Valsartan/Hydroklortiazid Novartis 80 mg/12,5 mg Filmdragerad tablett

Sverige - svenska - Läkemedelsverket (Medical Products Agency)

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Bipacksedel Bipacksedel (PIL)

22-04-2018

Produktens egenskaper Produktens egenskaper (SPC)

28-04-2018

Aktiva substanser:
hydroklortiazid; valsartan
Tillgänglig från:
Novartis Sverige AB
ATC-kod:
C09DA03
INN (International namn):
hydrochlorothiazide; valsartan
Dos:
80 mg/12,5 mg
Läkemedelsform:
Filmdragerad tablett
Sammansättning:
hydroklortiazid 12,5 mg Aktiv substans; valsartan 80 mg Aktiv substans
Klass:
Apotek
Receptbelagda typ:
Receptbelagt
Terapiområde:
Valsartan och diuretika
Produktsammanfattning:
Förpacknings: Blister, 28 tabletter (kalenderförpackning); Blister, 56 tabletter; Blister, 98 tabletter (kalenderförpackning); Blister, 280 x 1 tabletter (endos); Blister, 14 tabletter; Blister, 280 tabletter; Blister, 56 x 1 tabletter (endos); Blister, 98 x 1 tabletter (endos)
Bemyndigande status:
Godkänd
Godkännandenummer:
22462
Tillstånd datum:
2005-11-18

Dokument på andra språk

Bipacksedel Bipacksedel - engelska

31-08-2020

Produktens egenskaper Produktens egenskaper - engelska

31-08-2020

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Package leaflet: Information for the user

Valsartan/Hydroklortiazid Novartis 80 mg/12.5 mg film-coated tablets

Valsartan/Hydroklortiazid Novartis 160 mg/12.5 mg film-coated tablets

Valsartan/Hydroklortiazid Novartis 160 mg/25 mg film-coated tablets

Valsartan/Hydroklortiazid Novartis 320 mg/12.5 mg film-coated tablets

Valsartan/Hydroklortiazid Novartis 320 mg/25 mg film-coated tablets

Valsartan/hydrochlorothiazide

Read all of this leaflet carefully before you start taking this medicine because it contains

important information for you.

Keep this leaflet. You may need to read it again.

If you have any further questions, ask your doctor or pharmacist.

This medicine has been prescribed for you only. Do not pass it on to others. It may harm them,

even if their signs of illness are the same as yours.

If you get any side effects, talk to your doctor, or pharmacist This includes any possible side

effects not listed in this leaflet.See section 4.

What is in this leaflet:

What Valsartan/Hydroklortiazid Novartis is and what it is used for

What you need to know before you take Valsartan/Hydroklortiazid Novartis

How to take Valsartan/Hydroklortiazid Novartis

Possible side effects

How to store Valsartan/Hydroklortiazid Novartis

Contents of the pack and other information

1.

What Valsartan/Hydroklortiazid Novartis is and what it is used for

Valsartan/Hydroklortiazid Novartis film-coated tablets contain two active substances called valsartan

and hydrochlorothiazide. Both of these substances help to control high blood pressure (hypertension).

Valsartan belongs to a class of medicines known as “angiotensin II receptor antagonists”,

which help to control high blood pressure. Angiotensin II is a substance in the body that causes

vessels to tighten, thus causing your blood pressure to increase. Valsartan works by blocking the

effect of angiotensin II. As a result, blood vessels relax and blood pressure is lowered.

Hydrochlorothiazide belongs to a group of medicines called thiazide diuretics (also known as

“water tablets”). Hydrochlorothiazide increases urine output, which also lowers blood pressure.

Valsartan/Hydroklortiazid Novartis is used to treat high blood pressure which is not adequately

controlled by a single substance alone.

High blood pressure increases the workload of the heart and arteries. If not treated, it can damage the

blood vessels of the brain, heart, and kidneys, and may result in a stroke, heart failure or kidney

failure. High blood pressure increases the risk of heart attacks. Lowering your blood pressure to

normal reduces the risk of developing these disorders.

2.

What you need to know before you take Valsartan/Hydroklortiazid Novartis

Do not take Valsartan/Hydroklortiazid Novartis:

if you are allergic (hypersensitive) to valsartan, hydrochlorothiazide, sulphonamide derivatives

(substances chemically related to hydrochlorothiazide) or to any of the other ingredients of this

medicine (listed in section 6).

if you are more than 3 months pregnant (it is also better to avoid Valsartan/Hydroklortiazid

Novartis in early pregnancy – see pregnancy section).

if you have severe liver disease, destruction of the small bile ducts within the liver (biliary

cirrhosis) leading to the build up of bile in the liver (cholestasis).

if you have severe kidney disease.

if you are unable to produce urine (anuria).

if you are treated with an artificial kidney.

if the level of potassium or sodium in your blood is lower than normal, or if the level of calcium

in your blood is higher than normal despite treatment.

if you have gout.

if you have diabetes or impaired kidney function and you are treated with a blood pressure

lowering medicine containing aliskiren.

If any of the above apply to you, tell your doctor and do not take Valsartan/Hydroklortiazid

Novartis.

Warnings and precautions

Talk to your doctor

if you are taking potassium-sparing medicines, potassium supplements, salt substitutes

containing potassium or other medicines that increase the amount of potassium in your blood

such as heparin. Your doctor may need to check the amount of potassium in your blood

regularly.

if you have low levels of potassium in your blood.

if you have diarrhoea or severe vomiting.

if you are taking high doses of water tablets (diuretics).

if you have severe heart disease.

if you are suffering from heart failure or have experienced a heart attack. Follow your doctor’s

instruction for the starting dose carefully. Your doctor may also check your kidney function.

if you suffer from a narrowing of the kidney artery.

if you have recently received a new kidney.

if you suffer from hyperaldosteronism. This is a disease in which your adrenal glands make too

much of the hormone aldosterone. If this applies to you, the use of Valsartan/Hydroklortiazid

Novartis is not recommended.

if you have liver or kidney disease.

if you have ever experienced swelling of the tongue and face caused by an allergic reaction

called angioedema when taking another drug (including ACE inhibitors), tell your doctor. If

these symptoms occur when you are taking Valsartan/Hydroklortiazid Novartis, stop taking

Valsartan/Hydroklortiazid Novartis immediately and never take it again. See also 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 levels of cholesterol or triglycerides in your blood.

if you have had allergic reactions with the use of other blood pressure-lowering agents of this

class (angiotensin II receptor antagonists) or if you have allergy or asthma.

if you experience a decrease in vision or eye pain. These could be symptoms of an increase of

pressure in your eye and can happen within hours to a week of taking Valsartan/Hydroklortiazid

Novartis. This can lead to permanent vision loss, if not treated. If you earlier have had a

penicillin or sulphonamide allergy you can be at higher risk of developing this.

if you are taking any of the following medicines used to treat high blood pressure:

an ACE inhibitors (for example enalapril, lisinopril, ramipril), in particular if you have

diabetes-related kidney problems.

aliskiren.

Your doctor may check your kidney function, blood pressure, and the amount of electrolytes (e.g.

potassium) in your blood at regular intervals.

See also information under the heading “Do not take Valsartan/Hydroklortiazid Novartis”

Valsartan/Hydroklortiazid Novartis may cause increased sensitivity of the skin to sun.

The use of Valsartan/Hydroklortiazid Novartis in children and adolescents (below the age of 18 years)

is not recommended.

You must tell your doctor if you think you are (or might become) pregnant. Valsartan/Hydroklortiazid

Novartis 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).

Other medicines and Valsartan/Hydroklortiazid Novartis

Tell your doctor or pharmacist if you are taking, have recently taken, or might take any other

medicines.

The effect of the treatment can be influenced if Valsartan/Hydroklortiazid Novartis is taken together

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 especially applies to the following medicines:

lithium, a medicine used to treat some types of psychiatric diseases

medicines or substances that may increase the amount of potassium in your blood. These

include potassium supplements or salt substitutes containing potassium, potassium-sparing

medicines and heparin.

medicines that may reduce the amount of potassium in your blood, such as diuretics (water

tablets), corticosteroids, laxatives, carbenoxolone, amphotericin or penicillin G.

some antibiotics (rifamycin group), a drug used to protect against transplant rejection

(ciclosporin) or an antiretroviral drug used to treat HIV/AIDS infection (ritonavir). These drugs

may increase the effect of Valsartan/Hydroklortiazid Novartis.

medicines that may induce “torsades de pointes” (irregular heart beat), such as antiarrhythmics

(medicines used to treat heart problems) and some antipsychotics.

medicines that may reduce the amount of sodium in your blood, such as antidepressants,

antipsychotics, antiepileptics

medicines for the treatment of gout, such as allopurinol, probenecid, sulfinpyrazone

therapeutic vitamin D and calcium supplements

medicines for the treatment of diabetes (oral agents such as metformin or insulins)

other medicines to lower your blood pressure including methyldopa, ACE inhibitors (such as

enalapril, lisinopril, etc.) or aliskiren (see also information under the headings “Do not take

Valsartan/Hydroklortiazid Novartis” and “Warnings and precautions”).

medicines to increase blood pressure, such as noradrenaline or adrenaline

digoxin or other digitalis glycosides (medicines used to treat heart problems).

medicines that may increase blood sugar levels, such as diazoxide or beta blockers

cytotoxic medicines (used to treat cancer), such as methotrexate or cyclophosphamide

pain killers such as non-steroidal anti-inflammatory agents (NSAIDs), including selective

cyclooxygenase-2 inhibitors (Cox-2 inhibitors) and acetylsalicylic acid > 3 g

muscle relaxing medicines, such as tubocurarine

anti-cholinergic medicines (medicines used to treat a variety of disorders such as gastrointestinal

cramps, urinary bladder spasm, asthma, motion sickness, muscular spasms, Parkinson's disease

and as an aid to anaesthesia)

amantadine (medicine used to treat Parkinson’s disease and also used to treat or prevent certain

illnesses caused by viruses)

cholestyramine and colestipol (medicines used mainly to treat high levels of lipids in the blood)

ciclosporin, a medicine used for organ transplant to avoid organ rejection

alcohol, sleeping pills and anaesthetics (medicines with sleeping or painkilling effect used for

example during surgery)

iodine contrast media (agents used for imaging examinations)

Valsartan/Hydroklortiazid Novartis with food, drink and alcohol

Avoid taking alcohol until you have talked to your doctor. Alcohol may make your blood pressure fall

more and/or increase the risk of you becoming dizzy or feeling faint.

Pregnancy and breast-feeding

You must tell your doctor if you think that you are (or might become) pregnant

Your doctor will normally advise you to stop taking Valsartan/Hydroklortiazid Novartis before you

become pregnant or as soon as you know you are pregnant, and will advise you to take another

medicine instead of Valsartan/Hydroklortiazid Novartis. Valsartan/Hydroklortiazid Novartis is not

recommended in early pregnancy, and must not be taken when more than 3 months pregnant, as it may

cause serious harm to your baby if it is used after the third month of pregnancy.

Tell your doctor if you are breast-feeding or about to start breast-feeding

Valsartan/Hydroklortiazid Novartis is not recommended for mothers who are breast-feeding, and your

doctor may choose another treatment for you if you wish to breast-feed, especially if your baby is

newborn, or was born prematurely.

Driving and using machines

Before you drive a vehicle, use tools or operate machines or carry out other activities that require

concentration, make sure you know how Valsartan/Hydroklortiazid Novartis affects you. Like many

other medicines used to treat high blood pressure, Valsartan/Hydroklortiazid Novartis may

occasionally cause dizziness and affect the ability to concentrate.

3.

How to take Valsartan/Hydroklortiazid Novartis

Always take this medicine exactly as your doctor has told you. This will help you to get the best

results and lower the risk of side effects. Check with your doctor or pharmacist if you are not sure.

People with high blood pressure often do not notice any signs of this problem. Many may feel quite

normal. This makes it all the more important for you to keep your appointments with your doctor

even if you are feeling well.

Your doctor will tell you exactly how many tablets of Valsartan/Hydroklortiazid Novartis to take.

Depending on how you respond to the treatment, your doctor may suggest a higher or lower dose.

The recommended dose of Valsartan/Hydroklortiazid Novartis is one tablet per day.

Do not change the dose or stop taking the tablets without consulting your doctor.

The medicine should be taken at the same time each day, usually in the morning.

You can take Valsartan/Hydroklortiazid Novartis with or without food.

Swallow the tablet with a glass of water.

If you take more Valsartan/Hydroklortiazid Novartis than you should

If you experience severe dizziness and/or fainting, lay down and contact your doctor immediately.

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

If you forget to take Valsartan/Hydroklortiazid Novartis

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

next dose, skip the dose you missed.

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

If you stop taking Valsartan/Hydroklortiazid Novartis

Stopping your treatment with Valsartan/Hydroklortiazid Novartis may cause your high blood pressure

to get worse. Do not stop taking your medicine unless your doctor tells you to.

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

4.

Possible side effects

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

Some side effects can be serious and need immediate medical attention:

You should see your doctor immediately if you experience symptoms of angioedema, such as:

swollen face, tongue or pharynx

difficulty in swallowing

hives and difficulties in breathing

Severe skin disease that causes rash, red skin, blistering of the lips, eyes or mouth, skin peeling,

fever (toxic epidermal necrolysis)

Decrease in vision or pain in your eyes due to high pressure (possible signs of acute angle-

closure glaucoma)

Fever, sore throat, more frequent infections (agranulocytosis)

These side effects are very rare or of frequency not known.

If you get any of these symptoms, stop taking Valsartan/Hydroklortiazid Novartis and contact

your doctor straight away (see also section 2 “Warnings and precautions”).

Other side effects include:

Uncommon (may affect up to 1 in 100 people):

cough

low blood pressure

light-headedness

dehydration (with symptoms of thirst, dry mouth and tongue, infrequent urination, dark colored

urine, dry skin)

muscle pain

tiredness

tingling or numbness

blurred vision

noises (e.g. hissing, buzzing) in ears

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

dizziness

diarrhoea

joint pain

Not known (frequency cannot be estimated from the available data):

breathing difficulty

severely decreased urine output

low level of sodium in the blood (which can trigger 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 cells in the blood (with symptoms such as fever, skin infections, sore throat

or mouth ulcers due to infections, weakness)

the level of bilirubin increased in blood (which can, in severe cases, trigger yellow skin and

eyes)

the level of blood urea nitrogen and creatinine increased in blood (which can indicate abnormal

kidney function)

the level of uric acid in blood increased (which can, in severe cases, trigger gout)

syncope (fainting)

The following side effects have been reported with products containing valsartan or

hydrochlorothiazide alone:

Valsartan

Uncommon (may affect up to 1 in 100 people):

spinning sensation

abdominal pain

Not known (frequency cannot be estimated from the available data):

blistering skin (sign of dermatitis bullous)

skin rash with or without itching together with some of the following signs or symptoms: fever,

joint pain, muscle pain, swollen lymph nodes and/or flu-like symptoms

rash, purplished-red spots, fever, itching (symptoms of inflammation of blood vessels)

low level of blood platelets (sometimes with unusual bleeding or bruising)

high 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

elevation of liver function values

the level of haemoglobin decreased and the percentage of red cells decreased in the blood

(which both can, in severe cases, trigger an anaemia).

kidney failure

low level of sodium in the blood (which can trigger tiredness, confusion, muscle twitching

and/or convulsions in severe cases)

Hydrochlorothiazide

Very common (may affect more than 1 in 10 people):

low level of potassium in the blood

increase of lipids in the blood

Common (may affect up to 1 in 10 people):

low level of sodium in the blood

low level of magnesium in the blood

high level of uric acid in the blood

itchy rash and other types of rash

reduced appetite

mild nausea and vomiting

dizziness, fainting on standing up

inability to achieve or maintain erection

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

swelling and blistering of the skin (due to increased sensitivity to sun)

high level of calcium in the blood

high level of sugar in the blood

sugar in the urine

worsening of diabetic metabolic state

constipation, diarrhoea, discomfort of the stomach or bowels, liver disorders which can occur

together with yellow skin and eyes

irregular heart beat

headache

sleep disturbances

sad mood (depression)

low level of blood platelets (sometimes with bleeding or bruising underneath the skin)

dizziness

tingling or numbness

vision disorder

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

inflammation of blood vessels with symptoms such as rash, purplish-red spots, fever (vasculitis)

rash, itching, hives, difficulty breathing or swallowing, dizziness (hypersensitivity reactions)

facial rash, joint pain, muscle disorder, fever (lupus erythematosus)

severe upper stomach pain (pancreatitis)

difficulty breathing with fever, coughing, wheezing, breathlessness (respiratory distress

including pneumonitis and pulmonary oedema)

pale skin, tiredness, breathlessness, dark urine (haemolytic anaemia)

fever, sore throat or mouth ulcers due to infections (leucopenia)

confusion, tiredness, muscle twitching and spasm, rapid breathing (hypochloraemic alkalosis)

Not known (frequency cannot be estimated from the available data):

weakness, bruising and frequent infections (aplastic anemia)

severely decreased urine output (possible signs of renal disorder or renal failure)

rash, red skin, blistering of the lips, eyes or mouth, skin peeling, fever (possible signs of

erythema multiforme)

muscle spasm

fever (pyrexia)

weakness (asthenia)

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects

not listed in this leaflet. You can also report side effects directly via the national reporting system

listed in Appendix V. By reporting side effects you can help provide more information on the safety of

this medicine.

5.

How to store Valsartan/Hydroklortiazid Novartis

Keep this medicine out of the sight and reach of children

Do not use this medicine after the expiry date which is stated on the carton. The expiry date

refers to the last day of that month.

Do not store above 30°C. Store in the original package in order to protect from moisture.

Do not use this medicine if you notice that the pack is damaged or shows signs of tampering.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how

to throw away medicines you no longer use. These measures will help protect the environment.

6.

Contents of the pack and other information

What Valsartan/Hydroklortiazid Novartis contains

The active substance is valsartan and hydrochlorothiazide. Each tablet contains 80 mg, 160 mg

or 320 mg valsartan, respectively and 12.5 mg or25 mg hydrochlorothiazide, respectively.

The tablet core contains microcrystalline cellulose, crospovidone, silica, colloidal anhydrous,

magnesium stearate.

The tablet coating contains hypromellose, macrogol 8000 (only 80 mg/12.5 mg and

160 mg/12.5 mg), macrogol 4000 (only 160 mg/25 mg, 320 mg/12.5 mg and 320 mg/25 mg),

talc, red iron oxide (E 172, not 320 mg/25 mg), yellow iron oxide (E 172, only 80 mg/12.5 mg,

160 mg/25 mg and 320 mg/25 mg), black iron oxide (E 172, only 160 mg/25 mg and

320 mg/12.5 mg), titanium dioxide (E 171).

What Valsartan/Hydroklortiazid Novartis looks like and contents of the pack

Valsartan/Hydroklortiazid Novartis 80 mg/12.5 mg film-coated tablets are light orange, ovaloid tablets

imprinted with HGH on one side and CG on the other side.

Valsartan/Hydroklortiazid Novartis 160 mg/12.5 mg film-coated tablets are dark red, ovaloid tablets

imprinted with HHH on one side and CG on the other side.

Valsartan/Hydroklortiazid Novartis 160 mg/25 mg film-coated tablets are brown, ovaloid tablets

imprinted with HXH on one side and NVR on the other side.

Valsartan/Hydroklortiazid Novartis 320 mg/12.5 mg film-coated tablets are pink, ovaloid shaped,

beveled edge tablets, imprinted with NVR on one side and HIL on the other side.

Valsartan/Hydroklortiazid Novartis 320 mg/25 mg film-coated tablets are yellow, ovaloid shaped,

beveled edge tablet, imprinted with NVR on one side and CTI on the other side.

The tablets are supplied in blister packs of 7 tablets (only for Valsartan/Hydroklortiazid Novartis

320 mg/12.5 mg and 320 mg/25 mg), 14 tablets, 28 tablets as calendar pack, 30 tablets (only for

Valsartan/Hydroklortiazid Novartis 80 mg/12.5 mg), 56 tablets, 98 tablets as calendar pack or

280 tablets. Perforated unit dose blister packs of 56x1, 98x1 or 280x1 tablets are also available.

Not all pack sizes may be marketed.

Marketing Authorisation Holder and Manufacturer

<[To be completed nationally]>

{Name and address}

<{tel}>

<{fax}>

<{e-mail}>

This medicinal product is authorised in the Member States of the EEA under the following

names:

Sweden

Valsartan/Hydroklortiazid Novartis

Portugal, Spain

Co-Novasan

Portugal, Spain

Co-Novasan Forte

Belgium

Co-Novacard

Germany

Provas comp

Germany

Provas maxx

This leaflet was last revised in 2015-04-09

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Produktinformationen för Valsartan/Hydroklortiazid Novartis, 80 mg/12,5 mg, filmdragerad tablett,

MTnr 22462, gäller vid det tillfälle då läkemedlet godkändes. Informationen kommer inte att

uppdateras eftersom läkemedlet inte marknadsförs i Sverige. Av samma anledning finns inte någon

svensk produktinformation.

Den engelska produktinformationen kommer dock att uppdateras för de produkter där Sverige är

referensland.

Om läkemedelsnamnet i följande produktinformation inte stämmer med namnet på dokumentet, beror

det på att läkemedlet i Sverige är godkänt under ett annat namn.

SUMMARY OF PRODUCT CHARACTERISTICS

1.

NAME OF THE MEDICINAL PRODUCT

Valsartan/Hydroklortiazid Novartis 80

mg/12.5 mg film-coated tablets

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 80 mg of valsartan and 12.5 mg of hydrochlorothiazide.

For a full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Film-coated tablet.

Light orange, ovaloid tablet imprinted with HGH on one side and CG on the other side.

4.

CLINICAL PARTICULARS

4.1

Therapeutic indications

Treatment of essential hypertension in adults.

Valsartan/Hydroklortiazid Novartis fixed-dose combination is indicated in patients whose blood

pressure is not adequately controlled on valsartan or hydrochlorothiazide monotherapy.

4.2

Posology and method of administration

Posology

The recommended dose of Valsartan/Hydroklortiazid Novartis 80 mg/12.5 mg is one film-coated

tablet once daily. Dose titration with the individual components is recommended. In each case, up-

titration of individual components to the next dose should be followed in order to reduce the risk of

hypotension and other adverse events.

When clinically appropriate direct change from monotherapy to the fixed combination may be

considered in patients whose blood pressure is not adequately controlled on valsartan or

hydrochlorothiazide monotherapy, provided the recommended dose titration sequence for the

individual components is followed.

The clinical response to Valsartan/Hydroklortiazid Novartis should be evaluated after initiating

therapy and if blood pressure remains uncontrolled, the dose may be increased by increasing either one

of the components to a maximum dose of Valsartan/Hydroklortiazid Novartis 320 mg/25 mg.

The antihypertensive effect is substantially present within 2 weeks.

In most patients, maximal effects are observed within 4 weeks. However, in some patients 4-8 weeks

treatment may be required. This should be taken into account during dose titration.

Method of administration

Valsartan/Hydroklortiazid Novartis can be taken with or without food and should be administered with

water.

Special populations

Renal impairment

No dose adjustment is required for patients with mild to moderate renal impairment (creatinine

clearance

30 ml/min). Due to the hydrochlorothiazide component, Valsartan/Hydroklortiazid

Novartis is contraindicated in patients with severe renal impairment (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). Valsartan/Hydroklortiazid Novartis is contraindicated in patients

with severe hepatic impairment (see sections 4.3, 4.4 and 5.2).

Elderly

No dose adjustment is required in elderly patients.

Paediatric patients

Valsartan/Hydroklortiazid Novartis is not recommended for use in children below the age of 18 years

due to a lack of data on safety and efficacy.

4.3

Contraindications

Hypersensitivity to valsartan, hydrochlorothiazide, other sulfonamide-derived medicinal

products or to any of the excipients.

Second and third trimester of pregnancy (section 4.4 and 4.6).

Severe hepatic impairment, biliary cirrhosis and cholestasis.

Severe renal impairment (creatinine clearance <30 ml/min), anuria.

Refractory hypokalaemia, hyponatraemia, hypercalcaemia, and symptomatic hyperuricaemia.

4.4

Special warnings and precautions for use

Serum electrolyte changes

Valsartan

Concomitant use with potassium supplements, potassium-sparing diuretics, salt substitutes containing

potassium, or other agents that may increase potassium levels (heparin, etc.) is not recommended.

Monitoring of potassium should be undertaken as appropriate.

Hydrochlorothiazide

Hypokalaemia has been reported under treatment with thiazide diuretics, including

hydrochlorothiazide. Frequent monitoring of serum potassium is recommended.

Treatment with thiazide diuretics, including hydrochlorothiazide, has been associated with

hyponatraemia and hypochloraemic alkalosis. Thiazides, including hydrochlorothiazide, increase the

urinary excretion of magnesium, which may result in hypomagnesaemia. Calcium excretion is

decreased by thiazide diuretics. This may result in hypercalcaemia.

As for any patient receiving diuretic therapy, periodic determination of serum electrolytes should be

performed at appropriate intervals.

Sodium and/or volume-depleted patients

Patients receiving thiazide diuretics, including hydrochlorothiazide, should be observed for clinical

signs of fluid or electrolyte imbalance.

In severely sodium-depleted and/or volume-depleted patients, such as those receiving high doses of

diuretics, symptomatic hypotension may occur in rare cases after initiation of therapy with

Valsartan/Hydroklortiazid Novartis. Sodium and/or volume depletion should be corrected before

starting treatment with Valsartan/Hydroklortiazid Novartis.

Patients with severe chronic heart failure or other conditions with stimulation of the renin-angiotensin-

aldosterone-system

In patients whose renal function may depend on the activity of the renin-angiotensin-aldosterone

system (e.g. patients with severe congestive heart failure), treatment with angiotensin converting

enzyme inhibitors has been associated with oliguria and/or progressive azotaemia, and in rare cases

with acute renal failure. The use of Valsartan/Hydroklortiazid Novartis in patients with severe chronic

heart failure has not been established.

Hence it cannot be excluded that because of the inhibition of the renin-angiotensin-aldosterone system

the application of Valsartan/Hydroklortiazid Novartis as well may be associated with impairment of

the renal function. Valsartan/Hydroklortiazid Novartis should not be used in these patients.

Renal artery stenosis

Valsartan/Hydroklortiazid Novartis should not be used to treat hypertension in patients with unilateral

or bilateral renal artery stenosis or stenosis of the artery to a solitary kidney, since blood urea and

serum creatinine may increase in such patients.

Primary hyperaldosteronism

Patients with primary hyperaldosteronism should not be treated with Valsartan/Hydroklortiazid

Novartis as their renin-angiotensin system is not activated.

Aortic and mitral valve stenosis, hypertrophic obstructive cardiomyopathy

As with all other vasodilators, special caution is indicated in patients suffering from aortic or mitral

stenosis, or hypertrophic obstructive cardiomyopathy (HOCM).

Renal impairment

No dosage adjustment is required for patients with renal impairment with a creatinine clearance

30 ml/min (see section 4.2). Periodic monitoring of serum potassium, creatinine and uric acid levels

is recommended when Valsartan/Hydroklortiazid Novartis is used in patients with renal impairment.

Kidney transplantation

There is currently no experience on the safe use of Valsartan/Hydroklortiazid Novartis in patients who

have recently undergone kidney transplantation.

Hepatic impairment

In patients with mild to moderate hepatic impairment without cholestasis, Valsartan/Hydroklortiazid

Novartis should be used with caution (see sections 4.2 and 5.2).

Systemic lupus erythematosus

Thiazide diuretics, including hydrochlorothiazide, have been reported to exacerbate or activate

systemic lupus erythematosus.

Other metabolic disturbances

Thiazide diuretics, including hydrochlorothiazide, may alter glucose tolerance and raise serum levels

of cholesterol, triglycerides and uric acid. In diabetic patients dosage adjustments of insulin or oral

hypoglycaemic agents may be required.

Thiazides may reduce urinary calcium excretion and cause an intermittent and slight elevation of

serum calcium in the absence of known disorders of calcium metabolism. Marked hypercalcaemia

may be evidence of underlying hyperparathyroidism. Thiazides should be discontinued before carrying

out tests for parathyroid function.

Photosensitivity

Cases of photosensitivity reactions have been reported with thiazide diuretics (see section 4.8). If

photosensitivity reaction occurs during treatment, it is recommended to stop the treatment. If a re-

administration of the diuretic is deemed necessary, it is recommended to protect exposed areas to the

sun or to artificial UVA.

Pregnancy

Angiotensin II Receptor Antagonists (AIIRAs) should not be initiated during pregnancy. Unless

continued AIIRAs therapy is considered essential, patients planning pregnancy should be changed to

alternative anti-hypertensive treatments which have an established safety profile for use in pregnancy.

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

Caution should be exercised in patients who have shown prior hypersensitivity to other angiotensin II

receptor antagonists. Hypersensitivity reactions to hydrochlorothiazide are more likely in patients with

allergy and asthma.

4.5

Interaction 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 lithium concentrations and toxicity have been reported during

concurrent use of ACE inhibitors and thiazide, including hydrochlorothiazide. Due to the lack of

experience with concomitant use of valsartan and lithium, this combination is not recommended. If the

combination proves necessary, careful monitoring of serum lithium levels is recommended.

Concomitant use requiring caution

Other antihypertensive agents

Valsartan/Hydroklortiazid Novartis

ay increase the effects of other agents with antihypertensive

properties (e.g. ACEI, beta blockers, calcium channel blockers).

Pressor amines

(e.g. noradrenaline, adrenaline)

Possible decreased response to pressor amines but not sufficient to preclude their use.

Non-steroidal anti-inflammatory medicines (NSAIDs), including selective COX-2 inhibitors,

acetylsalicylic acid >3 g/day), and non-selective NSAIDs

NSAIDS can attenuate the antihypertensive effect of both angiotensin II antagonists and

hydrochlorothiazide when administered simultaneously. Furthermore, concomitant use of

Valsartan/Hydroklortiazid Novartis and NSAIDs may lead to worsening of renal function and an

increase in serum potassium. Therefore, monitoring of renal function at the beginning of the treatment

is recommended, as well as adequate hydration of the patient.

Interactions related to valsartan

Concomitant use not recommended

Potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium and other

substances that may increase potassium levels

If a medicinal product that affects potassium levels is considered necessary in combination with

valsartan, monitoring of potassium plasma levels is advised.

No interaction

In drug interaction studies with valsartan, no interactions of clinical significance have been found with

valsartan or any of the following substances: cimetidine, warfarin, furosemide, digoxin, atenolol,

indomethacin, hydrochlorothiazide, amlodipine, glibenclamide. Digoxin and indomethacin could

interact with the hydrochlorothiazide component of Valsartan/Hydroklortiazid Novartis (see

interactions related to hydrochlorothiazide).

Interactions related to hydrochlorothiazide

Concomitant use requiring caution

Medicinal products associated with potassium loss and hypokalaemia

(e.g. kaliuretic diuretics,

corticosteroids, laxatives, ACTH, amphotericin, carbenoxolone, penicillin G, salicylic acid and

derivatives)

If these medicinal products are to be prescribed with the hydrochlorothiazide-valsartan combination,

monitoring of potassium plasma levels is advised. These medicinal products may potentiate the effect

of hydrochlorothiazide on serum potassium (see section 4.4).

Medicinal products that could induce torsades de pointes

Class Ia antiarrhythmics (e.g. quinidine, hydroquinidine, disopyramide)

Class III antiarrhythmics (e.g. amiodarone, sotalol, dofetilide, ibutilide)

Some antipsychotics (e.g. thioridazine, chlorpromazine, levomepromazine, trifluoperazine,

cyamemazine, sulpiride, sultopride, amisulpride, tiapride, pimozide, haloperidol, droperidol)

Others (e.g. bepridil, cisapride, diphemanil, erythromycin i.v., halofantrin, ketanserin,

mizolastin, pentamidine, sparfloxacine, terfenadine, vincamine i.v.)

Due to the risk of hypokalaemia, hydrochlorothiazide should be administered with caution when

associated with medicinal products that could induce torsades de pointes.

Digitalis glycosides

Thiazide-induced hypokalaemia or hypomagnesaemia may occur as unwanted effects favouring the

onset of digitalis-induced cardiac arrhythmias.

Calcium salts and vitamin D

Administration of thiazide diuretics, including hydrochlorothiazide, with vitamin D or with calcium

salts may potentiate the rise in serum calcium.

Antidiabetic agents

(oral agents and insulin)

The treatment with a thiazide may influence the glucose tolerance. Dose adjustment of the antidiabetic

medicinal product may be necessary.

Metformin should be used with caution because of the risk of lactic acidosis induced by possible

functional renal failure linked to hydrochlorothiazide.

Beta blockers and diazoxide

Concomitant use of thiazide diuretics, including hydrochlorothiazide, with beta blockers may increase

the risk of hyperglycaemia. Thiazide diuretics, including hydrochlorothiazide, may enhance the

hyperglycaemic effect of diazoxide.

Medicinal products used in the treatment of gout

(probenecid, sulfinpyrazone and allopurinol)

Dose adjustment of uricosuric medications may be necessary as hydrochlorothiazide may raise the

level of serum uric acid. Increase of dosage of probenecid or sulfinpyrazone may be necessary. Co-

administration of thiazide diuretics, including hydrochlorothiazide, may increase the incidence of

hypersensitivity reactions to allopurinol.

Anticholinergic agents

(e.g. atropine, biperiden)

The bioavailability of thiazide-type diuretics may be increased by anticholinergic agents, apparently

due to a decrease in gastrointestinal motility and the stomach emptying rate.

Amantadine

Thiazides, including hydrochlorothiazide, may increase the risk of adverse effects caused by

amantadine.

Cholestyramine and cholestipol resins

Absorption of thiazide diuretics, including hydrochlorothiazide, is impaired in the presence of anionic

exchange resins.

Cytotoxic agents

(e.g. cyclophosamide, methotrexate)

Thiazides, including hydrochlorothiazide, may reduce renal excretion of cytotoxic agents and

potentiate their myelosuppressive effects.

Non-depolarising skeletal muscle relaxants

(e.g. tubocurarine)

Thiazides, including hydrochlorothiazide, potentiate the action of curare derivatives.

Ciclosporin

Concomitant treatment with ciclosporin may increase the risk of hyperuricaemia and gout-type

complications.

Alcohol, anaesthetics and sedatives

Potentiation of orthostatic hypotension may occur.

Methyldopa

There have been isolated reports of haemolytic anaemia in patients receiving concomitant treatment

with methyldopa and hydrochlorothiazide.

Carbamazepine

Patients receiving hydrochlorothiazide concomitantly with carbamazepine may develop hyponatremia.

Such patients should therefore be advised about the possibility of hyponatraemic reactions, and should

be monitored accordingly.

Iodine contrast media

In case of diuretic-induced dehydration, there is an increased risk of acute renal failure, especially with

high doses of the iodine product. Patients should be rehydrated before the administration.

4.6

Pregnancy and lactation

Pregnancy

Valsartan

The use of Angiotensin II Receptor Antagonists (AIIRAs) is not recommended during first trimester of

pregnancy (see section 4.4).The use of AIIRAs is contra-indicated during the second and third

trimester of pregnancy (see sections 4.3 and 4.4).

Epidemiological evidence regarding 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. Whilst there is no controlled epidemiological data on the risk with Angiotensin II

Receptor Inhibitors (AIIRAs), similar risks may exist for this class of drugs. Unless continued AIIRAs

therapy is considered essential, patients planning pregnancy should be changed to alternative anti-

hypertensive treatments which have an established safety profile for use in pregnancy. When

pregnancy is diagnosed, treatment with AIIRAs should be stopped immediately and, if appropriate,

alternative therapy should be started.

AIIRAs therapy exposure during the second and third trimesters is known to induce human

fetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal

toxicity (renal failure, hypotension, hyperkalaemia) (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.

Infants whose mothers have taken AIIRAs should be closely observed for hypotension (see also

section 4.3 and 4.4).

Hydrochlorothiazide

There is limited experience with hydrochlorothiazide during pregnancy, especially during the first

trimester. 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 may compromise foeto-placental perfusion and may cause foetal and neonatal effects like

icterus, disturbance of electrolyte balance and thrombocytopenia.

Lactation

No information is available regarding the use of valsartan during breastfeeding. Hydrochlorothiazide

is excreted in human milk. Therefore the use of Valsartan/Hydroklortiazid Novartis during breast

feeding is not recommended. Alternative treatments with better established safety profiles during

breast-feeding are preferable, especially while nursing a newborn or preterm infant.

4.7

Effects on ability to drive and use machines

No studies on the effect of Valsartan/Hydroklortiazid Novartis on the ability to drive and use machines

have been performed. When driving vehicles or operating machines it should be taken into account

that occasionally dizziness or weariness may occur.

4.8

Undesirable effects

Adverse reactions reported in clinical trials and laboratory findings occurring more frequently with

valsartan plus hydrochlorothiazide versus placebo and individual postmarketing reports are presented

below according to system organ class. Adverse reactions known to occur with each component given

individually but which have not been seen in clinical trials may occur during treatment with

valsartan/hydrochlorothiazide.

Adverse drug reactions are ranked by frequency, the most frequent first, using the following

convention: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100);

rare (≥ 1/10,000 to <

1/1,000); very rare (< 1/10,000), not known (cannot be estimated from the

available data). Within each frequency grouping, adverse reactions are ranked in order of decreasing

seriousness.

Table 1. Frequency of adverse reactions with valsartan/hydrochlorothiazide

Metabolism and nutrition disorders

Uncommon

Dehydration

Nervous system disorders

Very rare

Dizziness

Uncommon

Paraesthesia

Not known

Syncope

Eye disorders

Uncommon

Vision blurred

Ear and labyrinth disorders

Uncommon

Tinnitus

Vascular disorders

Uncommon

Hypotension

Respiratory, thoracic and mediastinal disorders

Uncommon

Cough

Not known

Non cardiogenic pulmonary oedema

Gastrointestinal disorders

Very rare

Diarrhoea

Musculoskeletal and connective tissue disorders

Uncommon

Myalgia

Very rare

Arthralgia

Renal and urinary disorders

Not known

Impaired renal function

General disorders and administration site conditions

Uncommon

Fatigue

Investigations

Not known

Serum uric acid increased, Serum bilirubin and Serum

creatinine increased, Hypokalaemia, Hyponatraemia,

Elevation of Blood Urea Nitrogen, Neutropenia

Additional information on the individual components

Adverse reactions previously reported with one of the individual components may be potential

undesirable effects with Valsartan/Hydroklortiazid Novartis as well, even if not observed in clinical

trials or during postmarketing period.

Table 2. Frequency of adverse reactions with valsartan

Blood and lymphatic system disorders

Not known

Decrease in haemoglobin, decrease in haematocrit,

thrombocytopenia

Immune system disorders

Not known

Other hypersensitivity/allergic reactions including

serum sickness

Metabolism and nutrition disorders

Not known

Increase of serum potassium

, hyponatraemia

Ear and labyrinth disorders

Uncommon

Vertigo

Vascular disorders

Not known

Vasculitis

Gastrointestinal disorders

Uncommon

Abdominal pain

Hepatobiliary disorders

Not known

Elevation of liver function values

Skin and subcutaneous tissue disorders

Not known

Angioedema, rash, pruritus

Renal and urinary disorders

Not known

Renal failure

Table 3: Frequency of adverse reactions with hydrochlorothiazide

Hydrochlorothiazide has been extensively prescribed for many years, frequently in higher doses than

those administered with Valsartan/Hydroklortiazid Novartis. The following adverse reactions have

been reported in patients treated with monotherapy of thiazide diuretics, including

hydrochlorothiazide:

Blood and lymphatic system disorders

Rare

Thrombocytopenia sometimes with purpura

Very rare

Agranulocytosis, leucopenia, haemolytic anaemia,

bone marrow depression

Immune system disorders

Very rare

Hypersenstivity reactions

Psychiatric disorders

Rare

Depression, sleep disturbances

Nervous system disorders

Rare

Headache

Cardiac disorders

Rare

Cardiac arrhythmias

Vascular disorders

Common

Postural hypotension

Respiratory, thoracic and mediastinal disorders

Very rare

Respiratory distress including pneumonitis and

pulmonary oedema

Gastrointestinal disorders

Common

Loss of appetite, mild nausea and vomiting

Rare

Constipation, gastrointestinal discomfort

Very rare

Pancreatitis

Hepatobiliary disorders

Rare

Intrahepatic cholestasis or jaundice

Skin and subcutaneous tissue disorders

Common

Urticaria and other forms of rash

Rare

Photosensitisation

Very rare

Necrotising vasculitis and toxic epidermal

necrolysis, cutaneous lupus erythematosus-like

reactions, reactivation of cutaneous lupus

erythematosus

Reproductive system and breast disorders

Common

Impotence

4.9

Overdose

Symptoms

Overdose with valsartan may result in marked hypotension, which could lead to depressed level of

consciousness, circulatory collapse and/or shock. In addition, the following signs and symptoms may

occur due to an overdose of the hydrochlorothiazide component: nausea, somnolence, hypovolaemia,

and electrolyte disturbances associated with cardiac arrhythmias and muscle spasms.

Treatment

The therapeutic measures depend on the time of ingestion and the type and severity of the symptoms,

stabilisation of the circulatory condition being of prime importance.

If hypotension occurs, the patient should be placed in the supine position and salt and volume

supplementation should be given rapidly.

Valsartan cannot be eliminated by means of haemodialysis because of its strong plasma binding

behaviour whereas clearance of hydrochlorothiazide will be achieved by dialysis.

5.

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

Pharmacotherapeutic group: Angiotensin II antagonists and diuretics, valsartan and diuretics; ATC

code: C09D A03.

Valsartan/hydrochlorothiazide

In a double-blind, randomised, active-controlled trial in patients not adequately controlled on

hydrochlorothiazide 12.5 mg, significantly greater mean systolic/diastolic BP reductions were

observed with the combination of valsartan/hydrochlorothiazide 80/12.5 mg (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 greater percentage of patients responded (diastolic BP

<90 mmHg or reduction ≥10 mmHg) with valsartan/hydrochlorothiazide 80/12.5 mg (60%) compared

to hydrochlorothiazide 12.5 mg (25%) and hydrochlorothiazide 25 mg (27%).

In a double-blind, randomised, active-controlled trial in patients not adequately controlled on valsartan

80 mg, significantly greater mean systolic/diastolic BP reductions were observed with the combination

of 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 greater percentage

of patients responded (diastolic BP <90 mmHg or reduction ≥10 mmHg) with

valsartan/hydrochlorothiazide 80/12.5 mg (51%) compared to valsartan 80 mg (36%) and valsartan

160 mg (37%).

In a double-blind, randomised, placebo-controlled, factorial design trial comparing various dose

combinations of valsartan/hydrochlorothiazide to their respective components, significantly greater

mean systolic/diastolic BP reductions were observed with the combination of

valsartan/hydrochlorothiazide 80/12.5 mg (16.5/11.8 mmHg) compared to 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 greater percentage of patients responded (diastolic BP <90 mmHg or

reduction ≥10 mmHg) with valsartan/hydrochlorothiazide 80/12.5 mg (64%) compared to placebo

(29%) and hydrochlorothiazide (41%).

Dose-dependent decreases in serum potassium occurred in controlled clinical studies with valsartan +

hydrochlorothiazide. Reduction in serum potassium occurred more frequently in patients given 25 mg

hydrochlorothiazide than in those given 12.5 mg hydrochlorothiazide. In controlled clinical trials with

valsartan/hydrochlorothiazide the potassium lowering effect of hydrochlorothiazide was attenuated by

the potassium-sparing effect of valsartan.

Beneficial effects of valsartan in combination with hydrochlorothiazide on cardiovascular mortality

and morbidity are currently unknown.

Epidemiological studies have shown that long-term treatment with hydrochlorothiazide reduces the

risk of cardiovascular mortality and morbidity.

Valsartan

Valsartan is an orally active and specific angiotensin II (Ang II) receptor antagonist. It acts selectively

on the AT

receptor subtype, which is responsible for the known actions of angiotensin II. The

increased plasma levels of Ang II following AT

receptor blockade with valsartan may stimulate the

unblocked AT

receptor, which appears to counterbalance the effect of the AT

receptor. Valsartan

does not exhibit any partial agonist activity at the AT

receptor and has much (about 20,000-fold)

greater affinity for the AT

receptor than for the AT

receptor. Valsartan is not known to bind to or

block other hormone receptors or ion channels known to be important 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 and no potentiation of bradykinin or substance P,

angiotensin II antagonists are unlikely to be associated with coughing. In clinical trials where valsartan

was compared with an ACE inhibitor, the incidence of dry cough was significantly (P <0.05) lower in

patients treated with valsartan than in those treated with an ACE inhibitor (2.6% versus 7.9%

respectively). In a clinical trial of patients with a history of dry cough during ACE inhibitor therapy,

19.5% of trial subjects receiving valsartan and 19.0% of those receiving a thiazide diuretic

experienced cough compared to 68.5% of those treated with an ACE inhibitor (P <0.05).

Administration of valsartan to patients with hypertension results in reduction of blood pressure

without affecting pulse rate. In most patients, after administration of a single oral dose, onset of

antihypertensive activity occurs within 2 hours, and the peak reduction of blood pressure is achieved

within 4–6 hours. The antihypertensive effect persists over 24 hours after dosing. During repeated

dosing, the maximum reduction in blood pressure with any dose is generally attained within 2–

4 weeks and is sustained during long-term therapy. Combined with hydrochlorothiazide, a significant

additional reduction in blood pressure is achieved.

Abrupt withdrawal of valsartan has not been associated with rebound hypertension or other adverse

clinical events.

In hypertensive patients with type 2 diabetes and microalbuminuria, valsartan has been shown to

reduce the urinary excretion of albumin. The MARVAL (Micro Albuminuria Reduction with

Valsartan) study assessed the reduction in urinary albumin excretion (UAE) with valsartan

(80-160 mg/od) versus amlodipine (5-10 mg/od), in 332 type 2 diabetic patients (mean age: 58 years;

265 men) with microalbuminuria (valsartan: 58 µg/min; amlodipine: 55.4 µg/min), normal or high

blood pressure and with preserved renal function (blood creatinine <120 µmol/l). At 24 weeks, UAE

was reduced (p <0.001) by 42% (–24.2 µg/min; 95% CI: –40.4 to –19.1) with valsartan and

approximately 3% (–1.7 µg/min; 95% CI: –5.6 to 14.9) with amlodipine despite similar rates of blood

pressure reduction in both groups. The Diovan Reduction of Proteinuria (DROP) study further

examined the efficacy of valsartan in reducing UAE in 391 hypertensive patients (BP=150/88 mmHg)

with type 2 diabetes, albuminuria (mean=102 µg/min; 20-700 µg/min) and preserved renal function

(mean serum creatinine = 80 µmol/l). Patients were randomised to one of 3 doses of valsartan (160,

320 and 640 mg/od) and treated for 30 weeks. The purpose of the study was to determine the optimal

dose of valsartan for reducing UAE in hypertensive patients with type 2 diabetes. At 30 weeks, the

percentage change in UAE was significantly reduced by 36% from baseline with valsartan 160 mg

(95%CI: 22 to 47%), and by 44% with valsartan 320 mg (95%CI: 31 to 54%). It was concluded that

160-320 mg of valsartan produced clinically relevant reductions in UAE in hypertensive patients with

type 2 diabetes.

Hydrochlorothiazide

The site of action of thiazide diuretics is primarily in the renal distal convoluted tubule. It has been

shown that there is a high-affinity receptor in the renal cortex as the primary binding site for the

thiazide diuretic action and inhibition of NaCl transport in the distal convoluted tubule. The mode of

action of thiazides is through inhibition of the Na

symporter perhaps by competing for the Cl

site,

thereby affecting electrolyte reabsorption mechanisms:directly increasing sodium and chloride

excretion to an approximately equal extent, and indirectly by this diuretic action reducing plasma

volume, with consequent increases in plasma renin activity, aldosterone secretion and urinary

potassium loss, and a decrease in serum potassium. The renin-aldosterone link is mediated by

angiotensin II, so with co-administration of valsartan the reduction in serum potassium is less

pronounced as observed under monotherapy with hydrochlorothiazide.

5.2

Pharmacokinetic properties

Valsartan/hydrochlorothiazide

The systemic availability of hydrochlorothiazide is reduced by about 30% when co-administered with

valsartan. The kinetics of valsartan are not markedly affected by the co-administration of

hydrochlorothiazide. This observed interaction has no impact on the combined use of valsartan and

hydrochlorothiazide, since controlled clinical trials have shown a clear anti-hypertensive effect, greater

than that obtained with either active substance given alone, or placebo.

Valsartan

Absorption

Following oral administration of valsartan alone, peak plasma concentrations of valsartan are reached

in 2–4 hours. Mean absolute bioavailability is 23%. Food decreases exposure (as measured by AUC)

to valsartan by about 40% and peak plasma concentration (C

) by about 50%, although from about

8 h post dosing plasma valsartan concentrations are similar for the fed and fasted groups. This

reduction in AUC is not, however, accompanied by a clinically significant reduction in the therapeutic

effect, and valsartan can therefore be given either with or without food.

Distribution

The steady-state volume of distribution of valsartan after intravenous administration is about 17 litres,

indicating that valsartan does not distribute into tissues extensively. Valsartan is highly bound to

serum proteins (94–97%), mainly serum albumin.

Biotransformation

Valsartan is not biotransformed to a high extent as only about 20% of dose is recovered as metabolites.

A hydroxy metabolite has been identified in plasma at low concentrations (less than 10% of the

valsartan AUC). This metabolite is pharmacologically inactive.

Elimination

Valsartan shows multiexponential decay kinetics (t

½α

<1 h and t

½ß

about 9 h). Valsartan is primarily

eliminated in faeces (about 83% of dose) and urine (about 13% of dose), mainly as unchanged drug.

Following intravenous administration, plasma clearance of valsartan is about 2 l/h and its renal

clearance is 0.62 l/h (about 30% of total clearance). The half-life of valsartan is 6 hours.

Hydrochlorothiazide

Absorption

The absorption of hydrochlorothiazide, after an oral dose, is rapid (t

about 2 h), with similar

absorption characteristics for both suspension and tablet formulations. Absolute bioavailability of

hydrochlorothiazide is 60–80% after oral administration. Concomitant administration with food has

been reported to both increase and decrease the systemic availability of hydrochlorothiazide compared

with the fasted state. The magnitude of these effects is small and has minimal clinical importance. The

increase in mean AUC is linear and dose proportional in the therapeutic range. There is no change in

the kinetics of hydrochlorothiazide on repeated dosing, and accumulation is minimal when dosed once

daily.

Distribution

The distribution and elimination kinetics have generally been described by a bi-exponential decay

function. 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 at approximately 1.8 times the level in plasma.

Elimination

For hydrochlorotiazide, >95% of the absorbed dose being excreted as unchanged compound in the

urine. The renal clearance is composed of passive filtration and active secretion into the renal tubule.

The terminal half-life is 6-15 h.

Special populations

Elderly

A somewhat higher systemic exposure to valsartan was observed in some elderly subjects than in

young subjects; however, this has not been shown to have any clinical significance.

Limited data suggest that the systemic clearance of hydrochlorothiazide is reduced in both healthy and

hypertensive elderly subjects compared to young healthy volunteers.

Renal impairment

At the recommended dose of Valsartan/Hydroklortiazid Novartis no dose adjustment is required for

patients with a creatinine clearance of 30–70 ml/min.

In patients with severe renal impairment (creatinine clearance <30 ml/min) and patients undergoing

dialysis no data are available for Valsartan/Hydroklortiazid Novartis. Valsartan is highly bound to

plasma protein and is not to be removed by dialysis, whereas clearance of hydrochlorothiazide will be

achieved by dialysis.

Renal clearance of hydrochlorothiazide is composed of passive filtration and active secretion into the

renal tubule. As expected for a compound which is cleared almost exclusively via the kidneys, renal

function has a marked effect on the kinetics of hydrochlorothiazide (see section 4.3).

Hepatic impairment

In a pharmacokinetics trial in patients with mild (n=6) to moderate (n=5) hepatic dysfunction,

exposure to valsartan was increased approximately 2-fold compared with healthy volunteers.

There is no data 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.

5.3

Preclinical safety data

The potential toxicity of the valsartan - hydrochlorothiazide combination after oral administration was

investigated in rats and marmosets in studies lasting up to six months. No findings emerged that would

exclude the use of therapeutic doses in man.

The changes produced by the combination in the chronic toxicity studies are most likely to have been

caused by the valsartan component. The toxicological target organ was the kidney, the reaction being

more marked in the marmoset than the rat. The combination led to kidney damage (nephropathy with

tubular basophilia, rises in plasma urea, plasma creatinine and serum potassium, increases in urine

volume and urinary electrolytes from 30 mg/kg/day valsartan + 9 mg/kg/day hydrochlorothiazide in

rats and 10 + 3 mg/kg/d in marmosets), probably by way of altered renal haemodynamics. These doses

in rat, respectively, represent 0.9 and 3.5-times the maximum recommended human dose (MRHD) of

valsartan and hydrochlorothiazide on a mg/m

basis. These doses in marmoset, respectively, represent

0.3 and 1.2-times the maximum recommended human dose (MRHD) of valsartan and

hydrochlorothiazide on a mg/m

basis. (Calculations assume an oral dose of 320 mg/day valsartan in

combination with 25 mg/day hydrochlorothiazide and a 60-kg patient.)

High doses of the valsartan - hydrochlorothiazide combination caused falls in red blood cell indices

(red cell count, haemoglobin, haematocrit, from 100 + 31 mg/kg/d in rats and 30 + 9 mg/kg/d in

marmosets). These doses in rat, respectively, represent 3.0 and 12 times the maximum recommended

human dose (MRHD) of valsartan and hydrochlorothiazide on a mg/m

basis. These doses in

marmoset, respectively, represent 0.9 and 3.5 times the maximum recommended human dose (MRHD)

of valsartan and hydrochlorothiazide on a mg/m

basis. (Calculations assume an oral dose of

320 mg/day valsartan in combination with 25 mg/day hydrochlorothiazide and a 60-kg patient).

In marmosets, damage was observed in the gastric mucosa (from 30 + 9 mg/kg/d). The combination

also led in the kidney to hyperplasia of the afferent aterioles (at 600 + 188 mg/kg/d in rats and from

30 + 9 mg/kg/d in marmosets). These doses in marmoset, respectively, represent 0.9 and 3.5 times the

maximum recommended human dose (MRHD) of valsartan and hydrochlorothiazide on a mg/m

basis.

These doses in rat, respectively, represent 18 and 73 times the maximum recommended human dose

(MRHD) of valsartan and hydrochlorothiazide on a mg/m

basis. (Calculations assume an oral dose of

320 mg/day valsartan in combination with 25 mg/day hydrochlorothiazide and a 60-kg patient).

The above mentioned effects appear to be due to the pharmacological effects of high valsartan doses

(blockade of angiotensin II-induced inhibition of renin release, with stimulation of the renin-producing

cells) and also occur with ACE inhibitors. These findings appear to have no relevance to the use of

therapeutic doses of valsartan in humans.

The valsartan - hydrochlorothiazide combination was not tested for mutagenicity, chromosomal

breakage or carcinogenicity, since there is no evidence of interaction between the two substances.

However, these tests were performed separately with valsartan and hydrochlorothiazide, and produced

no evidence of mutagenicity, chromosomal breakage or carcinogenicity.

In rats, maternally toxic doses of valsartan (600 mg/kg/day) during the last days of gestation and

lactation led to lower survival, lower weight gain and delayed development (pinna detachment and

ear-canal opening) in the offspring (see section 4.6). These doses in rats (600 mg/kg/day) are

approximately 18 times the maximum recommended human dose on a mg/m2 basis (calculations

assume an oral dose of 320 mg/day and a 60-kg patient). Similar findings were seen with

valsartan/hydrochlorothiazide in rats and rabbitsIn embryo-fetal development (Segment II) studies

with valsartan/hydrochlorothiazide in rat and rabbit, there was no evidence of teratogenicity; however,

fetotoxicity associated with maternal toxicity was observed.

6.

PHARMACEUTICAL PARTICULARS

6.1

List of excipients

Tablet core

Microcrystalline cellulose

Silica, colloidal anhydrous

Crospovidone

Magnesium stearate.

Coating

Hypromellose

Macrogol 8000

Talc

Red iron oxide (E 172)

Yellow iron oxide (E 172)

Titanium dioxide (E 171).

6.2

Incompatibilities

Not applicable.

6.3

Shelf life

3 years.

6.4

Special precautions for storage

Do not store above 30° C. Store in the original package in order to protect from moisture.

6.5

Nature and contents of container

PVC/PE/PVDC/Alu or PVC/PVDC/Alu blisters.

14; 28 as calendar pack; 30, 56; 98 as calendar pack; 280 film-coated tablets.

PVC/PE/PVDC/Alu or PVC/PVDC/Alu perforated unit dose blisters.

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

Not all pack sizes may be marketed.

To be completed nationally

6.6

Special precautions for disposal

No special requirements.

7.

MARKETING AUTHORISATION HOLDER

Novartis Sverige AB

Box 1150

183 11 Täby

8.

MARKETING AUTHORISATION NUMBER(S)

22060

9.

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

2005-11-18/ 2010-05-29

10.

DATE OF REVISION OF THE TEXT

2010-11-03

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