Vargatef: detailed information

Patient Information Leaflet

Vargatef 100 mg soft capsules

nintedanib
Please 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 they have the same symptoms as you, because it could be harmful.
If you experience any side effects, including those not listed in this leaflet, talk to your doctor or pharmacist. See section 4.

Contents of this leaflet

What Vargatef is and what it is used for
What you need to know before taking Vargatef
How to take Vargatef
Possible side effects
How to store Vargatef
Contents of the pack and other information

1. What Vargatef is and what it is used for

Vargatef capsules contain the active substance nintedanib. Nintedanib blocks the activity of a group of proteins involved in the development of new blood vessels that supply cancer cells with nutrients and oxygen. By inhibiting the activity of these proteins, nintedanib may help to stop the growth and spread of cancer.
This medicine is used in combination with another anticancer medicine (docetaxel) to treat a type of lung cancer called non-small cell lung cancer (NSCLC). This medicine is indicated for adult patients who have a certain type of NSCLC (“adenocarcinoma”) and who have already received prior treatment for this cancer, but in whom the tumour has started to grow again.

2. What you must know before taking Vargatef

Do not take Vargatef

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

Warnings and precautions
Talk to your doctor or pharmacist before taking this medicine

if you have or have had liver problems, or if you have had or currently have bleeding problems, especially recent lung bleeding
if you have or have had kidney problems or if increased levels of protein have been detected in your urine
if you are taking blood-thinning medicines (for example, warfarin, phenprocoumon, heparin, or acetylsalicylic acid) to prevent blood clots. Treatment with Vargatef may increase the risk of bleeding
if you have recently undergone or are about to undergo surgery. Nintedanib may affect wound healing. Therefore, treatment with Vargatef will usually be stopped in case of surgery. Your doctor will decide when you can 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 (a weakened and bulging blood vessel wall) or a tear in the wall of a blood vessel.

Based on this information, your doctor may carry out blood tests, for example, to
check liver function and to determine how long it takes for your blood to clot. Your
doctor will discuss the test results with you and decide whether you can receive Vargatef.
Contact your doctor immediately while taking this medicine

if you have diarrhoea. It is important to treat diarrhoea at the first sign (see section 4)
if you vomit or feel unwell (nausea)
if you experience unexplained symptoms such as yellowing of the skin or the whites of the eyes (jaundice), dark or brown-coloured urine (tea-coloured), pain in the upper right part of the abdomen, bleeding or bruising more easily than usual, or feeling tired. These could be symptoms of serious liver problems
if you have fever, chills, rapid breathing, or rapid heartbeat. These could be signs of infection or blood infection (sepsis) (see section 4)
if you have severe pain in the abdominal area, fever, chills, feeling unwell, vomiting, or abdominal stiffness or swelling, as these could be symptoms of a hole in the wall of the intestine ("gastrointestinal perforation")
if you experience a combination of some or all of the following symptoms: sudden onset of severe abdominal pain or cramps, red blood in stools, diarrhoea or constipation, nausea and vomiting, as these could be symptoms of intestinal inflammation due to reduced blood supply ("ischaemic colitis")
if you have pain, swelling, redness, or warmth in an arm or leg, or if you have chest pain and difficulty breathing, as these could be symptoms of a blood clot in a vein
if you have significant bleeding
if you feel pressure or pain in the chest, especially on the left side of the body, pain in the neck, jaw, shoulder, or arm, rapid heartbeat, shortness of breath, nausea or vomiting, as these could be symptoms of a heart attack
if you experience symptoms such as headache, vision changes, confusion, seizures, or other neurological disturbances such as weakness in one arm or leg, with or without high blood pressure. These could be symptoms of a brain condition called reversible posterior encephalopathy syndrome (PRES)
if one or more of the side effects that may occur (see section 4) become severe

Children and adolescents
This medicine has not been studied in children or adolescents for the treatment of lung cancer (NSCLC); therefore, it must not be used in children and adolescents under 18 years of age.
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 over-the-counter medicines.
This medicine may interact with certain medicines. The following medicines may increase the levels of nintedanib, the active substance in Vargatef, in the blood, potentially increasing 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, potentially reducing the effectiveness of Vargatef:

rifampicin (an antibiotic used to treat tuberculosis)
carbamazepine, phenytoin (used to treat epilepsy)
St. John’s wort (a herbal medicine used to treat depression)

Pregnancy and breastfeeding
If you are pregnant, think you might be pregnant, planning to become pregnant, or breastfeeding, consult your doctor or pharmacist before taking this medicine.
Pregnancy
Do not take this medicine during pregnancy, as it may harm the unborn child or cause birth defects.
Contraception

Women of childbearing potential must use a highly effective method of contraception to avoid pregnancy when starting treatment with Vargatef, during treatment with Vargatef, and for at least 3 months after stopping treatment.
Consult your doctor to evaluate the most suitable contraceptive methods for you.
Vomiting and/or diarrhoea or other gastrointestinal problems may affect the absorption of oral hormonal contraceptives, such as the pill, and may reduce their effectiveness. Therefore, if you experience these symptoms, consult your doctor to evaluate a more appropriate alternative contraceptive method.
Inform your doctor or pharmacist immediately if you become pregnant or suspect you are pregnant during treatment with Vargatef.

Breastfeeding
It is not known whether this medicine passes into breast milk or whether it may harm a breastfed infant. Therefore, breastfeeding is not recommended during treatment with Vargatef.
Fertility
The effect of this medicine on human fertility has not been studied.
Driving and using machines
Vargatef may have a minor influence on the ability to drive and use machines. If you do not feel well, you must not drive or operate machinery.
Vargatef contains soy
The capsules contain soy lecithin. If you are allergic to peanuts or soy, do not use this medicine.

3. How to take Vargatef

Dose reduction
If you do not tolerate the recommended dose of 400 mg per day due to side effects (see section 4), your doctor may reduce the daily dose of Vargatef. Do not reduce the dose or stop treatment 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 treatment with Vargatef 150 mg soft capsules.
If necessary, your doctor may further reduce the daily dose to 200 mg per day (two 100 mg capsules). In this case, your doctor will prescribe capsules of the appropriate strength.
In both cases, you must take one capsule of the appropriate strength twice daily, approximately 12 hours apart and at approximately the same time each day, with food (e.g. in the morning and in the evening).
If your doctor has stopped chemotherapy with docetaxel, you must continue taking Vargatef twice daily.

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 the missed dose. Take the next dose of Vargatef at the next scheduled time, as planned, and at the dose recommended by your doctor or pharmacist.

If you stop taking Vargatef
Do not stop treatment with Vargatef without first consulting your doctor. It is important to take this medicine every day for the entire period indicated by your doctor. If you do not take this medicine as prescribed, this cancer treatment may not work properly.

If you have any questions about how to use this medicine, consult 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 particular attention if you experience the following side effects during treatment with Vargatef:

Diarrhoea (very common, may affect more than 1 in 10 people)
Diarrhoea may cause loss of fluids and important salts (electrolytes such as sodium or potassium) from the body. At the first signs of diarrhoea, drink plenty of fluids and contact your doctor immediately. Start appropriate treatment for diarrhoea, for example with loperamide, as soon as possible after consulting your doctor.
Febrile neutropenia and sepsis (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 cells (neutropenia), which are important for the body's response to infections caused by bacteria or fungi. As a consequence of neutropenia, fever (febrile neutropenia) and blood infection (sepsis) may occur. If you have fever, chills, rapid breathing or rapid heartbeat, inform your doctor immediately. During treatment with Vargatef, your doctor will regularly monitor your blood cells and examine you regularly to rule out 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)

Diarrhoea – see above
Sensation of pain, numbness and/or tingling in the fingers and toes (peripheral neuropathy)
Feeling unwell (nausea)
Vomiting
Stomach (abdominal) pain
Bleeding
Decrease in the number of white blood cells (neutropenia)
Inflammation of the mucous membranes lining the digestive tract, including sores and ulcers in the mouth (mucositis, including stomatitis)
Rash
Reduced appetite
Electrolyte imbalance
Increased liver enzyme levels (alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase) in the blood, detected by blood tests
Hair loss (alopecia)

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

Blood infection (sepsis) – see above
Decrease in the 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 may travel through blood vessels to the lungs causing chest pain and difficulty breathing (if you notice any of these symptoms, contact a doctor immediately)
High blood pressure (hypertension)
Loss of fluids (dehydration)
Abscesses
Low platelet count (thrombocytopenia)
Jaundice (hyperbilirubinemia)
Increased liver enzyme levels (gamma-glutamyl transferase) in the blood, detected by blood tests
Weight loss
Itching (pruritus)
Headache (cephalalgia)
Increased amount of protein in the urine (proteinuria)

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

Formation of holes in the wall of the intestine (gastrointestinal perforation)
Severe liver problems
Inflammation of the pancreas (pancreatitis)
Myocardial infarction
Renal failure

Not known (frequency cannot be estimated from the available data)

Inflammation of the large intestine
Dilation and weakening of the wall of a blood vessel or tear in the wall of a blood vessel (aneurysms and arterial dissections)
Brain condition with symptoms such as headache, vision changes, confusion, seizures or other neurological disturbances such as weakness in one arm or leg, with or without high blood pressure (reversible posterior encephalopathy syndrome).

Reporting of side effects
If you get any side effects, including ones not listed in this leaflet, talk to your doctor or pharmacist.
You can also report side effects directly via the national reporting system listed in Annex V. By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Vargatef

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the carton, packaging, and blisters. The expiry date refers to the last day of that month.
Do not store above 25 °C.
Store in the original packaging to protect the medicine from moisture.
Do not use this medicine if you notice that the blister containing the capsules is open or if a capsule is broken.
If you come into contact with the capsule contents, wash your hands immediately with plenty of water (see section 3).
Do not dispose of medicines 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 Vargatef Contains
The active substance is nintedanib. Each soft capsule contains 100 mg of nintedanib (as esilate).
The excipients are:
Capsule contents: Medium-chain triglycerides, semi-synthetic solid glycerides, soya lecithin (E322)
Capsule shell: Gelatin, glycerol (85%), titanium dioxide (E171), red iron oxide (E172), yellow iron oxide (E172)

Description of the Appearance of Vargatef and Contents of the Package
Vargatef 100 mg soft capsules are peach-colored, opaque, oblong capsules (approximately 16 x 6 mm), with the Boehringer Ingelheim company logo and “100” imprinted on one side.
Three pack sizes of Vargatef 100 mg soft capsules are available:

One pack containing 60 capsules (6 aluminum blisters with 10 capsules each).
One pack containing 120 capsules (12 aluminum blisters with 10 capsules each).
A multiple pack containing 120 capsules (2 boxes of 60 capsules each, held together by a shrink wrap).

Not all pack 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

For further information about this medicinal product, please contact the local representative of the Marketing Authorization Holder:

België/Belgique/Belgien Lietuva
Boehringer Ingelheim SComm Boehringer Ingelheim RCV GmbH & Co KG
Tél/Tel: +32 2 773 33 11 Lietuvos filialas
Tel: +370 5 2595942

България Luxembourg/Luxemburg
Бьорингер Ингелхайм РЦВ ГмбХ и Ко. КГ ‑ Boehringer Ingelheim SComm
клон България Tél/Tel: +32 2 773 33 11
Тел.: +359 2 958 79 98

Česká republika Magyarország
Boehringer Ingelheim spol. s r.o. Boehringer Ingelheim RCV GmbH & Co KG
Tel: +420 234 655 111 Magyarországi Fióktelepe
Tel.: +36 1 299 89 00

Danmark Malta
Boehringer Ingelheim Danmark A/S Boehringer Ingelheim Ireland Ltd.
Tlf: +45 39 15 88 88 Tel: +353 1 295 9620

Deutschland Nederland
Boehringer Ingelheim Pharma GmbH & Co. KG Boehringer Ingelheim B.V.
Tel: +49 (0) 800 77 90 900 Tel: +31 (0) 800 22 55 889

Eesti Norge
Boehringer Ingelheim RCV GmbH & Co KG Boehringer Ingelheim Danmark
Eesti filiaal Norwegian branch
Tel: +372 612 8000 Tlf: +47 66 76 13 00

Ελλάδα Österreich
Boehringer Ingelheim Ελλάς Μονοπρόσωπη A.E. Boehringer Ingelheim RCV GmbH & Co KG
Tηλ: +30 2 10 89 06 300 Tel: +43 1 80 105‑7870

España Polska
Boehringer Ingelheim España, S.A. Boehringer Ingelheim Sp. z o.o.
Tel: +34 93 404 51 00 Tel.: +48 22 699 0 699

France Portugal
Boehringer Ingelheim France S.A.S. Boehringer Ingelheim Portugal, Lda.
Tél: +33 3 26 50 45 33 Tel: +351 21 313 53 00

Hrvatska România
Boehringer Ingelheim Zagreb d.o.o. Boehringer Ingelheim RCV GmbH & Co KG
Tel: +385 1 2444 600 Vienna – Bucharest Branch
Tel: +40 21 302 2800

Ireland Slovenija
Boehringer Ingelheim Ireland Ltd. Boehringer Ingelheim RCV GmbH & Co KG
Tel: +353 1 295 9620 Ljubljana Branch
Tel: +386 1 586 40 00

Ísland Slovenská republika
Vistor ehf. Boehringer Ingelheim RCV GmbH & Co KG
Sími: +354 535 7000 organisational unit
Tel: +421 2 5810 1211

Italia Suomi/Finland
Boehringer Ingelheim Italia S.p.A. Boehringer Ingelheim Finland Ky
Tel: +39 02 5355 1 Puh/Tel: +358 10 3102 800

Κύπρος Sverige
Boehringer Ingelheim Ελλάς Μονοπρόσωπη A.E. Boehringer Ingelheim AB
Tηλ: +30 2 10 89 06 300 Tel: +46 8 721 21 00

Latvija United Kingdom (Northern Ireland)
Boehringer Ingelheim RCV GmbH & Co KG Boehringer Ingelheim Ireland Ltd.
Latvijas filiāle Tel: +353 1 295 9620
Tel: +371 67 240 011

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

Patient Information Leaflet

Vargatef 150 mg soft capsules

nintedanib
Please 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, consult your doctor or pharmacist.
This medicine has been prescribed for you only. Do not give it to others, even if their symptoms are the same as yours, as it may be harmful.
If you experience any adverse reactions, including those not listed in this leaflet, consult your doctor or pharmacist. See section 4.

Contents of this leaflet

What Vargatef is and what it is used for
What you need to know before taking Vargatef
How to take Vargatef
Possible side effects
How to store Vargatef
Contents of the pack and other information

1. What Vargatef is and what it is used for

Vargatef capsules contain the active substance nintedanib. Nintedanib blocks the activity of a group of proteins involved in the development of new blood vessels that cancer cells need to receive nutrients and oxygen. By inhibiting the activity of these proteins, nintedanib may help to stop the growth and spread of cancer.
This medicine is used in combination with another anticancer medicine (docetaxel) to treat a type of lung cancer called non-small cell lung cancer (NSCLC). This medicine is indicated for adult patients who have a certain type of NSCLC (“adenocarcinoma”) and who have already received another anticancer treatment, but whose tumour has started to grow again.

2. What you should know before taking Vargatef

Do not take Vargatef

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

Warnings and precautions
Talk to your doctor or pharmacist before taking this medicine

if you have or have had liver problems, if you have or have had bleeding problems, especially recent lung bleeding
if you have or have had kidney problems or if an increased amount of protein has been detected in your urine
if you are taking medicines that thin the blood (e.g., warfarin, phenprocoumon, heparin, or acetylsalicylic acid) to prevent blood clots. Treatment with Vargatef may increase the risk of bleeding
if you have recently undergone or are about to undergo surgery. Nintedanib may affect wound healing. Therefore, treatment with Vargatef is usually stopped in case of surgery. Your doctor will decide when you can 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 (a weakened and bulging blood vessel wall) or a tear in the wall of a blood vessel.

Based on this information, your doctor may perform blood tests, for example, to
check liver function and to determine how long it takes for your blood to clot. Your
doctor will discuss the test results with you and decide whether you can receive Vargatef.
Inform your doctor immediately while taking this medicine

if you have diarrhea. It is important to treat diarrhea at the first signs (see section 4)
if you vomit or feel unwell (nausea)
if you experience unexplained symptoms such as yellowing of the skin or whites of the eyes (jaundice), dark or brown urine (tea-colored), pain in the upper right part of the stomach area (abdomen), bleeding or bruising more easily than usual, or feeling tired. These could be symptoms of serious liver problems
if you have fever, chills, rapid breathing, or rapid heartbeat. These could be signs of infection or blood infection (sepsis) (see section 4)
if you have severe pain in the stomach area, fever, chills, feeling unwell, vomiting, or abdominal stiffness or swelling, as these could be symptoms of a hole in the intestinal wall (“gastrointestinal perforation”)
if you experience a combination of some or all of the following symptoms: sudden onset of severe abdominal pain or cramps, red blood in stools, diarrhea or constipation, nausea and vomiting, as these could be symptoms of intestinal inflammation due to reduced blood supply (“ischemic colitis”)
if you have pain, swelling, redness, or warmth in a limb, or chest pain and difficulty breathing, as these could be symptoms of a blood clot in a vein
if you have significant bleeding
if you feel pressure or pain in the chest, especially on the left side of the body, pain in the neck, jaw, shoulder, or arm, rapid heartbeat, shortness of breath, 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 disturbances such as weakness in one arm or leg, with or without high blood pressure. These could be symptoms of a brain condition called posterior reversible encephalopathy syndrome (PRES)
if one or more of the side effects that may occur (see section 4) become severe

Children and adolescents
This medicine has not been studied in children or adolescents for the treatment of lung cancer (NSCLC), and therefore must not be used in children and adolescents under 18 years of age.
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 over-the-counter medicines.
This medicine may interact with certain medicines. The following medicines may increase levels of nintedanib, the active substance in Vargatef, in the blood, potentially increasing 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 levels of nintedanib in the blood, potentially reducing the effectiveness of Vargatef:

rifampicin (an antibiotic used to treat tuberculosis)
carbamazepine, phenytoin (used to treat epilepsy)
St. John’s wort (a herbal medicine used to treat depression)

Pregnancy and breastfeeding
If you are pregnant, suspect you may be pregnant, are planning a pregnancy, or are breastfeeding, consult your doctor or pharmacist before taking this medicine.
Pregnancy
Do not take this medicine during pregnancy, as it may harm the unborn child or cause birth defects.
Contraception

Women of childbearing potential must use a highly effective method of contraception to prevent pregnancy when starting treatment with Vargatef, during treatment with Vargatef, and for at least 3 months after stopping treatment.
Talk to your doctor to evaluate the most appropriate contraceptive methods for you.
Vomiting and/or diarrhea or other gastrointestinal problems may affect the absorption of oral hormonal contraceptives, such as the pill, and may reduce their effectiveness. Therefore, if you experience these symptoms, consult your doctor to evaluate a more appropriate alternative contraceptive method.
Inform your doctor or pharmacist immediately if you become pregnant or suspect you are pregnant during treatment with Vargatef.

Breastfeeding
It is not known whether the medicine passes into breast milk and whether it may harm a breastfed infant. Therefore, breastfeeding is not recommended during treatment with Vargatef.
Fertility
The effect of this medicine on human fertility has not been studied.
Driving and using machines
Vargatef may have a slight influence on the ability to drive and use machines. If you do not feel well, you should not drive or operate machinery.
Vargatef contains soy
The capsules contain soy lecithin. If you are allergic to peanuts or soy, do not use this medicine.

3. How to take Vargatef

Take this medicine exactly as instructed by your doctor or pharmacist. If you
have any doubts, consult your doctor or pharmacist.
Do not take Vargatef on the same day as chemotherapy treatment with docetaxel.
Swallow the capsules whole with water; do not chew them. It is recommended to take the capsule with
food, that is, during a meal or immediately before or after.
Do not open or crush the capsule (see section 5).
The recommended dose is two capsules per day (i.e. a total of 300 mg of nintedanib per day).
Do not take a higher dose.
This daily dose should be divided into two doses of one capsule each, taken approximately 12 hours apart, for
example, one capsule in the morning and one capsule in the evening. The two doses should be taken at approximately the
same time each day. Following these instructions ensures that a constant amount of
nintedanib is maintained in the body.
Dose reduction
If you do not tolerate the recommended dose of 300 mg per day due to side effects (see
section 4), your doctor may reduce the recommended daily dose of Vargatef to 200 mg per day
(two 100 mg capsules). In this case, your doctor will prescribe treatment with Vargatef 100 mg
soft capsules.
You must take one capsule of this dosage twice daily, approximately 12 hours apart and at approximately the same time each day, with
food (for example, in the morning and in the evening).
Do not reduce the dose or stop treatment without first consulting your doctor.
If your doctor has stopped chemotherapy with docetaxel, you must continue taking Vargatef twice
daily.
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 the missed dose. Take the next dose of
Vargatef at the next scheduled time, as planned, and at the dose recommended by your doctor or
pharmacist.
If you stop taking Vargatef
Do not stop treatment with Vargatef without first consulting your doctor. It is important to take
this medicine every day for the entire period prescribed by your doctor. If you do not take this
medicine as prescribed, this cancer treatment may not work properly.
If you have any questions about the use of this medicine, consult your doctor or pharmacist.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everyone gets them.
You should pay particular attention if you experience the following side effects during treatment with
Vargatef:

Diarrhoea (very common, may affect more than 1 in 10 people)
Diarrhoea can lead to loss of fluids and important salts (electrolytes such as sodium or potassium) from the body. At the first signs of diarrhoea, drink plenty of fluids and contact your doctor immediately. Start appropriate treatment for diarrhoea, for example with loperamide, as soon as possible after consulting your doctor.
Febrile neutropenia and sepsis (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 cells (neutropenia) which are important for the body's response to infections caused by bacteria or fungi. As a consequence of neutropenia, fever (febrile neutropenia) and blood infection (sepsis) may occur. If you develop fever, chills, or rapid breathing or heartbeat, inform your doctor immediately. During treatment with Vargatef, your doctor will regularly monitor your blood cells and will examine you regularly to rule out 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)

Diarrhoea – see above
Sensation of pain, numbness and/or tingling in the fingers and toes (peripheral neuropathy)
Feeling unwell (nausea)
Vomiting
Stomach (abdominal) pain
Bleeding
Decrease in the number of white blood cells (neutropenia)
Inflammation of the mucous membranes lining the digestive tract, including sores and ulcers in the mouth (mucositis, including stomatitis)
Skin rash
Reduced appetite
Electrolyte imbalance
Increased liver enzyme levels (alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase) in the blood, detected by blood tests
Hair loss (alopecia)

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

Blood infection (sepsis) – see above
Decrease in 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 one limb), which may travel through blood vessels to the lungs causing chest pain and difficulty breathing (if you notice any of these symptoms, seek immediate medical attention)
High blood pressure (hypertension)
Fluid loss (dehydration)
Abscesses
Low platelet count (thrombocytopenia)
Jaundice (hyperbilirubinemia)
Increased liver enzyme levels (gamma-glutamyl transferase) in the blood, detected by blood tests
Weight loss
Itching (pruritus)
Headache (cephalalgia)
Increased amount of protein in the urine (proteinuria)

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

Formation of holes in the wall of the intestine (gastrointestinal perforation)
Severe liver problems
Inflammation of the pancreas (pancreatitis)
Myocardial infarction
Renal failure

Not known (frequency cannot be estimated from the available data)

Inflammation of the large intestine
Swelling and weakening of the wall of a blood vessel or tearing of the wall of a blood vessel (aneurysms and arterial dissections)
Brain condition with symptoms such as headache, vision changes, confusion, seizures or other neurological disturbances such as weakness in one arm or leg, with or without high blood pressure (posterior reversible encephalopathy syndrome).

Reporting of side effects
If you experience any side effect, including those not listed in this leaflet, talk to your doctor or pharmacist.
You can also report side effects directly through the national reporting system listed in Annex V. By reporting side effects, you can help provide more information on the safety of this medicine.

5. How to store Vargatef

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date stated on the carton and on the blisters. The expiry date refers to the last day of that month.
Do not store above 25 °C.
Store in the original packaging to protect the medicine from moisture.
Do not use this medicine if the blister containing the capsules is open or if a capsule is broken.
If you come into contact with the capsule contents, wash your hands immediately with plenty of water (see section 3).
Do not dispose of any medicine via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. This will help protect the environment.

6. Package contents and other information

What Vargatef contains
The active substance is nintedanib. Each soft capsule contains 150 mg of nintedanib (as esilate).
The excipients are:
Contents of the capsule: Medium-chain triglycerides, semisynthetic solid glycerides, soybean lecithin (E322)
Capsule shell: Gelatin, glycerol (85%), titanium dioxide (E171), red iron oxide (E172), yellow iron oxide (E172)

Description of the appearance of Vargatef and package contents
Vargatef 150 mg soft capsules (capsules) are brown, opaque, oblong capsules (approximately 18 x 7 mm), marked on one side with the Boehringer Ingelheim corporate logo and “150”.
One package contains 60 capsules (6 aluminum blisters with 10 capsules each).

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

For further information about this medicinal product, please contact the local representative of the marketing authorization holder: