Package Insert:Information for the Patient

Dabigatrán etexilate Combix110 mg Hard Capsules EFG

dabigatrán etexilate

Read this package insert carefully before starting to take this medicine,because it contains important information for you.

• Keep this package insert, as you may need to read it again.
• If you have any questions, consult your doctor or pharmacist.
• This medicine has been prescribed only for you, and you should not give it to others even if they have the same symptoms as you, as it may harm them.
• If you experience any adverse effects, consult your doctor or pharmacist, even if they are not listed in this package insert. See section 4.

Dabigatrán etexilato Combixcontains the active ingredient dabigatrán etexilato and belongs to a group of medications known as anticoagulants. It works by blocking a substance in the body involved in the formation of blood clots.

Dabigatrán etexilato Combix is used in adults for:

• preventing the formation of blood clots in veins after knee or hip replacement surgery.

• preventing the formation of blood clots in the brain (stroke) and other blood vessels in the body if you have a type of irregular heart rhythm called non-valvular atrial fibrillation and have at least one additional risk factor.

• treating blood clots in the veins of your legs and lungs and to prevent new blood clots from forming in the veins of your legs and lungs.

Dabigatrán etexilato Combix is used in children for:

• treating blood clots and preventing new blood clots from forming.

Do not take Dabigatrán etexilato Combix

• if you are allergic to dabigatrán etexilato or any of the other ingredients of this medicine (listed in section 6).
• if your kidney function is severely reduced.
• if you are currently experiencing bleeding.
• if you have any disease in an organ of the body that increases the risk of severe bleeding (e.g., stomach ulcer, injury or cerebral hemorrhage, recent brain or eye surgery).
• if you are prone to bleeding. This tendency may be congenital, of unknown cause, or caused by other medications.
• if you are taking medications to prevent blood clotting in the blood (e.g., warfarin, rivaroxaban, apixaban, or heparin), except when changing anticoagulant treatment, while having a venous or arterial catheter, and heparin is administered through this catheter to keep it open, or while your normal heart rhythm is being restored by a procedure called catheter ablation for atrial fibrillation.
• if your liver function is severely reduced or if you have any liver disease that may be fatal.
• if you are taking ketoconazole oral or itraconazole, medications used in the treatment of fungal infections.
• if you are taking oral ciclosporin, a medication used to prevent organ rejection after a transplant.
• if you are taking dronedarone, a medication used to treat abnormal heart rhythm.
• if you are taking a combination product of glecaprevir and pibrentasvir, an antiviral medication used to treat hepatitis C.
• if you have had an artificial heart valve implanted that requires permanent anticoagulant treatment.

Warnings and precautions

Consult your doctor before starting to take Dabigatrán etexilato Combix. During treatment with this medication, you may also need to consult your doctor if you experience any symptoms or if you are to undergo surgery.

Inform your doctorif you have or have had any disorder or disease, especially any of the following:

• If you are at increased risk of bleeding, for example:
• • if you have recently experienced bleeding.
  • if you have had a surgical tissue extraction (biopsy) in the last month.
  • if you have suffered a severe injury (e.g., a bone fracture, a head injury, or any injury that required surgical treatment).
  • if you have inflammation of the esophagus or stomach.
  • if you have problems with reflux of stomach acid into the esophagus.
  • if you are taking medications that may increase the risk of bleeding. See “Other medications and Dabigatrán etexilato Combix below.
  • if you are taking anti-inflammatory medications such as diclofenac, ibuprofen, or piroxicam.
  • if you have a bacterial infection of the heart (endocarditis).
  • if you know that you have reduced kidney function or if you are dehydrated (symptoms include feeling thirsty and passing small amounts of dark-colored, concentrated urine with foam).
  • if you are over 75 years old.
  • if you are an adult and weigh 50 kg or less.
  • only if used in children: if the child has an infection in the brain or around it.

• if you have had a heart attack or if you have been diagnosed with diseases that increase the risk of having a heart attack.

• if you have liver disease associated with changes in blood tests. The use of this medication is not recommended in this case.

Be especially careful with Dabigatrán etexilato Combix

• if you need to undergo surgery:

In this case, Dabigatrán etexilato Combix should be temporarily discontinued due to an increased risk of bleeding during and shortly after surgery. It is very important that you take Dabigatrán etexilato Combix exactly as instructed by your doctor before and after surgery.

• if a surgical procedure requires the placement of a catheter or injection into the spinal column (e.g., for epidural or spinal anesthesia or for pain relief):
• • It is very important that you take Dabigatrán etexilato Combix exactly as instructed by your doctor before and after surgery.
  • Inform your doctor immediately if you experience numbness or weakness in your legs or intestinal or urinary problems after the end of anesthesia, as this situation requires urgent attention.
• if you fall or are injured during treatment, especially if you hit your head. Seek urgent medical attention. You may need a doctor to examine you, as you may have an increased risk of bleeding.

• if you know that you have a disease called antiphospholipid syndrome (a disorder of the immune system that increases the risk of blood clots), inform your doctor so that they can decide if your treatment needs to be modified.

Other medications and Dabigatrán etexilato Combix

Inform your doctor or pharmacist if you are taking, have taken recently, or may need to take any other medication.Particularly, inform your doctor before taking Dabigatrán etexilato Combix if you are taking any of the following medications:

• Medications to reduce blood clotting (e.g., warfarin, phenprocoumon, acenocoumarol, heparin, clopidogrel, prasugrel, ticagrelor, rivaroxaban, acetylsalicylic acid)
• Medications used to treat fungal infections (e.g., ketoconazole, itraconazole), except when applied to the skin
• Medications used to treat abnormal heart rhythm (e.g., amiodarone, dronedarone, quinidine, verapamil)

If you are taking medications that contain amiodarone, quinidine, or verapamil, your doctor may instruct you to use a reduced dose of Dabigatrán etexilato Combix according to the disease for which you were prescribed it. See section 3.

• Medications used to prevent organ rejection after a transplant (e.g., tacrolimus, ciclosporin)
• A combination product of glecaprevir and pibrentasvir (an antiviral medication used to treat hepatitis C)
• Anti-inflammatory and pain-relieving medications (e.g., acetylsalicylic acid, ibuprofen, diclofenac)
• St. John's Wort, a medicinal herb for depression
• Antidepressants called selective serotonin reuptake inhibitors or selective serotonin and norepinephrine reuptake inhibitors
• Rifampicin or clarithromycin (two antibiotics)
• Antiviral medications for HIV/AIDS (e.g., ritonavir)
• Certain medications used to treat epilepsy (e.g., carbamazepine, phenytoin)

Pregnancy and breastfeeding

The effects of Dabigatrán etexilato Combix on pregnancy and the fetus are unknown. Do not use this medication if you are pregnant unless your doctor tells you it is safe to do so. If you are of childbearing age, avoid becoming pregnant during treatment with Dabigatrán etexilato Combix.

It is not recommended to breastfeed naturally during treatment with Dabigatrán etexilato Combix.

Driving and operating machines

Dabigatrán etexilato Combix has no known effects on the ability to drive and operate machines.

Dabigatran etexilate Combix capsules can be used in adults and children aged 8 years or older who are able to swallow the capsules whole. There are other appropriate pharmaceutical forms for children under 8 years old.

Follow exactly the administration instructions of this medication as indicated by your doctor. If in doubt, consult your doctor again.

Take Dabigatran etexilate Combix as recommended for the following situations:

Prevention of blood clot formation after knee or hip replacement surgery

The recommended dose is 220 mg once a day (administered as 2 capsules of 110 mg).

If your renal function is decreased by more than half or if you are 75 years of age or older, the recommended dose is 150 mg once a day (administered as 2 capsules of 75 mg).

If you are taking medications containing amiodarone, quinidine, or verapamil, the recommended dose is 150 mg once a day (administered as 2 capsules of 75 mg).

If you are taking medications containing verapamil and your renal function is decreased by more than half, you should be instructed on a reduced dose of Dabigatran etexilate Combix of 75 mg, as your risk of bleeding may increase.

In both types of surgery, treatment should not be initiated if there is bleeding at the surgical site. If treatment cannot be initiated until the day after surgery, dosing should be initiated with 2 capsules once a day.

After knee replacement surgery

Initiate treatment with Dabigatran etexilate Combix 1-4 hours after surgery, taking a single capsule. Then, take 2 capsules once a day for a total of 10 days.

After hip replacement surgery

Initiate treatment with Dabigatran etexilate Combix 1-4 hours after surgery, taking a single capsule. Then, take 2 capsules once a day for a total of 28-35 days.

Prevention of cerebral or systemic vascular obstruction due to blood clot formation developed after abnormal heart rhythm and treatment of blood clots in the veins of your legs and lungs, including prevention of blood clots in the veins of your legs and lungs from recurring

The recommended dose is 300 mg administered as 1 capsule of 150 mg twice a day.

If you are 80 years of age or older, the recommended dose is 220 mg administered as 1 capsule of 110 mg twice a day.

If you are taking medications containing verapamil, you should be instructed on a reduced dose of Dabigatran etexilate Combix of 220 mg taken as 1 capsule of 110 mg twice a day, as your risk of bleeding may increase.

If you have a potentially higher risk of bleeding, your doctor may decide to prescribe a dose of 220 mg administered as 1 capsule of 110 mg twice a day.

You can continue taking this medication if necessary to restore your normal heart rhythm through a procedure called cardioversion. Take Dabigatran etexilate Combix as instructed by your doctor.

If you have had a medical device (vascular endoprosthesis) placed in a blood vessel to keep it open in a procedure called percutaneous coronary intervention with vascular endoprosthesis placement, you can receive treatment with Dabigatran etexilate Combix once your doctor has decided that normal blood clotting control has been achieved. Take Dabigatran etexilate Combix as instructed by your doctor.

Treatment of blood clots and prevention of blood clots from recurring in children

Dabigatran etexilate Combix should be taken twice a day, one dose in the morning and one dose in the evening, approximately at the same time every day. The administration interval should be as close as possible to 12 hours.

The recommended dose depends on weight and age. Your doctor will determine the correct dose. Your doctor may adjust the dose during treatment. Follow all other medications unless your doctor tells you to stop taking one.

Table 1 shows the single doses and total daily doses of Dabigatran etexilate Combix in milligrams (mg). The doses depend on the patient's weight in kilograms (kg) and age in years.

Table 1:Table of posology for Dabigatran etexilate Combix capsules

Single doses that require combinations of more than one capsule

How to take Dabigatran etexilate Combix

Dabigatran etexilate Combix capsules can be used in adults and children aged 8 years or older who are able to swallow the capsules whole.

Dabigatran etexilate Combix can be taken with or without food. The capsule should be swallowed whole with a glass of water, to ensure release in the stomach. Do not break, chew, or open the capsule to take only its contents, as this may increase the risk of bleeding.

Change in anticoagulant treatment

Do not change your anticoagulant treatment without specific instructions from your doctor.

If you take more Dabigatran etexilate Combix than you should

Taking too much of this medication increases the risk of bleeding. Contact your doctor immediately if you have taken too many capsules. There are specific treatment options available.

In case of overdose or accidental ingestion, consult your doctor or pharmacist immediately or call the Toxicology Information Service, phone: 91 562 04 20, indicating the medication and the amount ingested.

If you forget to take Dabigatran etexilate Combix

Prevention of blood clot formation after knee or hip replacement surgeryTake the remaining daily doses of Dabigatran etexilate Combix at the same time the next day.

Do not take a double dose to compensate for the missed doses.

Use in adults: Prevention of cerebral or systemic vascular obstruction due to blood clot formation developed after abnormal heart rhythm and treatment of blood clots in the veins of your legs and lungs, including prevention of blood clots in the veins of your legs and lungs from recurring

Use in children: Treatment of blood clots and prevention of blood clots from recurring

Blood clots

A missed dose can be taken up to 6 hours before the next dose.

A missed dose should be omitted if the remaining time before the next dose is less than 6 hours. Do not take a double dose to compensate for the missed doses.

If you interrupt treatment with Dabigatran etexilate Combix

Take Dabigatran etexilate Combix exactly as prescribed. Do not interrupt your treatment with this medication without consulting your doctor first, as the risk of developing a blood clot may be higher if you interrupt treatment too soon. Contact your doctor if you experience indigestion after taking Dabigatran etexilate Combix.

If you have any other questions about the use of this medication, ask your doctor or pharmacist

Like all medicines, this medicine can cause side effects, although not everyone will experience them.

Dabigatrán etexilato Combix acts on blood coagulation; therefore, most side effects are related to signs such as bruising or bleeding. Severe or life-threatening bleeding episodes, which can cause disability, may occur, regardless of their location. In some cases, these bleeding episodes may not be evident.

If you experience any bleeding episode that does not stop on its own or if you experience signs of excessive bleeding (exceptional weakness, fatigue, paleness, dizziness, headache, or unexplained swelling), consult your doctor immediately. Your doctor may decide to keep you under close observation or change your medication.

Inform your doctor immediately if you experience a severe allergic reaction that causes difficulty breathing or dizziness.

The possible side effects are listed below, grouped by frequency of occurrence.

Prevention of blood clot formation after knee or hip arthroplasty

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

• Decreased blood hemoglobin levels (the substance present in red blood cells)
• Anomalies in liver function tests

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

• Bleeding may occur from the nose, stomach, or intestines, penis/vagina, or urinary tract (including blood in the urine that turns the urine pink or red), hemorrhoids, rectum, under the skin, from a joint, from a wound, or after surgery
• Formation of hematomas or bruising after surgery
• Blood detected in stool in a laboratory test
• Decreased red blood cell count in the blood
• Decreased proportion of blood cells
• Allergic reaction
• Vomiting
• Frequent loose or liquid stools
• Feeling like vomiting
• Suppuration of wounds (secretion of liquid from a surgical wound)
• Increased liver enzymes
• Yellow discoloration of the skin or white of the eyes, caused by liver or blood problems

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

• Bleeding
• Bleeding may occur in the brain, at the site of a surgical incision, at the site of an injection, or at the site of a catheter in a vein
• Bleeding from a catheter in a vein with pus
• Coughing up blood or sputum with blood spots
• Decreased platelet count in the blood
• Decreased red blood cell count in the blood after surgery
• Severe allergic reaction that causes difficulty breathing or dizziness
• Severe allergic reaction that causes swelling of the face or throat
• Hives with dark, prominent, and itchy red bumps, caused by an allergic reaction
• Change in skin color and appearance
• Itching
• Ulcer in the stomach or intestines (including ulcer in the esophagus)
• Inflammation of the esophagus and stomach
• Reflex of stomach juice into the esophagus
• Abdominal pain or stomach pain
• Indigestion
• Difficulty swallowing
• Liquid leaking from a wound
• Liquid leaking from a wound after surgery

Unknown frequency (frequency cannot be estimated from available data):

• Difficulty breathing or wheezing
• Decreased white blood cell count (which helps fight infections)
• Hair loss

Prevention of cerebral or systemic blood clot formation developed after abnormal heart rhythm

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

• Bleeding may occur from the nose, stomach, or intestines, penis/vagina, or urinary tract (including blood in the urine that turns the urine pink or red), or under the skin
• Decreased red blood cell count in the blood
• Abdominal pain or stomach pain
• Indigestion
• Frequent loose or liquid stools
• Feeling like vomiting

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

• Bleeding
• Bleeding may occur from hemorrhoids, rectum, or brain
• Formation of hematomas
• Coughing up blood or sputum with blood spots
• Decreased platelet count in the blood
• Decreased hemoglobin levels in the blood (the substance present in red blood cells)
• Allergic reaction
• Change in skin color and appearance
• Itching
• Ulcer in the stomach or intestines (including ulcer in the esophagus)
• Inflammation of the esophagus and stomach
• Reflex of stomach juice into the esophagus
• Vomiting
• Difficulty swallowing
• Anomalies in liver function tests

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

• Bleeding may occur in a joint, at the site of a surgical incision, in a wound, at the site of an injection, or at the site of a catheter in a vein or from the brain
• Decreased platelet count in the blood
• Severe allergic reaction that causes difficulty breathing or dizziness
• Severe allergic reaction that causes swelling of the face or throat
• Hives with dark, prominent, and itchy red bumps, caused by an allergic reaction
• Decreased proportion of blood cells
• Increased liver enzymes
• Yellow discoloration of the skin or white of the eyes, caused by liver or blood problems

Unknown frequency (frequency cannot be estimated from available data):

• Difficulty breathing or wheezing
• Decreased white blood cell count (which helps fight infections)
• Hair loss

In a clinical trial, the index of heart attacks with Dabigatrán etexilato Combix was numerically higher than with warfarin. The global incidence was low.

Treatment of blood clots in the veins of your legs and lungs, including prevention of recurrence of blood clots in the veins of your legs and/or lungs

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

• Bleeding may occur from the nose, stomach, or intestines, rectum, penis/vagina, or urinary tract (including blood in the urine that turns the urine pink or red), or under the skin
• Indigestion

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

• Bleeding
• Bleeding may occur in a joint or in a wound
• Bleeding may occur from hemorrhoids
• Decreased red blood cell count in the blood
• Formation of hematomas
• Coughing up blood or sputum with blood spots
• Allergic reaction
• Change in skin color and appearance
• Itching
• Ulcer in the stomach or intestines (including ulcer in the esophagus)
• Inflammation of the esophagus and stomach
• Reflex of stomach juice into the esophagus
• Feeling like vomiting
• Vomiting
• Abdominal pain or stomach pain
• Frequent loose or liquid stools
• Anomalies in liver function tests
• Increased liver enzymes

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

• Bleeding may occur at the site of a surgical incision, at the site of an injection, at the site of a catheter in a vein, or from the brain
• Decreased platelet count in the blood
• Severe allergic reaction that causes difficulty breathing or dizziness
• Severe allergic reaction that causes swelling of the face or throat
• Hives with dark, prominent, and itchy red bumps, caused by an allergic reaction
• Difficulty swallowing

Unknown frequency (frequency cannot be estimated from available data):

• Difficulty breathing or wheezing
• Decreased hemoglobin levels in the blood (the substance present in red blood cells)
• Decreased proportion of blood cells
• Decreased white blood cell count (which helps fight infections)
• Yellow discoloration of the skin or white of the eyes, caused by liver or blood problems
• Hair loss

In the clinical trial program, the index of heart attacks with Dabigatrán etexilato Combix was higher than with warfarin. The global incidence was low. No imbalance in the index of heart attacks was observed in patients treated with dabigatrán compared to patients treated with placebo.

Treatment of blood clots and prevention of recurrence of blood clots in children

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

• Decreased red blood cell count in the blood
• Decreased platelet count in the blood
• Hives with dark, prominent, and itchy red bumps, caused by an allergic reaction
• Change in skin color and appearance
• Formation of hematomas
• Nasal bleeding
• Reflex of stomach juice into the esophagus
• Vomiting
• Feeling like vomiting
• Frequent loose or liquid stools
• Indigestion
• Hair loss
• Increased liver enzymes

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

• Decreased white blood cell count (which helps fight infections)
• Bleeding may occur from the stomach or intestines, brain, rectum, penis/vagina, or urinary tract (including blood in the urine that turns the urine pink or red), or under the skin
• Decreased hemoglobin levels in the blood (the substance present in red blood cells)
• Decreased proportion of blood cells
• Itching
• Coughing up blood or sputum with blood spots
• Abdominal pain or stomach pain
• Inflammation of the esophagus and stomach
• Allergic reaction
• Difficulty swallowing
• Yellow discoloration of the skin or white of the eyes, caused by liver or blood problems

Unknown frequency (frequency cannot be estimated from available data):

• Decreased white blood cell count (which helps fight infections)
• Severe allergic reaction that causes difficulty breathing or dizziness
• Severe allergic reaction that causes swelling of the face or throat
• Difficulty breathing or wheezing
• Bleeding
• Bleeding may occur in a joint or in a wound, at the site of a surgical incision, at the site of an injection, or at the site of a catheter in a vein
• Bleeding may occur from hemorrhoids
• Ulcer in the stomach or intestines (including ulcer in the esophagus)
• Anomalies in liver function tests

Reporting of side effects

If you experience any type of side effect, consult your doctor or pharmacist, even if it is a possible side effect that does not appear in this prospectus. You can also report them directly through theSistema Español de Farmacovigilancia de medicamentos de Uso Humano:https://www.notificaram.es.By reporting side effects, you can contribute to providing more information on the safety of this medicine.

Keepthis medicationout of the sight and reach of children.

Do not use this medication after the expiration date that appears on the box, blister pack, or bottle after “CAD”. The expiration date is the last day of the month indicated.

Aluminum – Aluminum (or PA/Al/PVC//Al blister):Do not store at a temperature above 30°C.

Aluminum with desiccant coating – Aluminum (OPA/Al/PE//PE/Al/LDPE):No special storage conditions are required.

Bottles: Store in the original packaging to protect it from moisture.

Medicines should not be disposed of through drains or in the trash.Depositthe packaging and medicines that you no longer need at the SIGRE collection pointat the pharmacy. If in doubt, ask your pharmacist how to dispose of the packaging and medicines that you no longer need. By doing so, you will help protect the environment.

Composition of Dabigatrán etexilate Combix

• The active ingredient is dabigatrán. Each hard capsule contains dabigatrán etexilate mesilate equivalent to 110 mg of dabigatrán etexilate

The other components are:

• Content of the capsule: tartaric acid, hypromellose, hydroxypropylcellulose, talc.
• Capsule coating: indigo carmine, carrageenan, potassium chloride, titanium dioxide, hypromellose.

Appearance of the product and content of the container

Hard capsules of approximately 19.0 mm with a blue-colored, opaque cap and a blue-colored, opaque body of size “1” filled with white to yellowish granules.

The capsules are stored in aluminum blisters with desiccant – aluminum (OPA/Al/PE// PE/Al/LDPE) and aluminum – aluminum (oPA/Al/PVC//Al blister) or a white plastic bottle with silica gel desiccant in the cap (PP).

Container sizes:

Blister packs containing: 10, 10x1 (single-dose blister), 30, 30x1 (single-dose blister), 60, 60x1 (single-dose blister), 100, or 180 hard capsules.

Bottles containing: 100 hard capsules.

Only some container sizes may be commercially available.

Holder of the marketing authorization and responsible for manufacturing

Holder of the marketing authorization

Combix Laboratories, S.L.U.

C/ Badajoz 2, Building 2

28223 Pozuelo de Alarcón (Madrid)

Spain

Responsible for manufacturing

Laboratories Liconsa S.A.
Avenida Miralcampo 7
Polígono Industrial Miralcampo
19200, Azuqueca De Henares

Guadalajara

Spain

Revision date of this prospectus:prospectus:

June 2024

The detailed information of this medicine is available on the website of the Spanish Agency for Medicines and Medical Devices (AEMPS) (http://www.aemps.gob.es/)