VARGATEF 100 mg SOFT GEL CAPSULES

2. What you need to know before you take Vargatef

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

Talk to your doctor or pharmacist before you start taking this medicine

• if you have or have had liver problems or if you have or have had bleeding problems, in particular recent bleeding in the lung

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

• if you are taking medicines to thin your 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 have planned surgery. Nintedanib may affect the way wounds heal. Therefore, treatment with Vargatef will usually be interrupted if you undergo surgery. Your doctor will decide when to restart 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 (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.

Tell your doctor immediately while you are taking this medicine

• if you have diarrhea. It is important 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 symptoms without an apparent cause such as yellowing of the skin or the whites of the eyes (jaundice), dark or brown urine (the color of tea), pain in the upper right side of the stomach area (abdomen), bleeding or bruising more easily than normal, or feeling tired. These could be symptoms of serious liver problems

• if you have a 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 severe abdominal pain, fever, chills, dizziness, vomiting or abdominal stiffness 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, blood in the stool, 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 warmth 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 a major bleeding
• if you experience pressure or pain in the chest, usually on the left side of the body, pain in the neck, jaw, shoulder or arm, a 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 disorders 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) get worse

Children and adolescents

This medicine has not been studied in children or adolescents to treat lung cancer (NSCLC) and therefore children and adolescents under 18 years should not take it.

Other medicines and Vargatef

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines, 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 in the blood, the active substance of Vargatef, 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 in the blood and thus reduce the effectiveness of Vargatef:

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

Pregnancy and breastfeeding

If you are pregnant or breastfeeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before taking this medicine.

Pregnancy

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

Contraception

• Women who may become pregnant must use a highly effective method of contraception to avoid becoming pregnant when starting to take Vargatef, while taking Vargatef, and for at least three months after finishing 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 hormonal contraceptives, such as birth control pills, and may reduce their effectiveness. Therefore, if you experience any of these situations, consult your doctor to assess an alternative contraceptive method that is more suitable.
• Tell your doctor or pharmacist immediately if you become pregnant or think you may be pregnant during treatment with Vargatef.

Breastfeeding

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

Fertility

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

Driving and using machines

Vargatef has little influence 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.

3. How to take Vargatef

Always take this medicine exactly as your doctor or pharmacist has told you. If you are not sure, check with your doctor or pharmacist.

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

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

Do not open or split the capsule (see section 5).

The recommended dose is four capsules a day (for a total of 400 mg 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 approximately 12 hours between them, for example, two capsules in the morning and two capsules in the evening. These two doses should be taken at approximately the same time every day. If you take the medicine in this way, you will ensure that you maintain a constant level of nintedanib in your body.

Dose reduction

If you cannot tolerate the recommended dose of 400 mg per day due to the appearance of side effects (see section 4), your doctor may reduce your daily dose of Vargatef. Do not reduce the dose or stop treatment yourself without first consulting your doctor.

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

If necessary, your doctor may further reduce the daily dose to 200 mg per day (two 100 mg capsules). If this happens, 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 approximately 12 hours between them (for example, in the morning and in the evening) and at approximately the same time of day.

If your doctor has stopped chemotherapy treatment with docetaxel, you should continue to take Vargatef twice a day.

If you take more Vargatef than you should

Contact your doctor or pharmacist immediately.

If you forget to take Vargatef

Do not take a double dose to make up for forgotten doses. Take your next dose of Vargatef as scheduled at the next scheduled time and at the recommended dose by your doctor or pharmacist.

If you stop taking Vargatef

Do not stop taking Vargatef without first consulting your doctor. It is important to take this medicine every day while your doctor prescribes it. If you do not take this medicine as your doctor has prescribed, this cancer treatment may not work properly.

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

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

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

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

Diarrhea can cause a loss of important fluids and salts (electrolytes, such as sodium or potassium) from the body. At the first symptoms of diarrhea, drink plenty of fluids and consult your doctor immediately. Start 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 may cause a reduction in the number of a type of white blood cell (neutropenia), which are important for the body to react properly to bacterial or fungal infections. As a result of neutropenia, fever (febrile neutropenia) and blood infection (sepsis) may occur. Tell 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 tests 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)

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

• Abdominal pain

• Bleeding

• Reduced number of white blood cells (neutropenia)
• Inflammation of the mucous membranes lining the digestive tract, including ulcers and sores in the mouth (mucositis, including stomatitis)
• Rash
• Decreased appetite

• Electrolyte imbalance

• Increased values 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
• Reduced number of white blood cells accompanied by fever (febrile neutropenia)
• Blood clots in the veins (venous thromboembolism), especially in the legs (symptoms include pain, redness, swelling and warmth in a limb), which can move through the blood vessels to the lungs and cause chest pain and difficulty breathing (if you notice any of these symptoms, seek medical attention immediately)
• High blood pressure (hypertension)
• Loss of fluids (dehydration)

• Abscesses
• Low platelet count (thrombocytopenia)
• Jaundice (hyperbilirubinemia)
• Increased values 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)

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

• Holes in the wall of the intestines (gastrointestinal perforation)
• Serious liver problems
• Pancreatitis (inflammation of the pancreas)
• Heart attack
• Kidney failure

Frequency not known (cannot be estimated from the available data)

• Inflammation of the large intestine
• Enlargement and weakening of the wall of a blood vessel or tear in the wall of a blood vessel (aneurysms and arterial dissections)
• Brain disorder with symptoms such as headache, changes in vision, confusion, seizures or other neurological disorders 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 side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly through the national reporting system listed in Appendix V. By reporting side effects, you can help provide more information on the safety of this medicine.

5. Storage of Vargatef

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

Do not use this medicine after the expiry date which is stated on the carton, packaging and blisters. The expiry date is the last day of the month shown.

Do not store above 25°C.

Store in the original package to protect from moisture.

Do not use this medicine if you notice that the blister 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 via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help protect the environment.

6. Package Contents and Additional Information

Compositionof Vargatef

The active ingredient is nintedanib. Each soft capsule contains 100 mg of nintedanib (as esilate).

The excipients are:

Capsule Content:Medium-chain triglycerides, hard fat, soy lecithin (E322)

Outer Capsule Shell:Gelatin, glycerol (85%), titanium dioxide (E171), red iron oxide (E172), yellow iron oxide (E172)

Product Appearanceand Package Contents

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

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

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

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

Marketing Authorization Holder

Boehringer Ingelheim International GmbH

Binger Strasse 173

55216 Ingelheim am Rhein

Germany

Manufacturer

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

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

Date of Last Revision of this Leaflet:

Detailed information on this medicinal product is available on the European Medicines Agency website: http://www.ema.europa.eu.