease sympathetic central nervous system activity or with direct vasodilator activity) may potentiate orthostatic hypotension.

Methyldopa

There have been isolated reports of haemolytic anemia occurring with concomitant administration of methyldopa and hydrochlorothiazide.

Iodine contrast media

In case of diuretic-induced dehydration, the risk of acute renal failure increases, especially with high doses of iodized products. Patients must be rehydrated prior to administration.

04.6 Pregnancy and breastfeeding -

Pregnancy

Valsartan

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 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 trimesters is known to induce fetal toxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia) in humans (see also paragraph 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, especially during the first trimester, is limited. Animal studies are insufficient. Hydrochlorothiazide crosses the placenta. Based on the pharmacological mechanism of action of hydrochlorothiazide, its use during the second and third trimester of pregnancy can impair fetal-placental perfusion and cause fetal and neonatal effects such as jaundice, electrolyte disturbance. and thrombocytopenia.

Feeding time

There are no data on the use of valsartan during lactation. Hydrochlorothiazide is excreted in breast milk. Therefore, the use of Combisartan during lactation is not recommended. Alternative therapies with a proven safety profile should be preferred for use during lactation, especially when breastfeeding and breastfeeding. premature.

04.7 Effects on ability to drive and use machines -

No studies on the effect of Combisartan on the ability to drive and use machines have been performed. When driving vehicles or using machines, the possibility of occasional dizziness or tiredness should be considered.

04.8 Undesirable effects -

Adverse reactions reported in clinical trials and laboratory findings occurring more frequently with valsartan + hydrochlorothiazide than placebo and individual post-marketing reports are presented below by system organ class. Adverse reactions known to each single component alone but not observed in clinical studies may also occur during treatment with valsartan / hydrochlorothiazide.

Adverse reactions are ranked by frequency, starting with the most frequent, using the following convention: very common (≥1 / 10); common (≥ 1/100,

Within each frequency class, undesirable effects are reported in descending order of severity.

Table 1. Frequency of adverse reactions with valsartan / hydrochlorothiazide

Metabolism and nutrition disorders Uncommon Dehydration Nervous system disorders Very rare Dizziness Uncommon Paresthesia Not known Syncope Eye disorders Uncommon Blurred vision Ear and labyrinth disorders Uncommon Tinnitus Vascular pathologies Uncommon Hypotension Respiratory, thoracic and mediastinal disorders Uncommon Cough Not known Non-cardiogenic pulmonary edema Gastrointestinal disorders Very rare Diarrhea Musculoskeletal and connective tissue disorders Uncommon Myalgia Very rare Arthralgia Renal and urinary disorders Not known Renal impairment General disorders and administration site conditions Uncommon Fatigue Diagnostic tests Not known Increases in serum uric acid, increases in serum creatinine and serum bilirubin, hypokalaemia, hyponatremia Blood urea nitrogen increases, neutropenia

Learn more about the individual components

Adverse reactions already reported for each of the individual components may also be potential undesirable effects of Combisartan, even if not observed in clinical trials or in the post-marketing period.

Table 2. Frequency of adverse reactions with valsartan

Disorders of the blood and lymphatic system Not known Decreased hemoglobin, decreased hematocrit, thrombocytopenia Disorders of the immune system Not known Other allergic / hypersensitivity reactions, including serum sickness Metabolism and nutrition disorders Not known Increase in serum potassium, hyponatremia Ear and labyrinth disorders Uncommon Vertigo Vascular pathologies Not known Vasculitis Gastrointestinal disorders Uncommon Abdominal pain Hepatobiliary disorders Not known Increased liver function values Skin and subcutaneous tissue disorders Not known Angioedema, bullous dermatitis, rash, pruritus Renal and urinary disorders Not known Kidney failure

Table 3. Frequency of adverse reactions with hydrochlorothiazide

Hydrochlorothiazide has been widely prescribed for many years, often at higher doses than those given with Combisartan. The following adverse reactions have been reported in patients treated as monotherapy with thiazide diuretics, including hydrochlorothiazide.

Disorders of the blood and lymphatic system Rare Thrombocytopenia, sometimes with purpura Very rare Agranulocytosis, leukopenia, haemolytic anemia, bone marrow failure Not known Aplastic anemia Disorders of the immune system Very rare Hypersensitivity reactions Metabolism and nutrition disorders Very common Hypokalaemia, increased blood lipids (especially at high doses) common Hyponatremia, hypomagnesemia, hyperuricemia Rare Hypercalcemia, hyperglycemia, glycosuria and worsening of the diabetic metabolic state Very rare Hypochloraemic alkalosis Psychiatric disorders Rare Depression, sleep disturbances Nervous system disorders Rare Headache, dizziness, paraesthesia Eye disorders Rare Visual impairment Not known Acute angle-closure glaucoma Cardiac pathologies Rare Cardiac arrhythmias Vascular pathologies common Postural hypotension Respiratory, thoracic and mediastinal disorders Very rare Respiratory distress, including pneumonia and pulmonary edema Gastrointestinal disorders common Loss of appetite, mild nausea and vomiting Rare Constipation, gastrointestinal discomfort, diarrhea Very rare Pancreatitis Hepatobiliary disorders Rare Intrahepatic cholestasis or jaundice Renal and urinary disorders Not known Renal dysfunction, acute renal failure Skin and subcutaneous tissue disorders common Hives and other forms of rash Rare Photosensitivity Very rare Necrotizing vasculitis and toxic epidermal necrolysis, skin reactions similar to lupus erythematosus, reactivation of cutaneous lupus erythematosus Not known Erythema multiforme General disorders and administration site conditions Not known Pyrexia, asthenia Musculoskeletal and connective tissue disorders Not known Muscle spasm Diseases of the reproductive system and breast common Impotence

04.9 Overdose -

Symptoms

Overdose of valsartan can result in marked hypotension, which can lead to a decreased level of consciousness, circulatory collapse and / or shock. The following signs and symptoms may also occur following hydrochlorothiazide overdose: nausea, somnolence, hypovolaemia, electrolyte disturbances associated with cardiac arrhythmias and muscle spasms.

Treatment

Therapeutic measures depend on the time of ingestion and on the type and severity of the symptoms, giving priority to the normalization of circulatory conditions.

In case of hypotension the patient should be placed in the supine position and saline solutions should be given rapidly.

Valsartan cannot be removed by hemodialysis due to its strong binding to plasma proteins, while the removal of hydrochlorothiazide can be done by dialysis.

05.0 PHARMACOLOGICAL PROPERTIES -

05.1 "Pharmacodynamic properties -

Pharmacotherapeutic group: Angiotensin II antagonists in combination with diuretics, valsartan and diuretics. ATC code: C09D A03.

Valsartan / hydrochlorothiazide

In a double-blind, randomized, active-controlled study in patients inadequately controlled with 12.5 mg hydrochlorothiazide, significantly greater decreases in systolic / diastolic blood pressure were observed with the combination valsartan / hydrochlorothiazide 160 / 12.5 mg. (12.4 / 7.5 mmHg) compared to hydrochlorothiazide 25 mg (5.6 / 2.1 mmHg). In addition, a significantly higher proportion of patients responded (blood pressure

In a double-blind, randomized, active-controlled study in patients inadequately controlled with 160 mg of valsartan, significantly greater decreases in systolic / diastolic blood pressure were observed with the combination valsartan / hydrochlorothiazide 160/25 mg (14.6 / 11.9 mmHg) and valsartan / hydrochlorothiazide 160 / 12.5 mg (12.4 / 10.4 mmHg) compared to valsartan 160 mg (8.7 / 8.8 mmHg).

The difference in blood pressure reduction between the 160/25 mg and 160 / 12.5 mg doses also reached statistical significance. In addition, a significantly higher percentage of patients responded (diastolic blood pressure

In a multifactorial, randomized, double-blind study comparing different doses of the valsartan / hydrochlorothiazide combinations versus the respective components, significantly greater decreases in systolic / diastolic blood pressure were observed with the valsartan / hydrochlorothiazide combination 160 / 12.5 mg ( 17.8 / 13.5 mmHg) and 160/25 mg (22.5 / 15.3 mmHg) versus placebo (1.9 / 4.1 mmHg) and their respective monotherapies, i.e. hydrochlorothiazide 12.5 mg (7.3 / 7.2 mmHg), hydrochlorothiazide 25 mg (12.7 / 9.3 mmHg) and valsartna 160 mg (12.1 / 9.4 mmHg). In addition, a significantly higher proportion of patients responded ( diastolic pressure

In controlled clinical trials with valsartan + hydrochlorothiazide there was a dose-dependent reduction in serum potassium. Decreases in serum potassium occurred more frequently in patients who received 25 mg of hydrochlorothiazide than in those who received 12.5 mg. In controlled clinical trials with valsartan / hydrochlorothiazide the potassium lowering effect of hydrochlorothiazide was attenuated by the potassium sparing effect of valsartan.

The beneficial effects of the combination of valsartan and hydrochlorothiazide on cardiovascular mortality and morbidity are currently unknown.

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

Valsartan

Valsartan is an orally active specific angiotensin II (Ang II) receptor antagonist. It acts selectively on the AT1 receptor subtype, responsible for the known actions of angiotensin II. The increase in plasma levels of Ang II, consequent to the blockade of AT1 receptors by valsartan, can stimulate the unblocked AT2 receptors, which seems to counterbalance the action of the AT1 receptors. Valsartan does not exhibit any partial agonist activity at the AT1 receptor and has a much greater (approximately 20,000-fold) affinity for the AT1 receptor than for the AT2 receptor. Valsartan does not bind to and block other hormone receptors or ion channels known for their importance in cardiovascular regulation.

Valsartan does not inhibit ACE, also known as kininase II, which converts Ang I to Ang II and degrades bradykinin. Since there is no effect on ACE or potentiation of the effects of bradykinin or substance P, angiotensin II receptor antagonists are unlikely to be associated with cough. In clinical trials where valsartan was compared with an ACE inhibitor, the incidence of dry cough was significantly (P

Administration of valsartan to patients with arterial hypertension induces a reduction in blood pressure without affecting the heart rate.

In most patients, after administration of a single oral dose, the onset of antihypertensive activity occurs within 2 hours and the peak reduction in blood pressure is achieved within 4-6 hours. The antihypertensive effect persists for more than 24 hours after administration. With repeated administration, with any dose the maximum reduction in blood pressure is usually achieved within 2-4 weeks and is maintained over the course of long-term treatment. significant reduction in blood pressure is obtained by associating the drug with hydrochlorothiazide.

Abrupt discontinuation of valsartan was not associated with rebound hypertension or other adverse clinical events.

In hypertensive patients with type 2 diabetes and microalbuminuria, valsartan has been shown to reduce urinary albumin excretion. The MARVAL (Micro Albuminuria Reduction with Valsartan) study evaluated the reduction in urinary albumin excretion (UAE) with valsartan ( 80-160 mg / od) vs. amlodipine (5-10 mg / od), in 332 patients with type 2 diabetes (mean age: 58 years; 265 males) with microalbuminuria (valsartan: 58 mcg / min; amlodipine: 55.4 mcg / min), normal or elevated blood pressure and intact kidney function (creatinine

The Diovan Reduction of Proteinuria (DROP) study further evaluated the efficacy of valsartan in reducing urinary albumin excretion (UAE) in 391 hypertensive patients (BP = 150/88 mmHg) with type 2 diabetes, albuminuria (mean = 102 mcg / min; 20-700 mcg / min) and intact renal function (mean serum creatinine = 80 mcmol / l). Patients were randomized to one of three different doses of valsartan (160, 320, and 640 mg / od) and were treated for 30 weeks. The aim of this study was to determine the optimal dose of valsartan to reduce UAE in hypertensive patients with type 2 diabetes. After 30 weeks, the percentage change in UAE was significantly reduced by 36% from baseline. with valsartan 160 mg (95% CI: 22% to 47%), and 44% with valsartan 320 mg (95% CI: 31% to 54%). It was found that 160-320 mg of valsartan produced clinically significant reductions in UAE in hypertensive patients with type 2 diabetes.

Other: dual blockade of the renin-angiotensin-aldosterone system

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.

Hydrochlorothiazide

The site of action of thiazide diuretics is predominantly in the distal convoluted tubule of the kidney. The presence of a high-affinity receptor in the renal cortex has been shown to be the primary binding site for the action of thiazide diuretics and inhibition of transport. of NaCl in the distal convoluted tubule. The mechanism of action of thiazides takes place through the inhibition of the transport of Na + Cl-, perhaps by competition with the Cl- site, thus influencing the mechanism of electrolyte reabsorption: directly increasing the "excretion of sodium and chlorine in equivalent quantities and indirectly reducing plasma volume by this diuretic action, with a consequent increase in plasma renin activity, secretion of aldosterone and loss of urinary potassium and a decrease in serum potassium. The renin-aldosterone link is mediated by angiotensin II, so that with concomitant administration of valsartan the decrease in serum potassium is less pronounced than that observed with hydrochlorothiazide monotherapy.

05.2 "Pharmacokinetic properties -

Valsartan / hydrochlorothiazide

The systemic availability of hydrochlorothiazide is reduced by approximately 30% when co-administered with valsartan. The kinetics of valsartan are not significantly affected by co-administration with hydrochlorothiazide. The observed interaction has no impact on the use of valsartan and hydrochlorothiazide. in combination, as controlled clinical trials have demonstrated a clear antihypertensive effect, superior to that obtained with the two active substances administered individually, or with placebo.

Valsartan

Absorption

After oral administration alone, peak concentrations of valsartan are reached after 2-4 hours. Its mean absolute bioavailability is 23%. Food decreases the exposure (measured by the AUC, area under the plasma concentration curve) to valsartan by approximately 40% and the peak plasma concentration (Cmax) by approximately 50%, although approximately 8 hours after administration of the The plasma concentrations of valsartan are similar in both fasted and non-fasted subjects. However, this reduction in AUC is not accompanied by a clinically significant reduction in therapeutic effect, therefore valsartan can be taken with or without food.

Distribution

The steady-state volume of distribution of valsartan following intravenous administration is approximately 17 liters, indicating that valsartan does not distribute extensively to tissues. Valsartan is highly (94-97%) bound to serum proteins, mainly serum albumin.

Biotransformation

Valsartan is not biotransformed to a high degree, as only about 20% of the dose is recovered as metabolites. Low concentrations of a hydroxylated metabolite (less than 10% of the AUC of valsartan) have been identified in plasma. This metabolite is pharmacologically inactive.

Elimination

Valsartan exhibits multiexponential decay kinetics (t½α faeces (approximately 83% of the dose) and urine (approximately 13% of the dose), mainly as unchanged drug. After intravenous administration, plasma clearance is approximately 2 l / h. its renal clearance is 0.62 l / h (approximately 30% of the total plasma clearance). The elimination half-life of valsartan is 6 hours.

Hydrochlorothiazide

Absorption

After oral administration, hydrochlorothiazide is rapidly absorbed (tmax = approximately 2 hours). Over the therapeutic range, the mean AUC increase is linear and dose proportional.

The effect of food on the absorption of hydrochlorothiazide, if it occurs, has little clinical significance. The absolute bioavailability of hydrochlorothiazide after oral administration is 70%.

Distribution

The apparent volume of distribution is 4-8 l / kg. Circulating hydrochlorothiazide is bound to serum proteins (40-70%), mainly serum albumin. Hydrochlorothiazide also accumulates in erythrocytes in amounts approximately 3 times higher than plasma levels.

Elimination

Hydrochlorothiazide is eliminated predominantly as an unmodified compound. In the final phase of elimination, hydrochlorothiazide is eliminated from plasma with an average half-life ranging from 6 to 15 hours. The kinetics of hydrochlorothiazide do not change with repeated dose administration and accumulation is minimal when given once daily. Over 95% of the absorbed dose of hydrochlorothiazide is excreted as unchanged compound in the urine. Renal clearance is composed of passive filtration and active secretion in the renal tubule.

Special populations

Senior citizens

In some elderly subjects, a slightly higher systemic exposure to valsartan was observed than in young subjects; however, this has not been shown to be of clinical significance.

Limited data suggest that the systemic clearance of hydrochlorothiazide is reduced in both healthy and hypertensive elderly compared to healthy young volunteers.

Renal impairment

At the recommended doses of Combisartan, no dose adjustment is required in patients with glomerular filtration rate between 30 and 70 ml / min. There are no data on the administration of Combisartan in patients with severe renal impairment (glomerular filtration rate and plasma protein is not removed by dialysis, while the removal of hydrochlorothiazide can be done by dialysis.

In the presence of renal impairment, mean peak plasma levels and AUC values ​​of hydrochlorothiazide increase and urinary elimination rate decreases. A 3-fold increase in AUC was observed in patients with mild to moderate renal impairment. An 8-fold increase in AUC has been observed in patients with severe renal impairment. Hydrochlorothiazide is contraindicated in patients with severe renal impairment (see section 4.3).

Hepatic impairment

In a pharmacokinetic study conducted in patients with mild (n = 6) or moderate (n = 5) hepatic dysfunction, exposure to valsartan increased approximately 2-fold compared to healthy volunteers (see sections 4.2 and 4.4). Not available data on the use of valsartan in patients with severe hepatic dysfunction (see section 4.3). Liver disease does not significantly affect the pharmacokinetics of hydrochlorothiazide.

05.3 Preclinical safety data -

The potential toxicity of the combination valsartan / hydrochlorothiazide administered orally was investigated in rats and monkeys (marmoset) in studies of up to 6 months duration. There were no results that exclude the use of therapeutic doses in humans. .

In chronic toxicity studies, the association-induced changes were most likely caused by valsartan. The toxicologically targeted organ was the kidney, with a much more pronounced reaction in the monkey than in the rat. The combination resulted in renal damage (nephropathy with tubular basophilia, increases in plasma urea, plasma creatinine and serum potassium, increases in urinary volume and urinary electrolytes from 30 mg / kg / day of valsartan + 9 mg / kg / day of hydrochlorothiazide in rats and 10 + 3 mg / kg / day in monkeys), probably through an alteration of renal haemodynamics. These doses in rats represent 0.9 and 3.5 times the maximum recommended human dose (MRHD) of valsartan and hydrochlorothiazide in mg / m², respectively. In monkeys, these doses represent 0.3 and 1.2 times the maximum dose, respectively. recommended in humans (MRHD) of valsartan and hydrochlorothiazide in mg / m² (calculations assume an oral dose of 320 mg / day of valsartan in combination with 25 mg / day of hydrochlorothiazide and a 60 kg patient).

High doses of the combination valsartan / hydrochlorothiazide caused a reduction in red cell indices (erythrocyte count, hemoglobin, hematocrit) from 100 + 31 mg / kg / day in the rat and 30 + 9 mg / kg / day in the monkey. These doses in rats represent 3.0 and 12 times the maximum recommended human dose (MRHD) of valsartan and hydrochlorothiazide in mg / m², respectively. In monkeys these doses represent 0.9 and 3.5 times the maximum recommended human dose (MRHD) of valsartan and hydrochlorothiazide in mg / m², respectively (calculations assume an oral dose of 320 mg / day of valsartan in combination with 25 mg / day of hydrochlorothiazide and a 60 kg patient).

In monkeys, damage to the gastric mucosa was observed (from 30 + 9 mg / kg / day). The combination also resulted in hyperplasia of afferent arterioles in the kidney (at 600 + 188 mg / kg / day in the rat and 30 + 9 mg / kg / day in the monkey). These doses in the monkey represent 0.9 and 3, respectively. 5 times the maximum recommended human dose (MRHD) of valsartan and hydrochlorothiazide in mg / m². In rats, these doses represent 18 and 73 times the maximum recommended human dose (MRHD) of valsartan and hydrochlorothiazide in mg / m², respectively (calculations assume an oral dose of 320 mg / day of valsartan in combination with 25 mg / day of hydrochlorothiazide and a 60 kg patient).

The above effects appear to be due to the pharmacological action of high doses of valsartan (blockade of angiotensin II-induced inhibition of renin release, with stimulation of renin-producing cells) and also occur with ACE inhibitors. appear to have no relevance for therapeutic doses of valsartan in humans.

The combination valsartan + hydrochlorothiazide has not been tested for mutagenicity, chromosomal breakdown or carcinogenesis, as no interaction between the two substances was evidenced. However, these tests were conducted separately with valsartan and hydrochlorothiazide and did not show mutagenicity, chromosomal breakdown. or carcinogenicity.

In rats, maternally toxic doses of valsartan (600 mg / kg / day) during the last days of pregnancy and during lactation resulted in lower survival rates, lower weight gain and delayed development (cartilage detachment). and ear canal opening) in offspring (see section 4.6). These doses in rats (600 mg / kg / day) are approximately 18 times the maximum recommended human dose in mg / m² (calculations assume an oral dose of 320 mg / day for a patient weighing 60 kg).

Similar results were observed for valsartan / hydrochlorothiazide in rats and rabbits. In embryo-fetal development (segment II) studies with valsartan / hydrochlorothiazide in rats and rabbits there was no evidence of teratogenicity, however fetotoxicity associated with maternal toxicity was observed.

06.0 PHARMACEUTICAL INFORMATION -

06.1 Excipients -

Core of the tablet:

Microcrystalline cellulose,

Anhydrous colloidal silica,

Crospovidone,

Magnesium stearate

Coating:

Hypromellose,

Macrogol 8000,

Talc,

Red iron oxide (E 172),

Titanium dioxide (E 171).

06.2 Incompatibility "-

Not relevant.

06.3 Period of validity "-

3 years

06.4 Special precautions for storage -

Store at a temperature not exceeding 30 ° C.

Store in the original package to protect from moisture.

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

PVC / PE / PVDC / Al or PVC / PVDC / Al blisters

14, 28, 56, 98, in calendar packs, 280 film-coated tablets

Divisible unit dose blisters of PVC / PE / PVDC / Al or PVC / PVDC / Al

56x1, 98x1, 280x1 film-coated tablets.

Not all pack sizes may be marketed.

06.6 Instructions for use and handling -

No special instructions.

07.0 HOLDER OF THE "MARKETING AUTHORIZATION" -

A. Menarini Industrie Farmaceutiche Riunite s.r.l. - Via Sette Santi, 3 - Florence

08.0 MARKETING AUTHORIZATION NUMBER -

AIC n. 034134039 - 160 mg / 12.5 mg film-coated tablets, 14 tablets in PVC / PE / PVDC / Al blister

AIC n. 034134041 - 160 mg / 12.5 mg film-coated tablets, 28 tablets in blister PVC / PE / PVDC / Al AIC n. 034134054 - 160 mg / 12.5 mg film-coated tablets, 56 tablets in PVC / PE / PVDC / Al blister

AIC n. 034134066 - 160 mg / 12.5 mg film-coated tablets, 98 tablets in PVC / PE / PVDC / Al blister

AIC n. 034134078 - 160 mg / 12.5 mg film-coated tablets, 98x1 tablets in PVC / PE / PVDC / Al blister

AIC n. 034134080 - 160 mg / 12.5 mg film-coated tablets, 280 (10x28) tablets in PVC / PE / PVDC / Al blister

AIC n. 034134092 - 160 mg / 12.5 mg film-coated tablets, 280 (20x14) tablets in PVC / PE / PVDC / Al blister

09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION -

Date of first authorization: 25 July 2004

Date of last renewal: May 29, 2010

10.0 DATE OF REVISION OF THE TEXT -

June 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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