Package Insert: Information for the Patient

Vargatef 100 mg Soft Capsules

nintedanib

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

• Keep this package insert, as you may need to refer to it again.
• If you have any questions, consult your doctor or pharmacist.
• This medication has been prescribed to you alone, 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.

1. What is Vargatef and how is it used

2. What you need to know before starting to take Vargatef

3. How to take Vargatef

4. Possible adverse effects

5. Storage of Vargatef

6. Contents of the package and additional information

Vargatef capsules containthe active ingredientnintedanib. Nintedanib blocks the activity of a group of proteins that areinvolved inthe development of new blood vessels that cancer cells need to supply them with food and oxygen. By blocking the activity of these proteins, nintedanib may help to stop the growth and spread of cancer.

This medication is used in combination with another cancer medication (docetaxel) to treat a type of lung cancer called non-small cell lung cancer (NSCLC). It is directed at adult patients with a specific type of NSCLC (“adenocarcinoma”) who have already received treatment with another medication to treat this cancer, but in whom the tumor has begun to grow again.

Do not take Vargatef

• if you are allergic to nintedanib, peanuts, soy, or any of the other ingredients of this medicine (listed in section 6).

Warnings and precautions

Consult your doctor or pharmacist before starting to take this medicine.

• if you have or have had liver problems or if you have or have had bleeding problems, particularly recent lung bleeding.

• if you have or have had kidney problems or if you have been found to have an increase in the amount of protein in your urine.

• if you are taking medicines to thin the blood (such as warfarin, phenprocoumon, heparin, or acetylsalicylic acid) to prevent blood clots. Treatment with Vargatef may increase the risk of bleeding.
• if you have recently undergone surgery or are scheduled to have surgery. Nintedanib may affect the way wounds heal. Treatment with Vargatef will usually be stopped if you undergo surgery. Your doctor will decide when to resume treatment with this medicine.
• if you have cancer that has spread to the brain.
• if you have high blood pressure.
• if you have or have had an aneurysm (an enlargement and weakening of the wall of a blood vessel) or a tear in the wall of a blood vessel.

Based on this information, your doctor may perform some blood tests, for example, to check your liver function and to determine how quickly your blood can clot. Your doctor will discuss the results of these tests with you to decide if you can receive Vargatef.

Inform your doctor immediately while taking this medicine.

• if you have diarrhea. It is essential to treat diarrhea as soon as the first symptoms appear (see section 4).
• if you have vomiting or feel like vomiting (nausea).

• if you have unexplained symptoms such as yellowing of the skin or the white of the eyes (jaundice), dark or tea-colored urine, upper right abdominal pain, bleeding or bruising more easily than usual, or feeling tired. These could be symptoms of severe liver problems.

• if you present fever, chills, rapid breathing, or a rapid heart rate, which could be signs of infection or blood infection (sepsis) (see section 4).
• if you experience acute abdominal pain, fever, chills, dizziness, vomiting, or abdominal rigidity or swelling, as these could be symptoms of having a hole in the wall of the intestines (“gastrointestinal perforation”).
• if you experience a combination of some or all of the following symptoms: severe and sudden abdominal pain, bloody stools, diarrhea or constipation, nausea, and vomiting, as these could be symptoms of intestinal inflammation due to reduced blood flow (“ischemic colitis”).
• if you experience pain, swelling, redness, or heat in a limb or if you experience chest pain and difficulty breathing, as these could be symptoms of having a blood clot in one of your veins.
• if you have significant bleeding.
• if you experience pressure or pain in the chest, usually on the left side of the body, chest pain, neck pain, jaw pain, shoulder pain, or arm pain, rapid heart rate, difficulty breathing, nausea, or vomiting, as these could be symptoms of a heart attack.
• if you experience symptoms such as headache, changes in vision, confusion, seizures, or other neurological changes such as weakness in an arm or leg, with or without high blood pressure, which could be symptoms of a brain disorder called posterior reversible encephalopathy syndrome (PRES).
• if any of the side effects you may have (see section 4) worsen.

Children and adolescents

This medicine has not been studied in children or adolescents for the treatment of lung cancer (NSCLC) and, therefore, children and adolescents under 18 years old should not take it.

Other medicines and Vargatef

Inform your doctor or pharmacist if you are taking, have taken recently, or may need to take any other medicine, including herbal medicines and medicines obtained without a prescription.

This medicine may interact with other medicines. The following medicines may increase the levels of nintedanib, the active ingredient in Vargatef, in the blood and, therefore, increase the risk of side effects (see section 4):

• Ketoconazole (used to treat fungal infections).
• Erythromycin (used to treat bacterial infections).

The following medicines may decrease the levels of nintedanib and, therefore, reduce the effectiveness of Vargatef:

• Rifampicin (an antibiotic used to treat tuberculosis).
• Carbamazepine, phenytoin (used to treat seizures).
• St. John's Wort (a medicinal herb used to treat depression).

Pregnancy and breastfeeding

If you are pregnant or breastfeeding, or if you think you may be pregnant, consult your doctor or pharmacist before using this medicine.

Pregnancy

Do not take this medicine during pregnancy, as it may harm the fetus and cause congenital defects.

Contraception

• Women who may become pregnant should use a highly effective contraceptive method to avoid pregnancy when starting Vargatef, while taking Vargatef, and for at least three months after stopping treatment.
• Consult your doctor to find out which contraceptive methods are most suitable.
• Vomiting and/or diarrhea or other gastrointestinal disorders may affect the absorption of oral contraceptives, such as birth control pills, and may reduce their effectiveness. Therefore, if you experience any of these situations, consult your doctor to evaluate an alternative contraceptive method that is more suitable.
• Inform your doctor or pharmacist immediately if you become pregnant or think you may be pregnant during treatment with Vargatef.

Breastfeeding

It is unknown whether the medicine passes into breast milk and may harm the baby. Therefore, women should not breastfeed their baby during treatment with Vargatef.

Fertility

The effect of this medicine on human fertility has not been studied.

Driving and operating machines

Vargatef has little effect on the ability to drive and use machines. Do not drive or use machines if you feel dizzy.

Vargatef contains soy

The capsules contain soy lecithin.If you are allergic to peanuts or soy, do not take this medicine.

Follow exactly the administration instructions of this medication indicated by your doctor or pharmacist. In case of doubt, consult your doctor or pharmacist again.

Do not take Vargatef on the same day that you receivechemotherapy treatment with docetaxel.

Swallow the capsules whole with water, without chewing them. It is recommended to take the capsules with food, that is, during meals or immediately before or after them.

Do not open or break the capsule (see section5).

The recommended dose is four capsules per day (which makes a total of 400mg of nintedanib per day). Do not take a dose higher than this.

This daily dose should be divided into two doses of two capsules with a 12-hour difference, for example, two capsules in the morning and two capsules at night. These two doses should be taken approximately at the same time each day. If you take the medication in this way, you will ensure that a constant level of nintedanib is maintained in the body.

Dose reduction

If you cannot tolerate the recommended dose of 400mg per day due to the appearance of adverse effects (see section4), your doctor may reduce your daily dose of Vargatef. Do not reduce the dose or discontinue treatment on your own without consulting your doctor first.

Your doctor may reduce your recommended dose to 300mg per day (two 150mg capsules). In this case, your doctor will prescribe Vargatef 150mg soft capsules for your treatment.

If necessary, your doctor may further reduce your daily dose to 200mg per day (two 100mg capsules). If this occurs, your doctor will prescribe the appropriate concentration of the capsule.

In both cases, you should take one capsule of the appropriate concentration twice a day with food, with a 12-hour difference (for example, in the morning and at night) and approximately at the same time of day.

If your doctor has suspended your chemotherapy treatment with docetaxel, you should continue taking Vargatef twice a day.

If you take more Vargatef than you should

Contact your doctor or pharmacist immediately.

If you forgot to take Vargatef

Do not take a double dose to compensate for the missed doses. Take your next dose of Vargatef according to the established schedule at the next scheduled hour and at the dose recommended by your doctor or pharmacist.

If you interrupt treatment with Vargatef

Do not stop taking Vargatefwithout consulting your doctor first. It is essential to take this medication every day while your doctor prescribes it. If you do not take this medication as prescribed by your doctor,the cancer treatment may not work properly.

If you have any other doubts 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.

You should pay special attention if you experience the following side effects during treatment with Vargatef:

• Diarrea(very common, may affect more than 1 in 10 people)

Diarrea can cause a loss of important body fluids and salts (electrolytes, such as sodium or potassium). If you experience the first symptoms of diarrhea, drink plenty of liquid and consult your doctor immediately. Start an appropriate anti-diarrheal treatment as soon as possible, for example, by taking loperamide after consulting your doctor.

• Febrile neutropeniaandsepsis(common, may affect up to 1 in 10 people)

Treatment with Vargatef can cause a reduction in the number of a type of white blood cell (neutropenia), which are important for the body to react appropriately to bacterial or fungal infections. As a consequence of neutropenia, fever (febrile neutropenia) and blood infection (sepsis) may occur. Inform your doctor immediately if you have a fever, chills, rapid breathing, or a rapid heart rate.

During treatment with Vargatef, your doctor will perform regular blood cell analyses and check for signs of infection, such as inflammation, fever, or fatigue.

The following side effects have been observed during treatment with this medicine:

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

• Diarrea; see above
• Sensation of pain, numbness, and/or tingling in the fingers of the hands or feet (peripheral neuropathy)
• Feeling of nausea (nausea)
• Vomiting

• Abdominal pain

• Bleeding

• Reduction in the number of white blood cells (neutropenia)
• Inflammation of the mucous membranes that line the digestive tract, including mouth sores and ulcers (mucositis, including stomatitis)
• Rash
• Loss of appetite

• Electrolyte imbalance

• Increased levels of liver enzymes (alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase in blood), which are detected in blood tests
• Hair loss (alopecia)

Common side effects (may affect up to 1 in 10 people)

• Blood infection (sepsis); see above
• Reduction in the number of white blood cells accompanied by fever (febrile neutropenia)
• Clots in the veins (venous thromboembolism), especially in the legs (symptoms include pain, redness, swelling, and heat in a limb), which can travel through the blood vessels to the lungs and cause chest pain and difficulty breathing (if you experience any of these symptoms, seek medical attention immediately)
• High blood pressure (hypertension)
• Dehydration

• Abcesses
• Low platelet count (thrombocytopenia)
• Jaundice (hyperbilirubinemia)
• Increased levels of liver enzymes (gamma-glutamyltransferase) in the blood, which are detected in blood tests
• Weight loss
• Itching
• Headache
• Increased amount of protein in the urine (proteinuria)

Rare side effects (may affect up to 1 in 100 people)

• Appearance of holes in the wall of the intestines (gastrointestinal perforation)
• Severe liver problems
• Inflammation of the pancreas (pancreatitis)
• Myocardial infarction
• Renal failure

Unknown frequency (cannot be estimated from available data)

• Inflammation of the large intestine
• Increased and weakened wall of a blood vessel or tearing of the wall of a blood vessel (aneurysms and arterial dissections)
• Cerebral disorder with symptoms such as headache, changes in vision, confusion, seizures, or other neurological changes such as weakness in an arm or leg, with or without high blood pressure (posterior reversible encephalopathy syndrome)

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 leaflet. You can also report them directly through the national notification system included in theAppendixV.By reporting side effects, you can contribute to providing more information on the safety of this medicine.

Keep this medication out of the sight and reach of children.

Do not use this medication after the expiration date that appears on the box, packaging, and blister packs. The expiration date is the last day of the month indicated.

Do not store above 25 °C.

Store in the original packaging to protect it from moisture.

Do not use this medication if you observe that the blister pack containing the capsules is open or that a capsule is broken.

If you come into contact with the contents of the capsule, wash your hands immediately with plenty of water (see section 3).

Medicines should not be disposed of through drains or in the trash. Ask your pharmacist how to dispose of the packaging and medications that you no longer need. This will help protect the environment.

Compositionof Vargatef

The active ingredient is nintedanib. Each soft capsulecontains100mg of nintedanib (as esilate).

The excipients are:

Content of the capsule:Medium-chain triglycerides, hard fat, soy lecithin (E322)

Outer coating of the capsule:Gelatin, glycerol (85%), titanium dioxide (E171), iron oxide red (E172), iron oxide yellow (E172)

Appearance of the productand contents of the package

Vargatef 100mg soft capsules(capsules) are oblong, opaque, and orange-colored (approximately 16 x 6 mm) capsules marked on one side with the Boehringer Ingelheim logo and“100”.

There are three package sizes of Vargatef 100mg soft capsules:

• One box containing 60 capsules (6 aluminum blisters with 10 capsules each).
• One box containing 120 capsules (12 aluminum blisters with 10 capsules each).
• A multiple pack containing 120 capsules (2 boxes of 60capsules each joined by a wrapper).

Only some package sizes of Vargatef 100mg soft capsules may be commercially available.

Marketing Authorization Holder

Boehringer Ingelheim International GmbH

Binger Strasse 173

55216 Ingelheim am Rhein

Germany

Responsible for manufacturing

Boehringer Ingelheim Pharma GmbH & Co.KG

Binger Strasse 173

55216 Ingelheim am Rhein

Germany

Boehringer Ingelheim France

100-104 Avenue de France

75013 Paris

France

For more information about this medicine, please contact the local representative of the marketing authorization holder:

Last update of this leaflet:

For detailed information about this medicine, please visit the website of the European Medicines Agency:http://www.ema.europa.eu.