Zetovar

Package leaflet: Information for the patient

ZETOVAR 10 mg/10 mg film-coated tablets, 10 mg/20 mg film-coated tablets, 10 mg/40 mg film-coated tablets, 10 mg/80 mg film-coated tablets

ezetimibe and atorvastatin
Generic medicine
Read 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 only. Do not give it to other people, even if their symptoms are the same as yours, because it may be harmful.
If you experience any adverse reaction, including those not listed in this leaflet, contact your doctor or pharmacist. See section 4.
Contents of this leaflet:

1. What ZETOVAR is and what it is used for
2. What you need to know before taking ZETOVAR
3. How to take ZETOVAR
4. Possible side effects
5. How to store ZETOVAR
6. Contents of the pack and other information

1. What ZETOVAR is and what it is used for

ZETOVAR is a medicine used to lower elevated cholesterol levels. ZETOVAR contains
ezetimibe and atorvastatin.
ZETOVAR is used in adults to lower blood levels of total cholesterol, "bad" cholesterol (LDL cholesterol), and fat substances called triglycerides. In addition, ZETOVAR increases levels of "good" cholesterol (HDL cholesterol).
ZETOVAR works in two ways to lower cholesterol. It reduces cholesterol absorbed in the gastrointestinal tract, as well as cholesterol naturally produced by the body.
Cholesterol is one of several fatty substances found in the bloodstream. Total cholesterol is mainly composed of LDL cholesterol and HDL cholesterol.
LDL cholesterol is often called "bad" cholesterol because it can accumulate in the walls of arteries, forming plaques. Over time, this plaque buildup can lead to narrowing of the arteries. This narrowing can slow down or block blood flow to vital organs such as the heart and brain. This blockage of blood flow can cause a heart attack or stroke.
HDL cholesterol is often called "good" cholesterol because it helps prevent "bad" cholesterol from accumulating in the arteries and provides protection against heart disease.
Triglycerides are another form of fat in the blood that can increase the risk of heart disease.
ZETOVAR is used to treat patients in whom diet alone is not sufficient to control cholesterol levels. While taking this medicine, you must continue to follow a cholesterol-lowering diet.
ZETOVAR is used as an additional therapy to diet to lower cholesterol if you have:

• elevated cholesterol levels in the blood (primary hypercholesterolemia [heterozygous familial and non-familial]) or elevated levels of fats in the blood (mixed hyperlipidemia) that are not adequately controlled with a statin alone; for which you have previously been treated with a statin and ezetimibe as separate tablets.
• an inherited disease (homozygous familial hypercholesterolemia) that increases your blood cholesterol levels. You may also be receiving other treatments.
• heart disease. ZETOVAR reduces the risk of heart attack, stroke, surgery to improve blood flow to the heart, or hospitalization for chest pain.

ZETOVAR does not help with weight loss.

2. What you need to know before taking ZETOVAR

Do not take ZETOVAR if
you are allergic to ezetimibe, atorvastatin, or any of the other ingredients of this medicine
(listed in section 6),
you have or have ever had liver disease,
you have had unexplained abnormal blood tests assessing liver function,
you are a woman of childbearing age and are not using a reliable contraceptive method,
you are pregnant, trying to become pregnant, or breastfeeding,

• you are using the combination glecaprevir/pibrentasvir for the treatment of hepatitis C.

Warnings and precautions
Talk to your doctor or pharmacist before taking ZETOVAR if
you have previously had a stroke with cerebral haemorrhage or if there are small accumulations of fluid in the brain due to previous strokes,
you have kidney problems,
you have an underactive thyroid gland (hypothyroidism),
you have had repeated or unexplained episodes of muscle discomfort or pain, or have a personal or family history of muscle problems,

• you have previously experienced muscle problems while being treated with other lipid-lowering medicines (e.g. other "statin" or "fibrate" medicines), regularly consume large amounts of alcohol, have a history of liver disease, are over 70 years old, or have been told by your doctor that you have an intolerance to certain sugars. Contact your doctor before taking this medicine,
• you are currently taking or have taken within the last 7 days an oral or injectable medicine called fusidic acid (a medicine for bacterial infection). The combination of fusidic acid and ZETOVAR may lead to serious muscle problems (rhabdomyolysis),
• you have or have had myasthenia (a disease causing generalised muscle weakness, sometimes including muscles used for breathing), or ocular myasthenia (a disease causing weakness of eye muscles), as statins may sometimes worsen the condition or trigger the onset of myasthenia (see section 4).

Contact your doctor immediately if you experience unexplained muscle pain, tenderness, or weakness
while taking ZETOVAR. This is because, although rarely, muscle problems can be serious, including muscle breakdown leading to kidney damage. It is known that atorvastatin may cause muscle problems, and cases of muscle problems have also been reported with ezetimibe.
Additionally, inform your doctor or pharmacist if you have persistent muscle weakness. Further tests and medicines may be needed to diagnose and treat this condition.
Before taking ZETOVAR, check with your doctor or pharmacist:

• if you have severe respiratory insufficiency.

If any of these conditions apply to you (or if you are unsure), consult your doctor or pharmacist before taking ZETOVAR, as your doctor may require you to have a blood test before and possibly during treatment with ZETOVAR to assess the risk of muscle-related side effects. It is known that the risk of developing muscle-related side effects, such as rhabdomyolysis, increases when certain medicines are taken concurrently (see section 2 “Other medicines and ZETOVAR”).
While being treated with this medicine, your doctor will monitor you carefully if you have diabetes or are at risk of developing diabetes. You are more likely to be at risk of developing diabetes if you have high levels of sugar and fat in your blood, are overweight, or have high blood pressure.
Inform your doctor about all your medical conditions, including allergies.
The combined use of ZETOVAR with fibrates (medicines used to lower cholesterol) should be avoided, as the use of ZETOVAR with fibrates has not been studied.
Children
The use of ZETOVAR is not recommended in children and adolescents.
Other medicines and ZETOVAR
Tell your doctor or pharmacist if you are taking, have recently taken, or might take any other medicines, including those obtained without a prescription.
Some medicines may alter the effect of ZETOVAR or their effect may be altered by ZETOVAR (see section 3). This type of interaction could reduce the effectiveness of one or both medicines. Alternatively, it could increase the risk of developing side effects or the severity of side effects, including the serious condition of muscle breakdown known as “rhabdomyolysis” described in section 4:

• cyclosporine (a medicine often used in organ transplant patients),
• erythromycin, clarithromycin, telithromycin, fusidic acid**, rifampicin (medicines used to treat bacterial infections),
• ketoconazole, itraconazole, voriconazole, fluconazole, posaconazole (medicines used to treat fungal infections),
• gemfibrozil, other fibrates, nicotinic acid, derivatives, colestipol, cholestyramine (medicines used to regulate lipid levels),
• certain calcium channel blockers used to treat angina or hypertension, e.g. amlodipine and diltiazem,
• digoxin, verapamil, amiodarone (medicines used to regulate heart rhythm),
• medicines used to treat HIV, e.g. ritonavir, lopinavir, atazanavir, indinavir, darunavir, the combination tipranavir/ritonavir, etc. (medicines for the treatment of AIDS), some medicines used to treat hepatitis C, e.g. telaprevir, boceprevir and the combination elbasvir/grazoprevir,
• daptomycin (a medicine used to treat complicated skin and soft tissue infections and bloodstream infections).

**If you need to take oral fusidic acid to treat a bacterial infection, you must temporarily stop taking this medicine. Your doctor will tell you when it is safe to restart treatment with ZETOVAR. Taking ZETOVAR with fusidic acid may rarely cause muscle weakness, tenderness, or pain (rhabdomyolysis). See further information on rhabdomyolysis in section 4.

• Other medicines known to interact with ZETOVAR include oral contraceptives (medicines to prevent pregnancy), stiripentol (an anticonvulsant medicine for the treatment of epilepsy), cimetidine (a medicine used to treat heartburn and peptic ulcers), phenazone (a painkiller), antacids (medicines containing aluminium or magnesium used for digestive problems), warfarin, phenprocoumon, acenocoumarol or fluindione (medicines to prevent blood clots), colchicine (used to treat gout), St. John’s wort (a herbal medicine used to treat depression).

ZETOVAR with food and alcohol
For instructions on how to take ZETOVAR, see section 3. Pay attention to the following:
Grapefruit juice
Do not drink more than one or two small glasses of grapefruit juice per day, as large quantities of grapefruit juice may alter the effects of ZETOVAR.
Alcohol
Avoid drinking excessive amounts of alcohol while being treated with this medicine. For further information, consult section 2 “Warnings and precautions”.
Pregnancy and breastfeeding
Do not take ZETOVAR if you are pregnant, planning to become pregnant, or suspect you may be pregnant. Do not take ZETOVAR if you are a woman of childbearing age unless you are using an effective method of contraception.
If you become pregnant while taking ZETOVAR, stop treatment immediately and consult your doctor.
Do not take ZETOVAR if you are breastfeeding.
The safety of ZETOVAR during pregnancy and breastfeeding has not yet been established.
Ask your doctor or pharmacist for advice before taking this medicine.
Driving and using machines
ZETOVAR is not expected to affect your ability to drive or use machines. However, you should be aware that some people may experience dizziness after taking ZETOVAR.
ZETOVAR contains lactose
ZETOVAR tablets contain a sugar called lactose. If your doctor has diagnosed you with an intolerance to certain sugars, contact your doctor before taking this medicine.
ZETOVAR contains sodium
This medicine contains less than 1 mmol (23 mg) of sodium per tablet, i.e. essentially “sodium-free”.

3. How to take ZETOVAR

Take this medicine exactly as your doctor has instructed you. Your doctor will determine the appropriate tablet dosage for you based on your ongoing treatment and your individual risk profile. If you have any doubts, consult your doctor or pharmacist.

• Before starting treatment with ZETOVAR, you must have already started a cholesterol-lowering diet.
• During treatment with ZETOVAR, you must continue to follow this cholesterol-lowering diet.
  What dose to take
  The recommended dose is one ZETOVAR tablet taken orally once daily.

When to take the dose
Take ZETOVAR at any time of the day. You may take it with or without food.
If your doctor has prescribed ZETOVAR together with cholestyramine or another bile acid sequestrant (medicines used to lower cholesterol levels), you must take ZETOVAR at least 2 hours before or 4 hours after taking the bile acid sequestrant.

If you take more ZETOVAR than you should
Contact your doctor or pharmacist.

If you forget to take ZETOVAR
Do not take a double dose; take only the usual normal dose of ZETOVAR the following day at the regular time.

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

4. Possible side effects

Like all medicines, ZETOVAR can cause side effects, although not everyone experiences them.
If you notice any of the following serious side effects or symptoms listed below, stop taking the tablets and contact your doctor immediately or go to the nearest hospital emergency department.

• severe allergic reaction causing swelling of the face, tongue and throat, which may cause severe breathing difficulties
• severe illness with extensive peeling and swelling of the skin, blistering rash on the skin, mouth, eyes, genitals and fever; skin rash with pink-red patches, particularly on the palms of the hands or soles of the feet, which may develop into blisters
• muscle weakness, tenderness, pain or muscle breakdown, or red-brown discoloration of the urine, especially if you also feel unwell and have high fever; this may be due to abnormal muscle damage, which can be life-threatening and may lead to kidney problems
• lupus-like syndrome (including skin rash, joint problems and effects on blood cells)

If you experience unusual or unexpected bleeding or bruising, consult your doctor as soon as possible, as these may be signs of liver problems.
Other possible side effects with ZETOVAR
Common: may affect up to 1 in 10 people

• diarrhoea
• muscle pain

Uncommon: may affect up to 1 in 100 people
influenza-like illness,
depression; difficulty falling asleep; sleep disturbances,
dizziness; headache; tingling sensation,
slow heartbeat,
hot flushes,
shortness of breath,
abdominal pain; abdominal swelling; constipation; indigestion; flatulence; frequent bowel movements;
inflammation of the stomach; nausea; stomach discomfort; stomach disorders,
acne; hives,
joint pain; back pain; leg cramps; muscle fatigue, spasms or weakness; pain in arms and legs,

• unusual weakness; feeling tired or unwell; swelling, especially in the ankles (oedema), increases in blood test values indicating liver or muscle function (CK), weight gain.

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

• skin rash which may appear on the skin or mouth ulcers (drug-induced lichenoid reaction),
• purple skin lesions (signs of blood vessel inflammation, vasculitis).

Not known: frequency cannot be estimated from available data

• severe myasthenia gravis (a condition causing generalised muscle weakness, including in some cases the muscles used for breathing),
• ocular myasthenia (a condition causing weakness of the eye muscles).

In addition, the following side effects have been reported in people taking ezetimibe/atorvastatin combination tablets, or ezetimibe or atorvastatin tablets alone:

• allergic reactions including swelling of the face, lips, tongue and/or throat, which may cause difficulty breathing or swallowing (a condition requiring immediate medical attention),
• raised, red rash, sometimes accompanied by target-shaped skin lesions,
• liver problems,
• cough,
• heartburn,
• decreased appetite; loss of appetite,
• high blood pressure,
• skin rash and itching; allergic reactions including skin rash and hives,
• tendon injury,
• gallstones or inflammation of the gallbladder (which may cause abdominal pain, nausea and vomiting),
• inflammation of the pancreas, often with severe abdominal pain,
• reduction in blood cell counts, which may cause bruising/bleeding (thrombocytopenia),
• nasal passage inflammation; nosebleeds,
• neck pain; pain; chest pain; throat pain,
• increase or decrease in blood sugar levels (if you have diabetes, you should continue to monitor your blood sugar levels closely),
• nightmares,
• numbness or tingling in fingers and toes,
• reduced sensitivity to pain or touch,
• altered sense of taste; dry mouth,
• memory loss,
• ringing in the ears and/or head; hearing loss,
• vomiting,
• belching,
• hair loss,
• increased body temperature,
• urine tests positive for white blood cells,
• blurred vision; visual disturbances,
• gynaecomastia (enlargement of breast tissue in men)

Contact your doctor if you experience worsening weakness in the arms or legs after periods of activity, double vision or drooping eyelids, difficulty swallowing or shortness of breath.
Possible side effects reported with some statins

• sexual difficulties,
• depression,
• breathing problems including persistent cough and/or shortness of breath or fever,
• diabetes. This is more likely if you have high levels of sugar and fat in your blood, are overweight, or have high blood pressure. Your doctor will monitor you during treatment with this medicine,
• muscle pain, tenderness or weakness that is persistent, and especially if, at the same time, you feel unwell or have a high fever that may not resolve after stopping treatment with ZETOVAR (frequency not known). Reporting of side effects If you experience any side effects, including those not listed in this leaflet, talk to your doctor or pharmacist. You may also report side effects directly via the national reporting system at https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse . Reporting side effects can help provide more information on the safety of this medicine.

5. How to store ZETOVAR

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the blister or carton after "Exp.".
The expiry date refers to the last day of that month.
This medicine does not require any special storage conditions.
Do not dispose of any medicine via wastewater or household waste. Ask your pharmacist how to dispose of medicines you no longer use. This will help protect the environment.

6. Package contents and other information

What ZETOVAR contains
The active substances are ezetimibe and atorvastatin. Each film-coated tablet contains 10 mg of ezetimibe
and 10 mg, 20 mg, 40 mg or 80 mg of atorvastatin (as trihydrated atorvastatin calcium).
The other components are: calcium carbonate; anhydrous colloidal silicon dioxide; sodium croscarmellose;
hydroxypropylcellulose; lactose monohydrate; povidone; magnesium stearate; microcrystalline cellulose;
polysorbate 80; sodium lauryl sulfate (E487).
The film coating contains: hypromellose, lactose monohydrate, titanium dioxide, macrogol, talc.

Description of the appearance of ZETOVAR and package contents
Film-coated tablets, capsule-shaped, biconvex, white to off-white in colour.
ZETOVAR 10 mg/10 mg tablets: “1T” engraved on one side.
ZETOVAR 10 mg/20 mg tablets: “2T” engraved on one side.
ZETOVAR 10 mg/40 mg tablets: “3T” engraved on one side.
ZETOVAR 10 mg/80 mg tablets: “4T” engraved on one side.
Pack sizes:
Aluminium/aluminium blister packs containing 10, 30, 90 or 100 film-coated tablets.
Not all pack sizes may be marketed.

Marketing Authorisation Holder and Manufacturer
Marketing Authorisation Holder
Zentiva Italia S.r.l.
Via P. Paleocapa, 7
20121 Milano
Italy

Manufacturers
Delorbis Pharmaceuticals Ltd
17 Athinon Street
Ergates Industrial Area
2643 Ergates Nicosia
Cyprus
or
Pharmadox Healthcare Ltd
KW20A Kordin Industrial Park
Paola PLA 3000
Malta

This medicinal product is authorised in the European Economic Area countries under the
following names:
Netherlands and Italy: Zetovar
Bulgaria: Зетовар
Germany: Atorvastatin Ezetimib Zentiva
Spain: Ezetimiba/Atorvastatina Zentiva
France: EZETIMIBE/ATORVASTATINE ZENTIVA
Ireland: Ezetimibe/Atorvastatin Zentiva
Portugal: Atorvastatina + Ezetimiba Zentiva