COTAREG - PACKAGE LEAFLET - LEAFLETS

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Cotareg - Package Leaflet

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

Active ingredients: Valsartan, Hydrochlorothiazide

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

Indications Why is Cotareg used? What is it for?

Cotareg 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 you pass and, in doing so, reduces blood pressure.

Cotareg 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 blood vessels in 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 Cotareg should not be used

Do not take Cotareg:

if you are allergic (hypersensitive) to valsartan, hydrochlorothiazide, sulphonamide derivatives (substances chemically related to hydrochlorothiazide) or any of the other ingredients of Cotareg
if you are more than 3 months pregnant (it is better to avoid Cotareg even 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 mellitus or reduced kidney function and are being treated with a blood pressure lowering medicine called 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 Cotareg

Take special care with Cotareg

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 Cotareg 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 you take Cootg, stop taking Cootg immediately and never take it again. See the section, "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 could be symptoms of "increased intraocular pressure and can occur a few hours to a week after taking Cotareg. If left untreated, this can lead to permanent loss of vision. If you have previously had an allergy to penicillins or sulphonamides it can have a higher 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" such as enalapril, lisinopril etc.
aliskiren

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

The use of Cotareg is not recommended in children and adolescents (under 18 years of age).

You should tell your doctor if you think you are pregnant (or if there is a possibility of becoming pregnant). Cotareg 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 can modify the effect of Cotareg

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

The effect of the treatment may be influenced if Cotareg is taken with certain other medicines. It may be necessary to adjust 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 can increase the effect of Cotareg
medicines that can induce torsades de pointes (irregular heartbeat), such as antiarrhythmics (medicines used to treat heart problems) 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 medicines that lower blood pressure, including methyldopa, ACE inhibitors
(such as enalapril, lisinopril, etc.) or aliskiren
medicines that increase blood pressure, such as norepinephrine or 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 Cotareg with food and drink

Cotareg 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 usually advise you to stop taking Cootg before becoming pregnant or as soon as you know you are pregnant and will advise you to take another medicine instead of Cootg. 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 taken after the third month of pregnancy.

Tell your doctor if you are breastfeeding, or about to start breastfeeding

Cotareg 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 Cotareg. Like many other medicines used to treat high blood pressure, Cootg 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 Cotareg: Posology

Always take Cotareg 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 Cotareg tablets to take. Based on your response to treatment, your doctor may suggest a higher or lower dose.

The usual dose of Cotareg is one tablet a 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 Cootg with or without food.
Swallow the tablet with a glass of water.

Overdose What to do if you have taken too much Cootg

If you take more Cootg than you should

In case of severe dizziness and / or fainting, it is good to lie down and contact your doctor immediately. If you have inadvertently taken too many tablets, contact your doctor, pharmacist or hospital.

If you forget to take Cootg

If you forget to take a dose, take it as soon as you remember it. However, if it is almost time for your next tablet, skip the forgotten dose. Do not take a double dose to make up for a forgotten dose.

If you stop using Cotareg

Stopping treatment with Cotareg may cause your high blood pressure to worsen. Do not stop using the medicine unless your doctor tells you to. If you have any further questions on the use of this product, ask your doctor or pharmacist.

Side Effects What are the side effects of Cotareg

Like all medicines, Cootg 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 get any of these symptoms, stop taking Cotareg and contact your doctor immediately (see also section "Take special care with Cotareg").

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)
increased 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 and 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
visual 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, more 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 and 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 Cotareg out of the reach and sight of children.
Do not use Cotareg after the expiry date which is stated on the label. The expiry date refers to the last day of the month.
Do not store above 30 ° C. Store in the original package to protect the medicine from moisture.
Do not use Cotareg 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.

What Cotareg 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, colloidal anhydrous 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 Cotareg looks like and contents of the pack

Cootg 80 mg / 12.5 mg film-coated tablets are light orange, ovaloid, debossed with "HGH" on one side and "CG" on the other side.

Cootg 160 mg / 12.5 mg film-coated tablets are dark red, ovaloid, debossed with "HHH" on one side and "CG" on the other side.

Cotareg 160 mg / 25 mg film-coated tablets are brown, ovaloid, debossed with "HXH" on one side and "NVR" on the other.

Cotareg 320 mg / 12.5 mg film-coated tablets are pink, ovaloid, bevelled edge, debossed with "NVR" on one side and "HIL" on the other.

Cotareg 320 mg / 25 mg film-coated tablets are yellow, ovaloid, debossed with "CTI" on one side and "NVR" on the other.

Cotareg 80 mg / 12.5 mg tablets are available in calendar blisters, in packs of 14 or 28 tablets. Cotareg 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. 10 perforated unit dose blisters are also available, in packs of 56x1 (320 mg / 12.5 mg and 320 mg / 25 mg only), 98x1 (except 80 / 12.5 mg) or 280x1 (320 mg / 12 only, 5 mg 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 Cotareg 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 interaction04.6 Pregnancy and lactation04.7 Effects on ability to drive and use machines04.8 Undesirable effects04.9 Overdose05.0 PHARMACOLOGICAL PROPERTIES05.1 Pharmacodynamic properties05.2 Pharmacokinetic properties05.3 Preclinical safety data06.0 INFORMATION PHARMACEUTICALS 06.1 Excipients 06.2 Incompatibilities 06.3 Shelf life 06.4 Special precautions for storage 06.5 Nature of the immediate packaging and contents of the package 06.6 Instructions for use and handling 07.0 MARKETING AUTHORIZATION HOLDER08 .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 RADIOPharmaceuticals, FULL DATA ON INTERNAL RADIATION DOSIMETRY 12.0 FOR RADIO DRUGS, FURTHER DETAILED INSTRUCTIONS ON ESTEMPORANEA PREPARATION AND CONTROL

01.0 NAME OF THE MEDICINAL PRODUCT

COTAREG 80 MG / 12.5 MG

02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 80 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.

Light orange, ovaloid tablet debossed with the letters "HGH" on one side and "CG" on the other.

04.0 CLINICAL INFORMATION

04.1 Therapeutic indications

Treatment of essential arterial hypertension in adults.

Cotareg 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 Cotareg 80 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.

After initiation of therapy, the clinical response to Cotareg should be evaluated and if blood pressure remains uncontrolled, the dose of one of the two components can be increased, up to a maximum dose of Cotareg 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

Cootg can be taken with or without food and should be given with water.

Special populations

Renal impairment

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

Hepatic impairment

In patients with mild to 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, Cotareg 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

The use of Cotareg is not recommended 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 renal impairment (creatinine clearance

- Refractory hypokalaemia, hyponatremia, hypercalcemia and symptomatic hyperuricemia.

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 Cotareg therapy. Sodium and / or volume depletion should be corrected first. to start treatment with Cotareg.

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 Cotareg in patients with severe chronic heart failure has not been established.

Therefore it cannot be excluded that, due to inhibition of the renin-angiotensin-aldosterone system, the administration of Cotareg may also be associated with impaired renal function. Cotareg should not be used in these patients.

Renal artery stenosis

Cootg 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 Cotareg as their renin-angiotensin system is not activated.

Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy

As with all other vasodilators, special caution is required in patients with aortic or mitral stenosis or hypertrophic obstructive 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 Cotareg is used in patients with renal impairment.

Kidney transplant

To date, there is no experience on the safe use of Cotareg in patients who have recently undergone kidney transplantation.

Hepatic impairment

In patients with mild or moderate hepatic impairment without cholestasis, Cotareg 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 Cotareg should be stopped immediately and should not be 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 deemed 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 required in patients who have previously had 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 acute 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.

04.5 Interactions with other medicinal products and other forms of interaction

Interactions related to both valsartan and hydrochlorothiazide

Concomitant use not recommended

Lithium

In case of concomitant use of ACE inhibitors and thiazides, including hydrochlorothiazide, reversible increases in serum concentrations and toxicity of lithium have been reported. Due to the lack of experience on the concomitant use of valsartan and lithium, this combination is not recommended. . Should the use of the combination prove necessary, it is recommended that serum lithium levels be carefully monitored.

Concomitant use requiring caution

Other antihypertensive agents

Cotareg 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 direct 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 given concurrently, NSAIDs may attenuate the antihypertensive effect of both angiotensin II antagonists and hydrochlorothiazide. Furthermore, concomitant use of Cotareg 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

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 involving 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 Cotareg (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 can be intensified by the concomitant administration of medicinal products such as antidepressants, antipsychotics, antiepileptics, etc. Caution is advised in the long-term administration of these medicinal products.

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 (oral antidiabetics and insulin)

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 serum uric acid levels. 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 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.

Iodized 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 lactation

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 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, 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, disturbance of electrolyte balance. and thrombocytopenia.

Feeding time

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

04.7 Effects on ability to drive and use machines

No studies on the effect of Cotareg 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 individual 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, 1 / 1,000); very rare (

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 previously reported for each of the individual components may also be potential undesirable effects for Cotareg, 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, rash, itching 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 Cotareg. The following adverse reactions have been reported in patients treated alone 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 the type and severity of the symptoms, giving priority to normalizing the 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 valsartan / hydrochlorothiazide 80 / 12.5 mg combination ( 14.9 / 11.3 mmHg) compared to hydrochlorothiazide 12.5 mg (5.2 / 2.9 mmHg) and hydrochlorothiazide 25 mg (6.8 / 5.7 mmHg). In addition, a significantly higher proportion of patients have responded (diastolic blood pressure

In a double-blind, randomized, active-controlled study in patients inadequately controlled with valsartan 80 mg, significantly greater decreases in systolic / diastolic blood pressure were observed with the combination valsartan / hydrochlorothiazide 80 / 12.5 mg (9 , 8 / 8.2 mmHg) compared to valsartan 80 mg (3.9 / 5.1 mmHg) and valsartan 160 mg (6.5 / 6.2 mmHg). In addition, a significantly higher proportion of patients responded (blood pressure diastolic

Significantly greater decreases in systolic / diastolic blood pressure were observed with the combination valsartan / hydrochlorothiazide 80 / 12.5 mg ( 16.5 / 11.8 mmHg) versus placebo (1.9 / 4.1 mmHg) and both hydrochlorothiazide 12.5 mg (7.3 / 7.2 mmHg) and valsartan 80 mg (8.8 / 8, 6 mmHg) In addition, a significantly higher percentage of patients responded (diastolic blood 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, resulting from 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 or 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, onset of antihypertensive activity occurs within 2 hours and peak blood pressure reduction 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 renal function (creatinine and proteinuria (DROP) 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.

Hydrochlorothiazide

The site of action of thiazide diuretics is predominantly in the distal renal convoluted tubule. 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 is implemented 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 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, primarily 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 recommended doses of Cotareg, no dose adjustment is required in patients with glomerular filtration rates between 30 and 70 ml / min.

There are no data on the administration of Cotareg in patients with severe renal impairment (glomerular filtration rate plasma protein and 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. Hydrochlorothiazia 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) to moderate (n = 5) hepatic dysfunction, exposure to valsartan increased approximately 2-fold compared to healthy volunteers (see sections 4.2 and 4.3).

No data are available on the use of valsartan in patients with severe hepatic dysfunction (see section 4.3). Hepatic 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 rats and 30 + 9 mg / kg / day in monkeys. 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 rats and 30 + 9 mg / kg / day in monkeys). These doses in monkeys represent 0.9 and 3.5, respectively. 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 has been 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 opening of the ear canal) 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 60 kg patient). 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.