PACKAGE LEAFLET: INFORMATION FOR THE USER

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

Valsartan/hydrochlorothiazide
Please read all of this leaflet carefully before taking this medicine because it contains
important information for you.

Keep this leaflet. You may need to read it again.
If you have any questions, ask your doctor or pharmacist.
This medicine has been prescribed for you. Do not give it to other people, even if they have the same symptoms as you, because it could be harmful.
If you experience any side effect, including those not listed in this leaflet, tell your doctor or pharmacist. See section 4.

Contents of this leaflet:

What Combisartan is and what it is used for
What you need to know before taking Combisartan
How to take Combisartan
Possible side effects
How to store Combisartan
Contents of the pack and other information

1. WHAT COMBISARTAN IS AND WHAT IT IS USED FOR

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

Valsartan belongs to a class of medicines known as "angiotensin II receptor antagonists", which help control high blood pressure. Angiotensin II is a substance in the body that causes blood vessels to narrow, thereby increasing blood pressure. Valsartan works by blocking the effect of angiotensin II. As a result, blood vessels relax and blood pressure decreases.
Hydrochlorothiazide belongs to a group of medicines called thiazide diuretics.
Hydrochlorothiazide increases the amount of urine produced, thereby reducing blood pressure.

Combisartan is used to treat high blood pressure when it is not adequately 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, leading to stroke, heart failure, or kidney failure. High blood pressure also increases the risk of heart attack. Lowering blood pressure to normal levels reduces the risk of developing these conditions.

2. WHAT YOU SHOULD KNOW BEFORE TAKING COMBISARTAN

Do not take Combisartan:

if you are allergic to the active substances valsartan and hydrochlorothiazide, sulphonamide derivatives (chemically related substances 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 better to avoid taking Combisartan even in the early stages of pregnancy - see section Pregnancy)
if you have severe liver problems, destruction of the small bile ducts within the liver (biliary cirrhosis) leading to bile accumulation in the liver (cholestasis)
if you have severe kidney problems
if you are unable to urinate (anuria)
if you are undergoing treatment with an artificial kidney
if your blood potassium or sodium levels are lower than normal, or if your blood calcium levels are higher than normal despite treatment
if you have gout
if you have diabetes or impaired kidney function and are being treated with a blood pressure-lowering medicine containing aliskiren.

If any of these situations apply to you, do not take this medicine and consult your doctor.
Warnings and precautions
Talk to your doctor or pharmacist before taking Combisartan.
Take special care with Combisartan:

if you are taking potassium-sparing medicines, potassium supplements, salt substitutes containing potassium, or other medicines that increase blood potassium levels, such as heparin. Your doctor may need to check your blood potassium levels regularly
if your blood potassium levels are low
if you have diarrhoea or severe vomiting
if you are taking high doses of medicines that increase fluid elimination (diuretics)
if you have serious heart problems
if you suffer from heart failure or have had a heart attack. Follow your doctor's instructions carefully regarding the starting dose of therapy. Your doctor will also monitor your kidney function.
if you have narrowing of the renal artery
if you have recently received a new kidney
if you suffer from hyperaldosteronism, a condition in which the adrenal glands produce too much aldosterone hormone. If this applies to you, use of Combisartan is not recommended
if you have liver or kidney diseases
if you previously experienced swelling of the tongue and face due to an allergic reaction called angioedema when taking other medicines (including ACE inhibitors), inform your doctor. If these symptoms occur while taking Combisartan, stop taking Combisartan immediately and never take it again. See section 4, "Possible side effects"
if you have fever, skin rash, and joint pain, which may be signs of systemic lupus erythematosus (SLE, an autoimmune disease)
if you have diabetes, gout, elevated cholesterol or triglyceride levels in the blood
if you have had allergic reactions with other blood pressure-lowering medicines belonging to the same class (angiotensin II receptor antagonists) or if you suffer from allergies or asthma.
if you experience decreased vision or eye pain. These may be symptoms of fluid accumulation in the vascular layer of the eye (choroidal effusion) or increased intraocular pressure and may occur from a few hours to several weeks after taking Combisartan. If untreated, this may lead to permanent vision loss. If you previously had an allergy to penicillins or sulphonamides, you have a higher risk of developing this condition
it may cause increased skin sensitivity to sunlight
if you are taking any of the following medicines used to treat high blood pressure:
an "ACE inhibitor" (e.g., enalapril, lisinopril, ramipril), particularly if you have kidney problems related to diabetes.
aliskiren
if you are being treated with an ACE inhibitor together with other medicines used to treat heart failure, known as mineralocorticoid receptor antagonists (MRAs) (e.g., spironolactone, eplerenone) or beta-blockers (e.g., metoprolol).
if you have previously had skin cancer or are developing unexpected skin lesions during treatment. Treatment with hydrochlorothiazide, particularly long-term use with high doses, may increase the risk of certain types of skin and lip cancer (non-melanoma skin cancer). Protect your skin from sun and UV exposure while taking Combisartan.

Your doctor may check your kidney function, blood pressure, and electrolyte levels
(e.g., potassium) in your blood at regular intervals.
See also information under the heading “Do not take Combisartan”.
If any of these situations apply to you, consult your doctor.
Children and adolescents
The use of Combisartan is not recommended in children and adolescents (under 18 years of age).
You must inform your doctor if you think you are pregnant (or if there is a possibility of becoming
pregnant). Combisartan is not recommended during early pregnancy and must not be taken if you are
more than 3 months pregnant, as it may cause serious harm to the baby if taken during this period (see section Pregnancy, breastfeeding and fertility).
Other medicines and Combisartan
Inform your doctor or pharmacist if you are taking, have recently taken, or might take any other
medicines, including those without a prescription.
The effect of treatment may be influenced if Combisartan is taken with certain other medicines.
It may be necessary to adjust the dose, take additional precautions, or in some cases, stop taking one of the medicines. This particularly applies to the following medicines:

lithium, a medicine used in the treatment of certain psychiatric disorders
medicines or substances that may increase blood potassium levels. These include potassium supplements or potassium-containing salt substitutes, potassium-sparing medicines, and heparin
medicines that may decrease blood potassium levels, such as diuretics (medicines that increase fluid elimination), corticosteroids, laxatives, carbenoxolone, amphotericin or penicillin G.
certain antibiotics (rifampicin group), a drug used to prevent transplant rejection (cyclosporine), and an antiretroviral drug used to treat HIV/AIDS infections (ritonavir). These medicines may increase the effect of Combisartan
medicines that may induce torsades de pointes (irregular heartbeat), such as antiarrhythmics (medicines used to treat heart disorders) and certain antipsychotics.
medicines that may reduce blood sodium levels, 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 (oral such as metformin or insulin)
other medicines that lower blood pressure, including methyldopa, ACE inhibitors (such as enalapril, lisinopril, etc.) or aliskiren (see also information under: “Do not take Combisartan” and “Take special care with Combisartan”).
medicines that increase blood pressure, such as noradrenaline and 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
painkillers such as non-steroidal anti-inflammatory drugs (NSAIDs), including selective cyclooxygenase-2 (Cox-2) inhibitors and acetylsalicylic acid > 3 g
muscle relaxants, such as tubocurarine
anticholinergic medicines (used to treat various disorders such as gastrointestinal cramps, bladder spasms, asthma, motion sickness, muscle spasms, Parkinson's disease, and to facilitate anaesthesia)
amantadine (a medicine used to treat Parkinson's disease and also to treat or prevent certain viral diseases)
cholestyramine and colestipol (medicines mainly used to treat high lipid levels in the blood)
cyclosporine, a medicine used in organ transplantation to prevent organ rejection
alcoholic beverages, sedatives and anaesthetics (medicines with narcotic or pain-relieving effects used, for example, during surgical procedures)
iodinated contrast agents (used for radiological examinations)

Combisartan with food, drinks and alcohol
Combisartan can be taken with or without food.
Avoid consuming alcohol unless you have discussed it with your doctor. Alcohol may further reduce
blood pressure and/or increase the risk of dizziness or fainting.
Pregnancy and breastfeeding
Ask your doctor or pharmacist for advice before taking any medicine.

You must inform 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 Combisartan before becoming pregnant or as soon as you learn you are pregnant and will recommend another medicine instead of Combisartan. Combisartan is not recommended during early pregnancy and must not be taken if you are more than 3 months pregnant, as it may cause serious harm to the baby if taken after the third month of pregnancy.
Inform your doctor if you are breastfeeding or planning to start breastfeeding. Combisartan is not recommended for women who are breastfeeding, and your doctor may choose another treatment for you if you wish to breastfeed, especially if the baby is a newborn or was born prematurely.

Driving and using machines
Before driving a vehicle, operating machinery, or performing other activities requiring concentration, you should be aware of your reaction to Combisartan. Like many other medicines used to treat high blood pressure, Combisartan may rarely cause dizziness and affect your ability to concentrate.
For athletes: using this medicine without therapeutic need constitutes doping and may result in a positive anti-doping test.
3 HOW TO TAKE COMBISARTAN
Take this medicine exactly as your doctor has instructed. If you are unsure, consult your doctor or pharmacist.
People with high blood pressure often do not notice any signs of this condition and many feel as well as usual. For this reason, it is very important that you keep regular appointments with your doctor, even when you feel well.
Your doctor will tell you exactly how many Combisartan tablets you should take. Based on your response to treatment, your doctor may recommend a higher or lower dose.

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

If you take more Combisartan than you should
In case of severe dizziness and/or fainting, lie 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 Combisartan
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 missed dose.
Do not take a double dose to make up for a forgotten dose.
If you stop taking Combisartan
Stopping treatment with Combisartan may cause worsening of high blood pressure.
Do not stop using this medicine unless instructed by your doctor.
If you have any doubts about using this product, consult your doctor or pharmacist.
4 POSSIBLE SIDE EFFECTS
Like all medicines, this medicine can cause side effects, although not everybody gets them.
These side effects may occur with certain frequencies, defined as follows:

very common: affects more than 1 in 10 people
common: affects 1 to 10 in 100 people
uncommon: affects 1 to 10 in 1,000 people
rare: affects 1 to 10 in 10,000 people
very rare: affects fewer than 1 in 10,000 people
not known: frequency cannot be estimated from the available data.

Some side effects may be serious and require immediate medical attention.
Contact your doctor immediately if you experience symptoms of angioedema, such as:

swelling of the face, tongue or throat
difficulty swallowing
hives and difficulty breathing

If you experience any of these symptoms, stop taking Combisartan and contact your doctor immediately (see also section 2 “Take special care with Combisartan”).
Other side effects are:
Uncommon

cough
low blood pressure
feeling of emptiness in the head
dehydration (with symptoms such as thirst, dry mouth and tongue, infrequent urination, dark urine, dry skin)
muscle pain
fatigue
tingling or numbness
blurred vision
noises in the ears (e.g., ringing, buzzing) Very rare
dizziness
diarrhoea
joint pain

Not known

difficulty breathing
marked decrease in urine output
low blood sodium levels (which may cause fatigue, mental confusion, muscle cramps and/or seizures in severe cases)
low blood potassium levels (sometimes with muscle weakness, muscle cramps, abnormal heart rhythm)
low white blood cell count in blood (with symptoms such as fever, skin infections, sore throat or mouth ulcers due to infections, weakness)
increased bilirubin levels in blood (which may, in severe cases, cause yellowing of the skin and eyes)
increased blood urea and creatinine levels (which may indicate kidney malfunction)
increased blood uric acid levels (which may, in severe cases, cause gout)
syncope (fainting)

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

dizziness
abdominal pain

Not known

appearance of blisters on the skin (sign of bullous dermatitis)
skin rash with or without itching together with one or more of the following signs or symptoms: fever, joint pain, muscle pain, swollen lymph nodes and/or flu-like symptoms
skin rash, red-purple spots, fever, itching (symptoms of blood vessel inflammation)
low platelet count in blood (sometimes with unusual bleeding or bruising)
increased potassium levels in blood (sometimes with muscle cramps, abnormal heart rhythm)
allergic reactions (with symptoms such as skin rash, itching, hives, difficulty breathing or swallowing, dizziness)
swelling, especially of the face and throat, skin rash, itching
increased liver function test values
decreased haemoglobin levels and red blood cell percentage in blood (which, in severe cases, may both cause anaemia)
kidney failure
low blood sodium levels (which may cause fatigue, mental confusion, muscle cramps and/or seizures in severe cases)

Hydrochlorothiazide
Very common

low blood potassium levels
increased blood lipids

Common

low blood sodium levels
low blood magnesium levels
high blood uric acid levels
itchy skin rash or other types of skin rash
decreased appetite
mild nausea and vomiting
dizziness, fainting when standing up
inability to achieve or maintain erection

Rare

swelling and blister formation on the skin (due to increased sensitivity to sunlight)
high blood calcium levels
high blood sugar levels
sugar in urine
worsening of diabetes metabolic status
constipation, diarrhoea, stomach or intestinal disorders, liver disorders that may present with yellowing of the skin or eyes
irregular heartbeat
headache
sleep disorders
sadness (depression)
low blood platelet count (sometimes with bleeding or bruising under the skin)
dizziness
tingling or numbness
vision disorders

Very rare

inflammation of blood vessels with symptoms such as skin rash, red-purple spots, fever (vasculitis)
skin rash, itching, hives, difficulty breathing or swallowing, dizziness (hypersensitivity reactions)
severe skin diseases causing skin rash, redness of the skin, blister formation on lips, eyes or mouth, skin peeling, fever (toxic epidermal necrolysis)
facial rash, joint pain, muscle disorders, fever (lupus erythematosus)
severe upper abdominal pain (pancreatitis)
difficulty breathing with fever, cough, wheezing, shortness of breath (respiratory difficulty, including pneumonia and pulmonary oedema)
fever, sore throat, frequent infections (agranulocytosis)
paleness, fatigue, shortness of breath, dark urine (haemolytic anaemia)
fever, sore throat or mouth ulcers due to infections (leucopenia)
confusion, fatigue, tremor or muscle spasm, laboured breathing (hypochloraemic alkalosis)

Not known

fatigue, bruising and frequent infections (aplastic anaemia)
severe decrease in urine output (possible sign of kidney disorder or kidney failure)
decreased vision or eye pain due to high ocular pressure (possible sign of fluid accumulation in the vascular layer of the eye (choroidal effusion) or acute angle-closure glaucoma)
skin rash, redness of the skin, blister formation on lips, eyes or mouth, skin peeling, fever (possible signs of erythema multiforme)
muscle cramp
fever (pyrexia)
weakness (asthenia)
skin and lip cancer (non-melanoma skin cancer).

If any of the side effects worsen, or if you notice any side effect not listed in this leaflet, inform your doctor or pharmacist.
Reporting of side effects
If you experience any side effect, including those not listed in this leaflet, talk to your doctor or pharmacist. You can also report side effects directly via the national reporting system at http://www.aifa.gov.it/content/segnalazioni-reazioni-avverse.
By reporting side effects, you can help provide more information on the safety of this medicine.
5 HOW TO STORE COMBISARTAN

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the label. The expiry date refers to the last day of that month.
Do not store above 30°C. Store in the original packaging to protect the medicine from moisture.
Do not use Combisartan if you notice that the packaging is damaged or shows signs of tampering.
Do not throw any medicine into wastewater or household waste. Ask your pharmacist how to dispose of medicines you no longer use. This will help protect the environment.

6 CONTENTS OF THE PACK AND OTHER INFORMATION
What Combisartan contains

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

Description of the appearance of Combisartan and contents of the pack
Film-coated tablets of Combisartan 80 mg/12.5 mg are light orange, ovaloid, with “HGH” printed on one side and “CG” on the opposite side or printed on one side only “HGH”.
Film-coated tablets of Combisartan 160 mg/12.5 mg are dark red, ovaloid, with “HHH” printed on one side and “CG” on the opposite side or printed on one side only “HHH”.
Film-coated tablets of Combisartan 160 mg/25 mg are brown, ovaloid, with “HXH” printed on one side and “NVR” on the opposite side or printed on one side only “HXH”.
Film-coated tablets of Combisartan 320 mg/12.5 mg are pink, ovaloid, with bevelled edges, with “NVR” printed on one side and “HIL” on the opposite side or printed on one side only “HIL”.
Film-coated tablets of Combisartan 320 mg/25 mg are yellow, ovaloid, with “CTI” printed on one side and “NVR” on the opposite side or printed on one side only “CTI”.
Combisartan 80 mg/12.5 mg tablets are available in calendar blister packs, in packs of 14 or 28 tablets. Combisartan 160 mg/12.5 mg, 160 mg/25 mg, 320 mg/12.5 mg and 320 mg/25 mg tablets are available in calendar blister packs, in packs of 7 (only 320 mg/12.5 and 320 mg/25 mg), 14, 28, 56, 98 or 280 tablets. Unit-dose divisible blisters are also available, in packs of 56x1 (only 320 mg/12.5 and 320 mg/25 mg), 98x1 (except 80 mg/12.5) or 280x1 (only 320 mg/12.5 and 320 mg/25 mg) tablets.
Not all pack sizes may be marketed.
Marketing Authorisation Holder and Manufacturer
Marketing Authorisation Holder
A.Menarini Industrie Farmaceutiche Riunite s.r.l., via Sette Santi, 3 - Florence
Manufacturer
FAMAR L'Aigle
Zone industrielle N°1, Route de Crulai
61303 L'Aigle
France