EZETIMIBE/SIMVASTATIN KRKA 10 mg/40 mg TABLETS

2. What you need to know before you take Ezetimibe/Simvastatin Krka

Do not take Ezetimibe/Simvastatin Krka

• if you are allergic to ezetimibe, simvastatin or any of the other ingredients of this medicine (listed in section 6),
• if you currently have liver problems,
• if you are pregnant or breast-feeding,
• if you are taking medicines with one or more of the following active substances:
• • itraconazole, ketoconazole, posaconazole or voriconazole (used to treat fungal infections).
  • erythromycin, clarithromycin or telithromycin (used to treat infections).
  • HIV protease inhibitors such as indinavir, nelfinavir, ritonavir and saquinavir (HIV protease inhibitors are used to treat HIV infections).
  • boceprevir or telaprevir (used to treat hepatitis C virus infection).
  • nefazodone (used to treat depression).
  • cobicistat.
  • gemfibrozil (used to lower cholesterol).
  • cyclosporine (often used in patients with transplanted organs).
  • danazol (a synthetic hormone used to treat endometriosis, a disease in which the lining of the uterus grows outside the uterus).
  • you are taking or have taken in the last 7 days a medicine containing fusidic acid (used to treat bacterial infections) by mouth or by injection. The combination of fusidic acid and ezetimibe/simvastatin can cause muscle problems (rhabdomyolysis).

Do not take more than 10 mg/40 mg of Ezetimibe/Simvastatin Krka if you are taking lomitapide (used to treat rare and serious genetic cholesterol disorders).

Consult your doctor if you are not sure if your medicine is mentioned above.

Warnings and precautions

Tell your doctor or pharmacist before taking Ezetimibe/Simvastatina Krka:

• about all your medical problems, including allergies.
• if you drink large amounts of alcohol or if you have ever had liver disease. Ezetimibe/Simvastatin Krka may not be suitable for you.
• if you are going to have an operation. You may need to stop taking the tablets of Ezetimibe/Simvastatin Krka for a short time.
• if you are Asian, as you may need a different dose.
• if you have or have had muscle weakness (myasthenia), or muscle weakness in the eyes (ocular myasthenia), as it may worsen the condition or cause myasthenia (see section 4).

Your doctor will do a blood test before you start taking Ezetimibe/Simvastatin Krka and also if you have any symptoms of liver problems while taking Ezetimibe/Simvastatin Krka. This is to check how well your liver is working.

Your doctor may also want to do blood tests to check how well your liver is working after you start taking Ezetimibe/Simvastatin Krka.

While you are taking this medicine, your doctor will check if you have diabetes or are at risk of getting diabetes. Your risk of diabetes is higher if you have high levels of sugars and fats in your blood, are overweight and have high blood pressure.

Talk to your doctor if you have severe lung disease.

The combined use of Ezetimibe/Simvastatin Krka and fibrates (certain cholesterol-lowering medicines) should be avoided, as the use of Ezetimibe/Simvastatin Krka with fibrates has not been studied.

Contact your doctor immediately if you experience unexplained muscle pain, tenderness or weakness. This is because, on rare occasions, muscle problems can be serious, such as muscle breakdown that can cause kidney damage; and very rarely, deaths have occurred.

The risk of muscle breakdown is greater with higher doses of Ezetimibe/Simvastatin Krka, especially the 10 mg/80 mg dose. The risk of muscle breakdown is also greater in certain patients. Tell your doctor in the following situations:

• you have kidney problems.
• you have thyroid problems.
• you are 65 years or older.
• you are a woman.
• you have ever had muscle problems while taking medicines to lower cholesterol called "statins" (such as simvastatin, atorvastatin and rosuvastatin) or fibrates (such as gemfibrozil or bezafibrate).
• you or a close relative have a hereditary muscle disorder.

Also, tell your doctor or pharmacist if you have persistent muscle weakness. You may need further tests and additional medicines for your diagnosis and treatment.

Paediatric population

Ezetimibe/Simvastatin Krka is not recommended in children under 10 years.

Taking Ezetimibe/Simvastatin Krka with other medicines

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines, including those obtained without a prescription. Taking Ezetimibe/Simvastatin Krka with some of the following medicines may increase the risk of muscle problems (some of which have already been mentioned in the "Do not take Ezetimibe/Simvastatin Krka" section).

• if you have to take fusidic acid by mouth to treat a bacterial infection, you will temporarily have to stop using this medicine. Your doctor will tell you when you can restart the treatment with this medicine. The use of this medicine with fusidic acid can rarely cause muscle weakness, sensitivity or pain (rhabdomyolysis). For more information on rhabdomyolysis, see section 4.
• cyclosporine (often used in patients with transplanted organs),
• danazol (a synthetic hormone used to treat endometriosis, a disease in which the lining of the uterus grows outside the uterus),
• medicines with an active substance such as itraconazole, ketoconazole, posaconazole or voriconazole (used to treat fungal infections),
• fibrates with active substances such as gemfibrozil and bezafibrate (used to lower cholesterol),
• erythromycin, clarithromycin or telithromycin (used to treat bacterial infections),
• HIV protease inhibitors such as indinavir, nelfinavir, ritonavir and saquinavir (used to treat HIV infections),
• antivirals for hepatitis C such as boceprevir, telaprevir, elbasvir or grazoprevir (used to treat hepatitis C virus infection)
• nefazodone (used to treat depression),
• medicines containing cobicistat,
• amiodarone (used to treat irregular heartbeats),
• verapamil, diltiazem or amlodipine (used to treat high blood pressure, chest pain associated with heart disease or other heart conditions),
• lomitapide (used to treat rare and serious genetic cholesterol disorders),
• daptomycin (a medicine used to treat skin and skin structure infections with complications and bacteremia). The side effects that affect the muscles may be greater when this medicine is taken during treatment with simvastatin (such as this medicine). Your doctor may decide that you should stop taking this medicine for a while,
• high doses (1 gram or more per day) of niacin or nicotinic acid (also used to lower cholesterol),
• colchicine (used to treat gout).

In addition to the medicines mentioned above, tell your doctor or pharmacist if you are taking or have recently taken other medicines, including those obtained without a prescription. In particular, tell your doctor if you are taking any of the following:

• medicines with an active substance to prevent blood clots, such as warfarin, fludione, phenprocoumon or acenocoumarol (anticoagulants),
• cholestyramine (also used to lower cholesterol), as it affects how Ezetimibe/Simvastatin Krka works,
• fenofibrate (also used to lower cholesterol),
• rifampicin (used to treat tuberculosis),
• ticagrelor (an antiplatelet medicine).

You should also tell any doctor who prescribes you a new medicine that you are taking Ezetimibe/Simvastatin Krka.

Taking Ezetimibe/Simvastatin Krka with food and drinks

Grapefruit juice contains one or more components that alter the metabolism of some medicines, including Ezetimibe/Simvastatin Krka. You should avoid drinking grapefruit juice, as it may increase the risk of muscle problems.

Pregnancy and breast-feeding

Do not take Ezetimibe/Simvastatin Krka if you are pregnant, trying to become pregnant or think you may be pregnant. If you become pregnant while taking Ezetimibe/Simvastatin Krka, stop taking it immediately and tell your doctor. Do not take Ezetimibe/Simvastatin Krka if you are breast-feeding, as it is not known whether this medicine passes into breast milk.

Consult your doctor or pharmacist before taking any medicine.

Driving and using machines

Ezetimibe/Simvastatin Krka is not expected to interfere with your ability to drive or use machines. However, some people may experience dizziness after taking Ezetimibe/Simvastatin Krka.

Ezetimibe/Simvastatin Krka contains lactose and sodium

If your doctor has told you that you have an intolerance to some sugars, consult your doctor before taking this medicine.

This medicine contains less than 1 mmol of sodium (23 mg) per tablet; this is essentially "sodium-free".

3. How to take Ezetimibe/Simvastatin Krka

Follow exactly the instructions of administration of this medicine given by your doctor or pharmacist. If you are in doubt, consult your doctor or pharmacist.

Your doctor will determine the appropriate dose of tablets for you, depending on your current treatment and your personal risk status.

• Before starting to take Ezetimibe/Simvastatin Krka, you should be following a cholesterol-lowering diet.
• You should continue with this cholesterol-lowering diet while taking Ezetimibe/Simvastatin Krka

Adults: The recommended dose is one tablet of Ezetimibe/Simvastatin Krka once a day by mouth.

Use in adolescents (10 to 17 years of age): the dose is 1 tablet of ezetimibe/simvastatin once a day by mouth (do not exceed a maximum dose of 10 mg/40 mg once a day).

The 10 mg/80 mg dose is only recommended in adults with very high cholesterol levels and a high risk of heart problems who have not reached their cholesterol goal with lower doses.

Not all recommended doses are possible with these products; however, other products with different dosages are also available (10 mg/80 mg).

Take Ezetimibe/Simvastatin Krka in the evening. You can take it with or without food.

If your doctor has prescribed ezetimibe/simvastatin along with another cholesterol-lowering medicine that contains the active substance colestyramine or any other bile acid sequestrant, you should take ezetimibe/simvastatin at least 2 hours before or 4 hours after taking the bile acid sequestrant.

If you take more Ezetimibe/Simvastatin Krka than you should

In case of overdose or accidental ingestion, contact the Toxicology Information Service. Telephone: 91 562 04 20, consult your doctor or pharmacist.

If you forget to take Ezetimibe/Simvastatin Krka

Do not take a double dose to make up for forgotten doses, take your normal dose of Ezetimibe/Simvastatin Krka at the usual time

If you stop taking Ezetimibe/Simvastatin Krka

Talk to your doctor or pharmacist because your cholesterol levels may rise again.

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

4. Possible Adverse Effects

Like all medicines, this medicine can cause adverse effects, although not all people suffer from them.

If you experience any of the following, stop taking the medicine and consult your doctor immediately:

• Muscle pain (frequent: may affect up to 1 in 10 people),
• Signs indicating blood disorders, e.g., fatigue, unexplained bleeding or bruising, mouth ulcers (frequency not known: cannot be estimated from available data),
• Pancreatitis that can cause severe abdominal and back pain accompanied by a feeling of discomfort (frequency not known: cannot be estimated from available data),
• Signs indicating liver problems, gallstones, or inflammation of the gallbladder, e.g., yellowish skin color, stomach pain, itching, dark urine, or pale stools (frequency not known: cannot be estimated from available data),
• Angioedema (stop taking Ezetimiba/Simvastatina Krka and contact your doctor immediately if you experience any of the following symptoms: swelling of the face, tongue, or throat, difficulty swallowing, hives, and breathing difficulties) (rare: may affect up to 1 in 1000 people).

Consult your doctor immediately if you experience pain, sensitivity, or weakness in the muscles that cannot be explained. The reason is that, in rare cases, muscle problems can be serious, such as muscle breakdown that causes kidney damage; and very rarely, deaths have occurred.

The following frequent adverse effects have been reported (may affect up to 1 in 10 people):

• Elevations in laboratory blood tests of liver function (transaminases) and/or muscle (CK).

The following infrequent adverse effects have been reported (may affect up to 1 in 100 people):

• Elevations of blood values indicating liver function; elevation of uric acid in the blood; increased time for blood to clot; presence of proteins in urine; weight loss.
• Dizziness; headache; tingling sensation.
• Abdominal pain; indigestion; flatulence; nausea; vomiting; abdominal swelling; diarrhea; dry mouth; heartburn.
• Rash; itching; hives.
• Joint pain; muscle pain, sensitivity, weakness, or spasms; neck pain; pain in the arms and legs; back pain.
• Unusual fatigue or weakness; feeling of tiredness; chest pain; swelling, especially of the hands and feet.
• Sleep disorders; difficulty sleeping.

Additionally, the following adverse effects have been reported in people taking Ezetimiba/Simvastatina Krka or medicines containing the active ingredients ezetimibe or simvastatin:

• Numbness or weakness in the arms and legs; poor memory, memory loss, confusion.
• Respiratory problems, including persistent cough and/or difficulty breathing or fever.
• Constipation.
• Hair loss; reddened rash, sometimes with target-like lesions (erythema multiforme).
• Blurred vision and vision problems (which may affect up to 1 in 1000 people).
• Skin rash that may appear on the skin or sores in the mouth (lichenoid drug eruptions) (which may affect up to 1 in 10,000 people).
• Hypersensitivity reactions, including some of the following: an allergic reaction accompanied by swelling of the face, lips, tongue, and/or throat that can cause difficulty breathing or swallowing and requires immediate treatment (angioedema), pain or inflammation of the joints, inflammation of blood vessels, unusual bruising, skin rash, and swelling, hives, skin sensitivity to the sun, fever, hot flashes, difficulty breathing, and feeling unwell, a condition similar to lupus (including skin rash, joint disorders, and effects on white blood cells). A very rare but serious adverse effect (which may affect up to 1 in 10,000 people) can occur and causes difficulty breathing or dizziness and requires immediate treatment (anaphylaxis).
• Muscle pain, sensitivity, weakness, or cramps; muscle failure; muscle rupture (which may affect up to 1 in 10,000 people), tendon problems, sometimes complicated by tendon rupture.
• Gynecomastia (breast enlargement in men) (which may affect up to 1 in 10,000 people).
• Decreased appetite.
• Hot flashes; high blood pressure.
• Pain.
• Erectile dysfunction.
• Depression.
• Alterations in some laboratory blood tests for liver function.
• Severe myasthenia (a disease that causes generalized muscle weakness, which in some cases affects the muscles used for breathing).
• Ocular myasthenia (a disease that causes weakness of the eye muscles).

Consult your doctor if you experience weakness in the arms or legs that worsens after periods of activity, double vision, or drooping eyelids, difficulty swallowing, or difficulty breathing.

Other possible adverse effects reported with some statins:

• Sleep disorders; including nightmares.
• Sexual problems.
• Diabetes. This is more likely if you have high sugar and fat levels in the blood, are overweight, and have high blood pressure. Your doctor will monitor you while you are taking this medicine.
• Muscle pain, sensitivity, or weakness that may not disappear after stopping Ezetimiba/Simvastatina Krka (frequency unknown).

Reporting Adverse Effects

If you experience any type of adverse effect, consult your doctor or pharmacist. Even if it is a possible adverse effect that is not listed in this prospectus. You can also report them directly through the Spanish Pharmacovigilance System for Human Use Medicines: https://www.notificaram.es. By reporting adverse effects, you can contribute to providing more information on the safety of this medicine.

5. Conservation of Ezetimiba/Simvastatina Krka

Keep this medicine out of sight and reach of children.

Do not use this medicine after the expiration date that appears on the packaging after CAD. The expiration date is the last day of the month indicated.

This medicine does not require any special storage temperature.

Keep it in the original packaging to protect it from light and moisture.

Medicines should not be thrown away through drains or into the trash. Deposit the packaging and medicines you no longer need at the SIGRE point in the pharmacy. In case of doubt, ask your pharmacist how to dispose of the packaging and medicines you no longer need. This way, you will help protect the environment.

6. Package Contents and Additional Information

Composition of Ezetimiba/Simvastatina Krka

• The active ingredients are ezetimibe and simvastatin.

Each tablet contains 10 mg of ezetimibe and 20 mg of simvastatin.

Each tablet contains 10 mg of ezetimibe and 40 mg of simvastatin.

• The other ingredients are lactose, microcrystalline cellulose, sodium croscarmellose, magnesium stearate, hypromellose 2910, and red iron oxide (E172) – only for the 10 mg/20 mg tablets. See section 2 "Ezetimiba/Simvastatina Krka contains lactose and sodium".

Appearance of the Product and Package Contents

10 mg/20 mg tablets are pinkish-white, oval, and biconvex. Tablet length is 11 mm, width is 5.5 mm.

10 mg/40 mg tablets are white to almost white, capsule-shaped, and biconvex. Tablet dimensions are 14 x 6 mm.

Ezetimiba/Simvastatina Krka is available in packages that contain:

• 14, 28, 30, 50, 56, 60, 90, 98, or 100 tablets in blisters,
  • 14 x 1, 28 x 1, 30 x 1, 56 x 1, 60 x 1, 90 x 1, 98 x 1, or 100 x 1 tablets in single-dose perforated blisters.

Not all package sizes may be marketed.

Marketing Authorization Holder

KRKA, d.d., Novo mesto, Šmarješka cesta 6, 8501 Novo mesto, Slovenia

Manufacturer:

KRKA, d.d., Novo mesto, Šmarješka cesta 6, 8501 Novo mesto, Slovenia

or

TAD Pharma GmbH, Heinz-Lohmann-Straße 5, 27472 Cuxhaven, Germany

You can request more information about this medicine by contacting the local representative of the marketing authorization holder:

KRKA Farmacéutica, S.L., Calle de Anabel Segura 10, 28108 Alcobendas, Madrid, Spain

This medicine is authorized in the member states of the European Economic Area with the following names:

Date of the last revision of this prospectus: November 2023

Detailed and updated information about this medicine is available on the website of the Spanish Agency for Medicines and Health Products (AEMPS) http://www.aemps.gob.es