nintedanib: package leaflet

Ofev contains the active substance nintedanib, a medicine belonging to the class of so-called tyrosine kinase inhibitors, and it is used for the treatment of the following diseases:

Idiopathic pulmonary fibrosis (IPF) in adults
IPF is a condition in which the tissue in your lungs becomes thickened, stiff and scarred over time. As a result, scarring reduces the ability to transfer oxygen from the lungs into the bloodstream and it becomes difficult to breathe deeply. Ofev helps to reduce further scarring and stiffening of the lungs.

Other chronic fibrosing interstitial lung diseases (ILDs) with a progressive phenotype in adults Besides IPF, there are other conditions in which the tissue in your lungs becomes thickened, stiff, and scarred over time (lung fibrosis) and keeps worsening (progressive phenotype). Examples of these conditions are hypersensitivity pneumonitis, autoimmune ILDs (e.g. rheumatoid arthritis associated ILD), idiopathic nonspecific interstitial pneumonia, unclassifiable idiopathic interstitial pneumonia, and other ILDs. Ofev helps to reduce further scarring and stiffening of the lungs.

Clinically significant, progressive fibrosing interstitial lung diseases (ILDs) in children and adolescents from 6 to 17 years old Lung fibrosis may occur in patients with Childhood Interstitial Lung Disease (chILD). When this is the case, the tissue in the lungs of children and adolescents becomes thickened, stiff, and scarred over time. Ofev helps to reduce further scarring and stiffening of the lungs.

Systemic sclerosis associated interstitial lung disease (SSc-ILD) in adults, adolescents and children aged 6 years and older Systemic sclerosis (SSc), also known as scleroderma (and juvenile systemic sclerosis in children and adolescents), is a rare chronic autoimmune disease that affects connective tissue in many parts of the body. SSc causes fibrosis (scarring and stiffening) of the skin and other internal organs such as the lungs. When the lungs are affected by fibrosis, it is called interstitial lung disease (ILD), and so the condition is called SSc-ILD. Fibrosis in the lungs reduces the ability to transfer oxygen into the bloodstream, and breathing capacity is reduced. Ofev helps to reduce further scarring and stiffening of the lungs.

Do not take Ofev
- if you are pregnant,
- if you are allergic to nintedanib, peanut or soya, or any of the other ingredients of this medicine (listed in section 6).

Warnings and precautions
Talk to your doctor or pharmacist before taking Ofev,
- if you have or have had liver problems,
- if you have or have had problems with your kidneys, or if an increased amount of protein has been detected in your urine, - if you have or have had bleeding problems, - if you take blood-thinning medicines (such as warfarin, phenprocoumon or heparin) to prevent blood clotting, - if you take pirfenidone as this may increase the risk of having diarrhoea, nausea, vomiting and liver problems, - if you have or have had problems with your heart (for example a heart attack), - if you have recently had surgery. Nintedanib may affect the way your wounds heal. Therefore, your treatment with Ofev will usually be stopped for a while if you are having a surgery. Your doctor will decide when to resume your treatment with this medicine.
- if you have high blood pressure,
- if you have abnormally high blood pressure in the blood vessels of the lungs (pulmonary hypertension), - if you have or have had an aneurysm (enlargement and weakening of a blood vessel wall) or a tear in a blood vessel wall.

Based on this information your doctor may do some blood tests, for example to check your liver function. Your doctor will discuss the results of these tests with you and decide whether you may receive Ofev.

Inform your doctor immediately while taking this medicine,
- if you get diarrhoea. Treating diarrhoea early is important (see section 4, ‘Posible side effects’);
- if you vomit or feel sick (nausea);
- if you have unexplained symptoms such as yellowing of your skin or the white part of your eyes (jaundice), dark or brown (tea coloured) urine, pain on the upper right side of your stomach area (abdomen), bleeding or bruising more easily than normal, or feeling tired. This could be symptoms of serious liver problems;
- if you have severe pain in your stomach, fever, chills, sickness, vomiting, or abdominal rigidity or bloating, as these could be symptoms of a hole in the wall of your gut (‘gastrointestinal perforation’). Also, tell your doctor if you had peptic ulcers or diverticular disease in the past, or are concomitantly treated with anti-inflammatory drugs (NSAIDs) (used to treat pain relief and swelling) or steroids (used for inflammation and allergies), as this may increase this risk;
- if you have a combination of severe pain or cramping in your stomach, red blood in your stool or diarrhea as these could be symptoms of a bowel inflammation from inadequate blood supply;
- if you have pain, swelling, reddening, warmth of a limb as this could be symptoms of a blood clot in one of your veins (a type of blood vessel);
- if you have chest pressure or pain, typically on the left side of the body, pain in the neck, jaw, shoulder or arm, a fast heartbeat, shortness of breath, nausea, vomiting, as this could be symptoms of a heart attack;
- if you have any major bleeding;
- if you experience bruising, bleeding, fever, fatigue and confusion. This may be a sign of damage to blood vessels known as thrombotic microangiopathy (TMA);
- if you experience symptoms such as headache, vision changes, confusion, seizure or other neurologic disturbances such as weakness in an arm or a leg, with or without high blood pressure.
This could be symptoms of a brain condition called posterior reversible encephalopathy syndrome (PRES).

Children and adolescents
Ofev should not be taken by children under 6 years of age.
Your doctor may perform regular dental examinations at least every 6 months until development of teeth is completed, and monitor your growth annually (bone imaging) while you take this medicine.

Other medicines and Ofev
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.

Ofev can interact with certain other medicines. The following medicines are examples that may increase the levels of nintedanib in your blood, and hence may increase the risk for side effects (see section 4, ‘Possible side effects’):
- a medicine used to treat fungal infections (ketoconazole)
- a medicine used to treat bacterial infections (erythromycin)
- a medicine that affects your immune system (cyclosporine)

The following medicines are examples that may lower the levels of nintedanib in your blood and thus may reduce the effectiveness of Ofev:
- an antibiotic used to treat tuberculosis (rifampicin)
- medicines to treat seizures (carbamazepine, phenytoin)
- a herbal medicine to treat depression (St. John’s Wort)

Pregnancy and breast-feeding
If you are pregnant or breast-feeding, 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 can harm your unborn baby and cause birth defects.

You must have a pregnancy test done to ensure you are not pregnant before starting treatment with Ofev. Please talk to your doctor.

Contraception
- Women who can become pregnant must use a highly effective method of birth control to prevent pregnancy when they start taking Ofev, while they are taking Ofev and for at least 3 months after stopping treatment.
- You should discuss the most appropriate methods of contraception for you with your doctor.
- Vomiting and/or diarrhoea or other gastrointestinal conditions can affect the absorption of oral hormonal contraceptives, such as birth control pills, and may reduce their effectiveness.Therefore, if experiencing these, talk to your doctor to discuss an alternative more appropriate method of contraception.
- Tell your doctor or pharmacist immediately if you become pregnant or think you may be pregnant during treatment with Ofev.

Breast-feeding
Do not breast-feed during the treatment with Ofev since there may be a risk of harm to the breast-fed child.

Driving and using machines
Ofev may have minor influence on your ability to drive and use machines. You should not drive or use machines if you feel sick.

Ofev contains soya lecithin
If you are allergic to soya or peanut, do not take this medicine (see section 2, under ‘Do not take Ofev’).

Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor or pharmacist if you are not sure.

Take the capsules twice daily approximately 12 hours apart at about the same time every day, for example one capsule in the morning and one capsule in the evening. This ensures that a steady amount of nintedanib is maintained in your blood stream. Swallow the whole capsules with water and do not chew the capsules. It is recommended that you take the capsules with food, i.e. during or immediately before or after a meal. Do not open or crush the capsule (see section 5, under ‘How to store Ofev’).
For the ease of swallowing, you can take the capsules with a small amount (one teaspoonful) of cold or room temperature soft food, such as apple sauce or chocolate pudding. Swallow immediately and do not chew the capsule, to ensure it stays intact.

Adults
The recommended dose is one capsule of 150 mg twice daily (a total of 300 mg per day).
Do not take more than the recommended dose of two Ofev 150 mg capsules per day.

If you do not tolerate the recommended dose of two Ofev 150 mg capsules per day (see possible side effects in section 4) your doctor may reduce the daily dose of Ofev. Do not reduce the dose or stop the treatment by yourself without consulting your doctor first.

Your doctor may reduce your recommended dose to two times 100 mg per day (a total of 200 mg per day). In this case your doctor will prescribe Ofev 100 mg capsules for your treatment. Do not take more than the recommended dose of two Ofev 100 mg capsules per day if your daily dose was reduced to 200 mg per day.

Use in children and adolescents
The recommended dose depends on the weight of the patient.
Tell your doctor if any time during the treatment the weight of the patient is below 13.5 kg.
Tell your doctor if you have liver problems.
Your doctor will determine the correct dose. Your doctor may adjust the dose as treatment progresses.
If you do not tolerate the recommended dose of Ofev capsules per day (see possible side effects in section 4) your doctor may reduce the daily dose of Ofev.
Do not reduce the dose or stop the treatment by yourself without consulting your doctor first.

Weight-Based dosing for Ofev capsules in children and adolescents:

If you take more Ofev than you should
Contact your doctor or pharmacist immediately.

If you forget to take Ofev
Do not take two capsules together if you have forgotten to take your earlier dose. You should take your next dose of Ofev as planned at the next scheduled time recommended by your doctor or pharmacist.
Weight range in kilograms (kg)
Ofev dose in milligrams (mg)
13.5 - 22.9 kg
50 mg (two 25 mg capsules) twice daily
23.0 - 33.4 kg
75 mg (three 25 mg capsules) twice daily
33.5 - 57.4 kg
100 mg (one 100 mg capsule or four 25 mg capsules) twice daily
57.5 kg and above
150 mg (one 150 mg capsule or six 25 mg capsules) twice daily

If you stop taking Ofev
Do not stop taking Ofev without consulting your doctor first. It is important to take this medicine every day, as long as your doctor prescribes it for you.

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

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

You need to pay special attention if you get the following side effects during treatment with Ofev:

Diarrhoea (very common, may affect more than 1 in 10 people):
Diarrhoea may lead to dehydration: a loss of fluid and important salts (electrolytes, such as sodium or potassium) from your body. At the first signs of diarrhoea drink plenty of fluids and contact your doctor immediately. Start appropriate anti-diarrhoeal treatment, e.g. with loperamide, as soon as possible.

The following other side effects were observed during treatment with this medicine.
Talk to your doctor if you get any side effects.

Idiopathic pulmonary fibrosis (IPF)

Very common side effects (may affect more than 1 in 10 people)
- Feeling sick (nausea)
- Pain in the lower body (abdomen)
- Abnormal liver test results

Common side effects (may affect up to 1 in 10 people)
- Vomiting
- Loss of appetite
- Weight loss
- Bleeding
- Rash
- Headache

Uncommon side effects (may affect up to 1 in 100 people)
- Pancreatitis
- Inflammation of the large bowel
- Serious liver problems
- Low platelet count (thrombocytopenia)
- High blood pressure (hypertension)
- Jaundice, that is a yellow colour to the skin and whites of the eyes due to high levels of bilirubin - Itching - Heart attack - Hair loss (alopecia) - Increased amount of protein in your urine (proteinuria)

Not known (cannot be estimated from the available data)
- Renal failure
- An enlargement and weakening of a blood vessel wall or a tear in a blood vessel wall (aneurysms and artery dissections) - A brain condition with symptoms such as headache, vision changes, confusion, seizure or other neurologic disturbances such as weakness in an arm or a leg, with or without high blood pressure (posterior reversible encephalopathy syndrome)

Other chronic fibrosing interstitial lung diseases (ILDs) with a progressive phenotype

Very common side effects (may affect more than 1 in 10 people)
- Feeling sick (nausea)
- Vomiting
- Loss of appetite
- Pain in the lower body (abdomen)
- Abnormal liver test results

Common side effects (may affect up to 1 in 10 people)
- Weight loss
- High blood pressure (hypertension)
- Bleeding
- Serious liver problems
- Rash
- Headache

Uncommon side effects (may affect up to 1 in 100 people)
- Pancreatitis
- Inflammation of the large bowel
- Low platelet count (thrombocytopenia)
- Jaundice, that is a yellow colour to the skin and whites of the eyes due to high levels of bilirubin - Itching - Heart attack - Hair loss (alopecia) - Increased amount of protein in your urine (proteinuria)

Not known (cannot be estimated from the available data)
- Renal failure
- An enlargement and weakening of a blood vessel wall or a tear in a blood vessel wall (aneurysms and artery dissections) - A brain condition with symptoms such as headache, vision changes, confusion, seizure or other neurologic disturbances such as weakness in an arm or a leg, with or without high blood pressure (posterior reversible encephalopathy syndrome)

Systemic sclerosis associated interstitial lung disease (SSc-ILD)

Very common side effects (may affect more than 1 in 10 people)
- Feeling sick (nausea)
- Vomiting
- Pain in the lower body (abdomen)
- Abnormal liver test results

Common side effects (may affect up to 1 in 10 people)
- Bleeding
- High blood pressure (hypertension)
- Loss of appetite
- Weight loss
- Headache

Uncommon side effects (may affect up to 1 in 100 people)
- Inflammation of the large bowel
- Serious liver problems
- Renal failure
- Low platelet count (thrombocytopenia)
- Rash

• Itching

Not known (cannot be estimated from the available data)
- Heart attack
- Pancreatitis
- Jaundice, that is a yellow colour to the skin and whites of the eyes due to high levels of bilirubin - An enlargement and weakening of a blood vessel wall or a tear in a blood vessel wall (aneurysms and artery dissections) - Hair loss (alopecia) - Increased amount of protein in your urine (proteinuria) - A brain condition with symptoms such as headache, vision changes, confusion, seizure or other neurologic disturbances such as weakness in an arm or a leg, with or without high blood pressure (posterior reversible encephalopathy syndrome)

Fibrosing interstitial lung diseases (ILDs) in children and adolescents

Side effects in children and adolescents were similar to side effects in adult patients.
Talk to your doctor if you get any side effects.

Reporting of side effects
If you get 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 via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine.

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, the blister or the bottle.
The expiry date refers to the last day of that month.

Do not store Ofev above 25 °C.
Blister: Store in the original package in order to protect from moisture.
Bottle: Keep the bottle tightly closed in order to protect from moisture.

Do not use this medicine if you notice that the blister containing the capsules is opened or a capsule is broken.
If you are in contact with the content of the capsule, wash off your hands immediately with plenty of water (see section 3, ‘How to take Ofev’).

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.

What Ofev contains
- The active substance is nintedanib. Each capsule contains 25 mg nintedanib (as esilate).
- The other ingredients are:

Capsule fill:
Triglycerides, medium-chain, hard fat, soya lecithin (E322) (see section 2, under ‘Do not take Ofev’).

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

What Ofev looks like and contents of the pack
Ofev 25 mg capsules are orange-coloured, opaque, oval soft-gelatin capsules (approx. 8 x 5 mm) marked on one side with the figure “25”.

Four pack-sizes of Ofev 25 mg capsules are available:
- 60 × 1 soft capsules in aluminium/aluminium perforated unit dose blisters
- 60 soft capsules in a plastic bottle with screw cap
- 120 soft capsules in a plastic bottle with screw cap
- 180 soft capsules in a plastic bottle with screw cap

Not all pack-sizes may be marketed.

Marketing Authorisation 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 any information about this medicine, please contact the local representative of the Marketing Authorisation Holder:

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

България
Бьорингер Ингелхайм РЦВ ГмбХ и Ко. КГ - клон България
Тел: +359 2 958 79 98

Luxembourg/Luxemburg
Boehringer Ingelheim SComm
Tél/Tel: +32 2 773 33 11

Česká republika
Boehringer Ingelheim spol. s r.o.
Tel: +420 234 655 111

Magyarország
Boehringer Ingelheim RCV GmbH & Co KG
Magyarországi Fióktelepe
Tel: +36 1 299 89 00

Danmark
Boehringer Ingelheim Danmark A/S
Tlf.: +45 39 15 88 88

Malta
Boehringer Ingelheim Ireland Ltd.
Tel: +353 1 295 9620
Deutschland
Boehringer Ingelheim Pharma GmbH & Co. KG
Tel: +49 (0) 800 77 90 900
Nederland
Boehringer Ingelheim B.V.
Tel: +31 (0) 800 22 55 889

Eesti
Boehringer Ingelheim RCV GmbH & Co KG
Eesti filiaal
Tel: +372 612 8000

Norge
Boehringer Ingelheim Danmark A/S NUF
Tlf: +47 66 76 13 00

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

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

France
Boehringer Ingelheim France S.A.S.
Tél: +33 3 26 50 45 33

Portugal
Boehringer Ingelheim Portugal, Lda.
Tel: +351 21 313 53 00

Hrvatska
Boehringer Ingelheim Zagreb d.o.o.
Tel: +385 1 2444 600

România
Boehringer Ingelheim RCV GmbH & Co KG
Viena - Sucursala Bucureşti
Tel: +40 21 302 2800

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

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

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

Κύπρος
Boehringer Ingelheim Ελλάς Μονοπρόσωπη A.E.
Tηλ: +30 2 10 89 06 300

Sverige
Boehringer Ingelheim AB
Tel: +46 8 721 21 00

Latvija
Boehringer Ingelheim RCV GmbH & Co KG
Latvijas filiāle
Tel: +371 67 240 011

This leaflet was last revised in

Detailed information on this medicine is available on the European Medicines Agency web site:
https://www.ema.europa.eu.

Ofev contains the active substance nintedanib, a medicine belonging to the class of so-called tyrosine kinase inhibitors, and it is used for the treatment of the following diseases:

Idiopathic pulmonary fibrosis (IPF) in adults
IPF is a condition in which the tissue in your lungs becomes thickened, stiff and scarred over time. As a result, scarring reduces the ability to transfer oxygen from the lungs into the bloodstream and it becomes difficult to breathe deeply. Ofev helps to reduce further scarring and stiffening of the lungs.

Other chronic fibrosing interstitial lung diseases (ILDs) with a progressive phenotype in adults Besides IPF, there are other conditions in which the tissue in your lungs becomes thickened, stiff, and scarred over time (lung fibrosis) and keeps worsening (progressive phenotype). Examples of these conditions are hypersensitivity pneumonitis, autoimmune ILDs (e.g. rheumatoid arthritis associated ILD), idiopathic nonspecific interstitial pneumonia, unclassifiable idiopathic interstitial pneumonia, and other ILDs. Ofev helps to reduce further scarring and stiffening of the lungs.

Clinically significant, progressive fibrosing interstitial lung diseases (ILDs) in children and adolescents from 6 to 17 years old Lung fibrosis may occur in patients with Childhood Interstitial Lung Disease (chILD). When this is the case, the tissue in the lungs of children and adolescents becomes thickened, stiff, and scarred over time. Ofev helps to reduce further scarring and stiffening of the lungs.

Systemic sclerosis associated interstitial lung disease (SSc-ILD) in adults, adolescents and children aged 6 years and older Systemic sclerosis (SSc), also known as scleroderma (and juvenile systemic sclerosis in children and adolescents), is a rare chronic autoimmune disease that affects connective tissue in many parts of the body. SSc causes fibrosis (scarring and stiffening) of the skin and other internal organs such as the lungs. When the lungs are affected by fibrosis, it is called interstitial lung disease (ILD), and so the condition is called SSc-ILD. Fibrosis in the lungs reduces the ability to transfer oxygen into the bloodstream, and breathing capacity is reduced. Ofev helps to reduce further scarring and stiffening of the lungs.

Do not take Ofev
- if you are pregnant,
- if you are allergic to nintedanib, peanut or soya, or any of the other ingredients of this medicine (listed in section 6).

Warnings and precautions
Talk to your doctor or pharmacist before taking Ofev,
- if you have or have had liver problems,
- if you have or have had problems with your kidneys, or if an increased amount of protein has been detected in your urine,
- if you have or have had bleeding problems,
- if you take blood-thinning medicines (such as warfarin, phenprocoumon or heparin) to prevent blood clotting,
- if you take pirfenidone as this may increase the risk of having diarrhoea, nausea, vomiting and liver problems,
- if you have or have had problems with your heart (for example a heart attack),
- if you have recently had surgery. Nintedanib may affect the way your wounds heal. Therefore, your treatment with Ofev will usually be stopped for a while if you are having a surgery. Your doctor will decide when to resume your treatment with this medicine.
- if you have high blood pressure,
- if you have abnormally high blood pressure in the blood vessels of the lungs (pulmonary hypertension),
- if you have or have had an aneurysm (enlargement and weakening of a blood vessel wall) or a tear in a blood vessel wall.

Based on this information your doctor may do some blood tests, for example to check your liver function. Your doctor will discuss the results of these tests with you and decide whether you may receive Ofev.

Inform your doctor immediately while taking this medicine,
- if you get diarrhoea. Treating diarrhoea early is important (see section 4, ‘Possible side effects’);
- if you vomit or feel sick (nausea);
- if you have unexplained symptoms such as yellowing of your skin or the white part of your eyes (jaundice), dark or brown (tea coloured) urine, pain on the upper right side of your stomach area (abdomen), bleeding or bruising more easily than normal, or feeling tired. This could be symptoms of serious liver problems;
- if you have severe pain in your stomach, fever, chills, sickness, vomiting, or abdominal rigidity or bloating, as these could be symptoms of a hole in the wall of your gut (‘gastrointestinal perforation’). Also, tell your doctor if you had peptic ulcers or diverticular disease in the past, or are concomitantly treated with anti-inflammatory drugs (NSAIDs) (used to treat pain relief and swelling) or steroids (used for inflammation and allergies), as this may increase this risk;
- if you have a combination of severe pain or cramping in your stomach, red blood in your stool or diarrhea as these could be symptoms of a bowel inflammation from inadequate blood supply;
- if you have pain, swelling, reddening, warmth of a limb as this could be symptoms of a blood clot in one of your veins (a type of blood vessel);
- if you have chest pressure or pain, typically on the left side of the body, pain in the neck, jaw, shoulder or arm, a fast heartbeat, shortness of breath, nausea, vomiting, as this could be symptoms of a heart attack;
- if you have any major bleeding;
- if you experience bruising, bleeding, fever, fatigue and confusion. This may be a sign of damage to blood vessels known as thrombotic microangiopathy (TMA);
- if you experience symptoms such as headache, vision changes, confusion, seizure or other neurologic disturbances such as weakness in an arm or a leg, with or without high blood pressure. This could be symptoms of a brain condition called posterior reversible encephalopathy syndrome (PRES).

Children and adolescents
Ofev should not be taken by children under 6 years of age.
Your doctor may perform regular dental examinations at least every 6 months until development of teeth is completed, and monitor your growth annually (bone imaging) while you take this medicine.

Other medicines and Ofev
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.

Ofev can interact with certain other medicines. The following medicines are examples that may increase the levels of nintedanib in your blood, and hence may increase the risk for side effects (see section 4, ‘Possible side effects’):
- a medicine used to treat fungal infections (ketoconazole)
- a medicine used to treat bacterial infections (erythromycin)
- a medicine that affects your immune system (cyclosporine)

The following medicines are examples that may lower the levels of nintedanib in your blood and thus may reduce the effectiveness of Ofev:
- an antibiotic used to treat tuberculosis (rifampicin)
- medicines to treat seizures (carbamazepine, phenytoin)
- a herbal medicine to treat depression (St. John’s Wort)

Pregnancy and breast-feeding
If you are pregnant or breast-feeding, 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 can harm your unborn baby and cause birth defects.

You must have a pregnancy test done to ensure you are not pregnant before starting treatment with Ofev. Please talk to your doctor.

Contraception
- Women who can become pregnant must use a highly effective method of birth control to prevent pregnancy when they start taking Ofev, while they are taking Ofev and for at least 3 months after stopping treatment.
- You should discuss the most appropriate methods of contraception for you with your doctor.
- Vomiting and/or diarrhoea or other gastrointestinal conditions can affect the absorption of oral hormonal contraceptives, such as birth control pills, and may reduce their effectiveness.
Therefore, if experiencing these, talk to your doctor to discuss an alternative more appropriate method of contraception.
- Tell your doctor or pharmacist immediately if you become pregnant or think you may be pregnant during treatment with Ofev.

Breast-feeding
Do not breast-feed during the treatment with Ofev since there may be a risk of harm to the breast-fed child.

Driving and using machines
Ofev may have minor influence on your ability to drive and use machines. You should not drive or use machines if you feel sick.

Ofev contains soya lecithin
If you are allergic to soya or peanut, do not take this medicine (see section 2, under ‘Do not take Ofev’).

Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor or pharmacist if you are not sure.

Take the capsules twice daily approximately 12 hours apart at about the same time every day, for example one capsule in the morning and one capsule in the evening. This ensures that a steady amount of nintedanib is maintained in your blood stream. Swallow the whole capsules with water and do not chew the capsules. It is recommended that you take the capsules with food, i.e. during or immediately before or after a meal. Do not open or crush the capsule (see section 5, under ‘How to store Ofev’).
For the ease of swallowing, you can take the capsules with a small amount (one teaspoonful) of cold or room temperature soft food, such as apple sauce or chocolate pudding. Swallow immediately and do not chew the capsule, to ensure it stays intact.

Adults
The recommended dose is one capsule of 100 mg twice daily (a total of 200 mg per day).
Do not take more than the recommended dose of two Ofev 100 mg capsules per day.

If you do not tolerate the recommended dose of two Ofev 100 mg capsules per day (see possible side effects in section 4) your doctor may advise you to stop taking this medicine. Do not reduce the dose or stop the treatment by yourself without consulting your doctor first.

Use in children and adolescents
The recommended dose depends on the weight of the patient.
Tell your doctor if any time during the treatment the weight of the patient is below 13.5 kg.
Tell your doctor if you have liver problems.
Your doctor will determine the correct dose. Your doctor may adjust the dose as treatment progresses.
If you do not tolerate the recommended dose of Ofev capsules per day (see possible side effects in section 4) your doctor may reduce the daily dose of Ofev.
Do not reduce the dose or stop the treatment by yourself without consulting your doctor first.

Weight-Based dosing for Ofev capsules in children and adolescents:

If you take more Ofev than you should
Contact your doctor or pharmacist immediately.

If you forget to take Ofev
Do not take two capsules together if you have forgotten to take your earlier dose. You should take your next dose of Ofev as planned at the next scheduled time recommended by your doctor or pharmacist.

If you stop taking Ofev
Do not stop taking Ofev without consulting your doctor first. It is important to take this medicine every day, as long as your doctor prescribes it for you.

Weight range in kilograms (kg)
Ofev dose in milligrams (mg)
13.5 - 22.9 kg
50 mg (two 25 mg capsules) twice daily
23.0 - 33.4 kg
75 mg (three 25 mg capsules) twice daily
33.5 - 57.4 kg
100 mg (one 100 mg capsule or four 25 mg capsules) twice daily
57.5 kg and above
150 mg (one 150 mg capsule or six 25 mg capsules) twice daily

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

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

You need to pay special attention if you get the following side effects during treatment with Ofev:

Diarrhoea (very common, may affect more than 1 in 10 people):
Diarrhoea may lead to dehydration: a loss of fluid and important salts (electrolytes, such as sodium or potassium) from your body. At the first signs of diarrhoea drink plenty of fluids and contact your doctor immediately. Start appropriate anti-diarrhoeal treatment, e.g. with loperamide, as soon as possible.

The following other side effects were observed during treatment with this medicine.
Talk to your doctor if you get any side effects.

Idiopathic pulmonary fibrosis (IPF)

Very common side effects (may affect more than 1 in 10 people)
- Feeling sick (nausea)
- Pain in the lower body (abdomen)
- Abnormal liver test results

Common side effects (may affect up to 1 in 10 people)
- Vomiting
- Loss of appetite
- Weight loss
- Bleeding
- Rash
- Headache

Uncommon side effects (may affect up to 1 in 100 people)
- Pancreatitis
- Inflammation of the large bowel
- Serious liver problems
- Low platelet count (thrombocytopenia)
- High blood pressure (hypertension)
- Jaundice, that is a yellow colour to the skin and whites of the eyes due to high levels of bilirubin
- Itching
- Heart attack
- Hair loss (alopecia)
- Increased amount of protein in your urine (proteinuria)

Not known (cannot be estimated from the available data)
- Renal failure
- An enlargement and weakening of a blood vessel wall or a tear in a blood vessel wall (aneurysms and artery dissections)
- A brain condition with symptoms such as headache, vision changes, confusion, seizure or other neurologic disturbances such as weakness in an arm or a leg, with or without high blood pressure (posterior reversible encephalopathy syndrome)

Other chronic fibrosing interstitial lung diseases (ILDs) with a progressive phenotype

Very common side effects (may affect more than 1 in 10 people)
- Feeling sick (nausea)

• Vomiting
• Loss of appetite
• Pain in the lower body (abdomen)
• Abnormal liver test results

Common side effects (may affect up to 1 in 10 people)
- Weight loss
- High blood pressure (hypertension)
- Bleeding
- Serious liver problems
- Rash
- Headache

Uncommon side effects (may affect up to 1 in 100 people)
- Pancreatitis
- Inflammation of the large bowel
- Low platelet count (thrombocytopenia)
- Jaundice, that is a yellow colour to the skin and whites of the eyes due to high levels of bilirubin
- Itching
- Heart attack
- Hair loss (alopecia)
- Increased amount of protein in your urine (proteinuria)

Not known (cannot be estimated from the available data)
- Renal failure
- An enlargement and weakening of a blood vessel wall or a tear in a blood vessel wall (aneurysms and artery dissections)
- A brain condition with symptoms such as headache, vision changes, confusion, seizure or other neurologic disturbances such as weakness in an arm or a leg, with or without high blood pressure (posterior reversible encephalopathy syndrome)

Systemic sclerosis associated interstitial lung disease (SSc-ILD)

Very common side effects (may affect more than 1 in 10 people)
- Feeling sick (nausea)
- Vomiting
- Pain in the lower body (abdomen)
- Abnormal liver test results

Common side effects (may affect up to 1 in 10 people)
- Bleeding
- High blood pressure (hypertension)
- Loss of appetite
- Weight loss
- Headache

Uncommon side effects (may affect up to 1 in 100 people)
- Inflammation of the large bowel
- Serious liver problems
- Renal failure
- Low platelet count (thrombocytopenia)
- Rash
- Itching

Not known (cannot be estimated from the available data)
- Heart attack
- Pancreatitis

• Jaundice, that is a yellow colour to the skin and whites of the eyes due to high levels of bilirubin
• An enlargement and weakening of a blood vessel wall or a tear in a blood vessel wall (aneurysms and artery dissections)
• Hair loss (alopecia)
• Increased amount of protein in your urine (proteinuria)
• A brain condition with symptoms such as headache, vision changes, confusion, seizure or other neurologic disturbances such as weakness in an arm or a leg, with or without high blood pressure (posterior reversible encephalopathy syndrome)

Fibrosing interstitial lung diseases (ILDs) in children and adolescents

Side effects in children and adolescents were similar to side effects in adult patients.
Talk to your doctor if you get any side effects.

Reporting of side effects
If you get 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 via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine.

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 and the blister. The expiry date refers to the last day of that month.

Do not store Ofev above 25 °C.
Store in the original package in order to protect from moisture.

Do not use this medicine if you notice that the blister containing the capsules is opened or a capsule is broken.
If you are in contact with the content of the capsule, wash off your hands immediately with plenty of water (see section 3, ‘How to take Ofev’).

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.

What Ofev contains
- The active substance is nintedanib. Each capsule contains 100 mg nintedanib (as esilate).
- The other ingredients are:
Capsule fill:
Triglycerides, medium-chain, hard fat, soya lecithin (E322) (see section 2, under ‘Do not take Ofev’) Capsule shell: Gelatin, glycerol (85%), titanium dioxide (E171), iron oxide red (E172), iron oxide yellow (E172)

What Ofev looks like and contents of the pack
Ofev 100 mg capsules are peach-coloured, opaque, oblong soft-gelatin capsules (approx. 16 x 6 mm) marked on one side with the Boehringer Ingelheim company symbol and the figure “100”.

Two pack-sizes of Ofev 100 mg capsules are available:
- 30 × 1 soft capsules in aluminium/aluminium perforated unit dose blisters
- 60 × 1 soft capsules in aluminium/aluminium perforated unit dose blisters

Not all pack-sizes may be marketed.

Marketing Authorisation 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 any information about this medicine, please contact the local representative of the Marketing Authorisation Holder:

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

България
Бьорингер Ингелхайм РЦВ ГмбХ и Ко. КГ - клон България
Тел: +359 2 958 79 98

Luxembourg/Luxemburg
Boehringer Ingelheim SComm
Tél/Tel: +32 2 773 33 11

Česká republika
Boehringer Ingelheim spol. s r.o.
Tel: +420 234 655 111

Magyarország
Boehringer Ingelheim RCV GmbH & Co KG
Magyarországi Fióktelepe
Tel: +36 1 299 89 00

Danmark
Boehringer Ingelheim Danmark A/S
Tlf.: +45 39 15 88 88

Malta
Boehringer Ingelheim Ireland Ltd.
Tel: +353 1 295 9620
Deutschland
Boehringer Ingelheim Pharma GmbH & Co. KG
Tel: +49 (0) 800 77 90 900
Nederland
Boehringer Ingelheim B.V.
Tel: +31 (0) 800 22 55 889

Eesti
Boehringer Ingelheim RCV GmbH & Co KG
Eesti filiaal
Tel: +372 612 8000

Norge
Boehringer Ingelheim Danmark A/S NUF
Tlf: +47 66 76 13 00

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

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

France
Boehringer Ingelheim France S.A.S.
Tél: +33 3 26 50 45 33

Portugal
Boehringer Ingelheim Portugal, Lda.
Tel: +351 21 313 53 00

Hrvatska
Boehringer Ingelheim Zagreb d.o.o.
Tel: +385 1 2444 600

România
Boehringer Ingelheim RCV GmbH & Co KG
Viena - Sucursala Bucureşti
Tel: +40 21 302 2800

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

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

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

Κύπρος
Boehringer Ingelheim Ελλάς Μονοπρόσωπη A.E.
Tηλ: +30 2 10 89 06 300

Sverige
Boehringer Ingelheim AB
Tel: +46 8 721 21 00

Latvija
Boehringer Ingelheim RCV GmbH & Co KG
Latvijas filiāle
Tel: +371 67 240 011

This leaflet was last revised in

Detailed information on this medicine is available on the European Medicines Agency web site:
https://www.ema.europa.eu.

Ofev contains the active substance nintedanib, a medicine belonging to the class of so-called tyrosine kinase inhibitors, and it is used for the treatment of the following diseases:

Idiopathic pulmonary fibrosis (IPF) in adults
IPF is a condition in which the tissue in your lungs becomes thickened, stiff and scarred over time. As a result, scarring reduces the ability to transfer oxygen from the lungs into the bloodstream and it becomes difficult to breathe deeply. Ofev helps to reduce further scarring and stiffening of the lungs.

Other chronic fibrosing interstitial lung diseases (ILDs) with a progressive phenotype in adults Besides IPF, there are other conditions in which the tissue in your lungs becomes thickened, stiff, and scarred over time (lung fibrosis) and keeps worsening (progressive phenotype). Examples of these conditions are hypersensitivity pneumonitis, autoimmune ILDs (e.g. rheumatoid arthritis associated ILD), idiopathic nonspecific interstitial pneumonia, unclassifiable idiopathic interstitial pneumonia, and other ILDs. Ofev helps to reduce further scarring and stiffening of the lungs.

Clinically significant, progressive fibrosing interstitial lung diseases (ILDs) in children and adolescents from 6 to 17 years old Lung fibrosis may occur in patients with Childhood Interstitial Lung Disease (chILD). When this is the case, the tissue in the lungs of children and adolescents becomes thickened, stiff, and scarred over time. Ofev helps to reduce further scarring and stiffening of the lungs.

Systemic sclerosis associated interstitial lung disease (SSc-ILD) in adults, adolescents and children aged 6 years and older Systemic sclerosis (SSc), also known as scleroderma (and juvenile systemic sclerosis in children and adolescents), is a rare chronic autoimmune disease that affects connective tissue in many parts of the body. SSc causes fibrosis (scarring and stiffening) of the skin and other internal organs such as the lungs. When the lungs are affected by fibrosis, it is called interstitial lung disease (ILD), and so the condition is called SSc-ILD. Fibrosis in the lungs reduces the ability to transfer oxygen into the bloodstream, and breathing capacity is reduced. Ofev helps to reduce further scarring and stiffening of the lungs.

Do not take Ofev
- if you are pregnant,
- if you are allergic to nintedanib, peanut or soya, or any of the other ingredients of this medicine (listed in section 6).

Warnings and precautions
Talk to your doctor or pharmacist before taking Ofev,
- if you have or have had liver problems,
- if you have or have had problems with your kidneys, or if an increased amount of protein has been detected in your urine,
- if you have or have had bleeding problems,
- if you take blood-thinning medicines (such as warfarin, phenprocoumon or heparin) to prevent blood clotting,
- if you take pirfenidone as this may increase the risk of having diarrhoea, nausea, vomiting and liver problems,
- if you have or have had problems with your heart (for example a heart attack),
- if you have recently had surgery. Nintedanib may affect the way your wounds heal. Therefore, your treatment with Ofev will usually be stopped for a while if you are having a surgery. Your doctor will decide when to resume your treatment with this medicine.
- if you have high blood pressure,
- if you have abnormally high blood pressure in the blood vessels of the lungs (pulmonary hypertension),
- if you have or have had an aneurysm (enlargement and weakening of a blood vessel wall) or a tear in a blood vessel wall.

Based on this information your doctor may do some blood tests, for example to check your liver function. Your doctor will discuss the results of these tests with you and decide whether you may receive Ofev.

Inform your doctor immediately while taking this medicine,
- if you get diarrhoea. Treating diarrhoea early is important (see section 4, ‘Possible side effects’);
- if you vomit or feel sick (nausea);
- if you have unexplained symptoms such as yellowing of your skin or the white part of your eyes (jaundice), dark or brown (tea coloured) urine, pain on the upper right side of your stomach area (abdomen), bleeding or bruising more easily than normal, or feeling tired. This could be symptoms of serious liver problems;
- if you have severe pain in your stomach, fever, chills, sickness, vomiting, or abdominal rigidity or bloating, as these could be symptoms of a hole in the wall of your gut (‘gastrointestinal perforation’). Also, tell your doctor if you had peptic ulcers or diverticular disease in the past, or are concomitantly treated with anti-inflammatory drugs (NSAIDs) (used to treat pain relief and swelling) or steroids (used for inflammation and allergies), as this may increase this risk;
- if you have a combination of severe pain or cramping in your stomach, red blood in your stool or diarrhea as these could be symptoms of a bowel inflammation from inadequate blood supply;
- if you have pain, swelling, reddening, warmth of a limb as this could be symptoms of a blood clot in one of your veins (a type of blood vessel);
- if you have chest pressure or pain, typically on the left side of the body, pain in the neck, jaw, shoulder or arm, a fast heartbeat, shortness of breath, nausea, vomiting, as this could be symptoms of a heart attack;
- if you have any major bleeding;
- if you experience bruising, bleeding, fever, fatigue and confusion. This may be a sign of damage to blood vessels known as thrombotic microangiopathy (TMA);
- if you experience symptoms such as headache, vision changes, confusion, seizure or other neurologic disturbances such as weakness in an arm or a leg, with or without high blood

pressure. This could be symptoms of a brain condition called posterior reversible encephalopathy syndrome (PRES).

Children and adolescents
Ofev should not be taken by children under 6 years of age.
Your doctor may perform regular dental examinations at least every 6 months until development of teeth is completed, and monitor your growth annually (bone imaging) while you take this medicine.

Other medicines and Ofev
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.

Ofev can interact with certain other medicines. The following medicines are examples that may increase the levels of nintedanib in your blood, and hence may increase the risk for side effects (see section 4, ‘Possible side effects’):
- a medicine used to treat fungal infections (ketoconazole)
- a medicine used to treat bacterial infections (erythromycin)
- a medicine that affects your immune system (cyclosporine)

The following medicines are examples that may lower the levels of nintedanib in your blood and thus may reduce the effectiveness of Ofev:
- an antibiotic used to treat tuberculosis (rifampicin)
- medicines to treat seizures (carbamazepine, phenytoin)
- a herbal medicine to treat depression (St. John’s Wort)

Pregnancy and breast-feeding
If you are pregnant or breast-feeding, 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 can harm your unborn baby and cause birth defects.

You must have a pregnancy test done to ensure you are not pregnant before starting treatment with Ofev. Please talk to your doctor.

Contraception
- Women who can become pregnant must use a highly effective method of birth control to prevent pregnancy when they start taking Ofev while they are taking Ofev and for at least 3 months after stopping treatment.
- You should discuss the most appropriate methods of contraception for you with your doctor.
- Vomiting and/or diarrhoea or other gastrointestinal conditions can affect the absorption of oral hormonal contraceptives, such as birth control pills, and may reduce their effectiveness.
Therefore, if experiencing these, talk to your doctor to discuss an alternative more appropriate method of contraception.
- Tell your doctor or pharmacist immediately if you become pregnant or think you may be pregnant during treatment with Ofev.

Breast-feeding
Do not breast-feed during the treatment with Ofev since there may be a risk of harm to the breast-fed child.

Driving and using machines
Ofev may have minor influence on your ability to drive and use machines. You should not drive or use machines if you feel sick.

Ofev contains soya lecithin
If you are allergic to soya or peanut, do not take this medicine (see section 2, under ‘Do not take

Ofev’).

Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor or pharmacist if you are not sure.

Take the capsules twice daily approximately 12 hours apart at about the same time every day, for example one capsule in the morning and one capsule in the evening. This ensures that a steady amount of nintedanib is maintained in your blood stream. Swallow the whole capsules with water and do not chew the capsules. It is recommended that you take the capsules with food, i.e. during or immediately before or after a meal. Do not open or crush the capsule (see section 5, under ‘How to store Ofev’).
For the ease of swallowing, you can take the capsules with a small amount (one teaspoonful) of cold or room temperature soft food, such as apple sauce or chocolate pudding. Swallow immediately and do not chew the capsule, to ensure it stays intact.

Adults
The recommended dose is one capsule of 150 mg twice daily (a total of 300 mg per day).
Do not take more than the recommended dose of two Ofev 150 mg capsules per day.

If you do not tolerate the recommended dose of two Ofev 150 mg capsules per day (see possible side effects in section 4) your doctor may reduce the daily dose of Ofev. Do not reduce the dose or stop the treatment by yourself without consulting your doctor first.

Your doctor may reduce your recommended dose to two times 100 mg per day (a total of 200 mg per day). In this case your doctor will prescribe Ofev 100 mg capsules for your treatment. Do not take more than the recommended dose of two Ofev 100 mg capsules per day if your daily dose was reduced to 200 mg per day.

Use in children and adolescents
The recommended dose depends on the weight of the patient.
Tell your doctor if any time during the treatment the weight of the patient is below 13.5 kg.
Tell your doctor if you have liver problems.
Your doctor will determine the correct dose. Your doctor may adjust the dose as treatment progresses.
If you do not tolerate the recommended dose of Ofev capsules per day (see possible side effects in section 4) your doctor may reduce the daily dose of Ofev.
Do not reduce the dose or stop the treatment by yourself without consulting your doctor first.

Weight-Based dosing for Ofev capsules in children and adolescents:

If you take more Ofev than you should
Contact your doctor or pharmacist immediately.

If you forget to take Ofev
Do not take two capsules together if you have forgotten to take your earlier dose. You should take Weight range in kilograms (kg) Ofev dose in milligrams (mg) 13.5 - 22.9 kg 50 mg (two 25 mg capsules) twice daily 23.0 - 33.4 kg 75 mg (three 25 mg capsules) twice daily 33.5 - 57.4 kg 100 mg (one 100 mg capsule or four 25 mg capsules) twice daily 57.5 kg and above 150 mg (one 150 mg capsule or six 25 mg capsules) twice daily

your next dose of Ofev as planned at the next scheduled time recommended by your doctor or pharmacist.

If you stop taking Ofev
Do not stop taking Ofev without consulting your doctor first. It is important to take this medicine every day, as long as your doctor prescribes it for you.

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

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

You need to pay special attention if you get the following side effects during treatment with Ofev:

Diarrhoea (very common, may affect more than 1 in 10 people):
Diarrhoea may lead to dehydration: a loss of fluid and important salts (electrolytes, such as sodium or potassium) from your body. At the first signs of diarrhoea drink plenty of fluids and contact your doctor immediately. Start appropriate anti-diarrhoeal treatment, e.g. with loperamide, as soon as possible.

The following other side effects were observed during treatment with this medicine.
Talk to your doctor if you get any side effects.

Idiopathic pulmonary fibrosis (IPF)

Very common side effects (may affect more than 1 in 10 people)
- Feeling sick (nausea)
- Pain in the lower body (abdomen)
- Abnormal liver test results.

Common side effects (may affect up to 1 in 10 people)
- Vomiting
- Loss of appetite
- Weight loss
- Bleeding
- Rash
- Headache

Uncommon side effects (may affect up to 1 in 100 people)
- Pancreatitis
- Inflammation of the large bowel
- Serious liver problems
- Low platelet count (thrombocytopenia)
- High blood pressure (hypertension)
- Jaundice, that is a yellow colour to the skin and whites of the eyes due to high levels of bilirubin
- Itching
- Heart attack
- Hair loss (alopecia)
- Increased amount of protein in your urine (proteinuria)

Not known (cannot be estimated from the available data)
- Renal failure
- An enlargement and weakening of a blood vessel wall or a tear in a blood vessel wall (aneurysms and artery dissections)
- A brain condition with symptoms such as headache, vision changes, confusion, seizure or other

neurologic disturbances such as weakness in an arm or a leg, with or without high blood pressure (posterior reversible encephalopathy syndrome)

Other chronic fibrosing interstitial lung diseases (ILDs) with a progressive phenotype

Very common side effects (may affect more than 1 in 10 people)
- Feeling sick (nausea)
- Vomiting
- Loss of appetite
- Pain in the lower body (abdomen)
- Abnormal liver test results

Common side effects (may affect up to 1 in 10 people)
- Weight loss
- High blood pressure (hypertension)
- Bleeding
- Serious liver problems
- Rash
- Headache

Uncommon side effects (may affect up to 1 in 100 people)
- Pancreatitis
- Inflammation of the large bowel
- Low platelet count (thrombocytopenia)
- Jaundice, that is a yellow colour to the skin and whites of the eyes due to high levels of bilirubin
- Itching
- Heart attack
- Hair loss (alopecia)
- Increased amount of protein in your urine (proteinuria)

Not known (cannot be estimated from the available data)
- Renal failure
- An enlargement and weakening of a blood vessel wall or a tear in a blood vessel wall (aneurysms and artery dissections)
- A brain condition with symptoms such as headache, vision changes, confusion, seizure or other neurologic disturbances such as weakness in an arm or a leg, with or without high blood pressure (posterior reversible encephalopathy syndrome)

Systemic sclerosis associated interstitial lung disease (SSc-ILD)

Very common side effects (may affect more than 1 in 10 people)
- Feeling sick (nausea)
- Vomiting
- Pain in the lower body (abdomen)
- Abnormal liver test results

Common side effects (may affect up to 1 in 10 people)
- Bleeding
- High blood pressure (hypertension)
- Loss of appetite
- Weight loss
- Headache

Uncommon side effects (may affect up to 1 in 100 people)
- Inflammation of the large bowel
- Serious liver problems
- Renal failure

• Low platelet count (thrombocytopenia)
• Rash
• Itching

Not known (cannot be estimated from the available data)
- Heart attack
- Pancreatitis
- Jaundice, that is a yellow colour to the skin and whites of the eyes due to high levels of bilirubin
- An enlargement and weakening of a blood vessel wall or a tear in a blood vessel wall (aneurysms and artery dissections)
- Hair loss (alopecia)
- Increased amount of protein in your urine (proteinuria)
- A brain condition with symptoms such as headache, vision changes, confusion, seizure or other neurologic disturbances such as weakness in an arm or a leg, with or without high blood pressure (posterior reversible encephalopathy syndrome)

Fibrosing interstitial lung diseases (ILDs) in children and adolescents

Side effects in children and adolescents were similar to side effects in adult patients.
Talk to your doctor if you get any side effects.

Reporting of side effects
If you get 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 via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine.

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 and the blister. The expiry date refers to the last day of that month.

Do not store Ofev above 25 °C.
Store in the original package in order to protect from moisture.

Do not use this medicine if you notice that the blister containing the capsules is opened or a capsule is broken.
If you are in contact with the content of the capsule, wash off your hands immediately with plenty of water (see section 3, ‘How to take Ofev’).

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.

What Ofev contains
- The active substance is nintedanib. Each capsule contains 150 mg nintedanib (as esilate).
- The other ingredients are:
Capsule fill:
Triglycerides, medium-chain, hard fat, soya lecithin (E322) (see section 2, under ‘Do not take Ofev’) Capsule shell: Gelatin, glycerol (85%), titanium dioxide (E171), iron oxide red (E172), iron oxide yellow (E172)

What Ofev looks like and contents of the pack
Ofev 150 mg capsules are brown-coloured, opaque, oblong soft-gelatin capsules (approx. 18 x 7 mm) marked on one side with the Boehringer Ingelheim company symbol and the figure “150”.

Two pack-sizes of Ofev 150 mg capsules are available:
- 30 × 1 soft capsules in aluminium/aluminium perforated unit dose blisters
- 60 × 1 soft capsules in aluminium/aluminium perforated unit dose blisters

Not all pack-sizes may be marketed.

Marketing Authorisation 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 any information about this medicine, please contact the local representative of the Marketing Authorisation Holder:

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

България
Бьорингер Ингелхайм РЦВ ГмбХ и Ко. КГ - клон България
Тел: +359 2 958 79 98

Luxembourg/Luxemburg
Boehringer Ingelheim SComm
Tél/Tel: +32 2 773 33 11

Česká republika
Boehringer Ingelheim spol. s r.o.
Tel: +420 234 655 111

Magyarország
Boehringer Ingelheim RCV GmbH & Co KG
Magyarországi Fióktelepe
Tel: +36 1 299 89 00

Danmark
Boehringer Ingelheim Danmark A/S
Tlf.: +45 39 15 88 88

Malta
Boehringer Ingelheim Ireland Ltd.
Tel: +353 1 295 9620
Deutschland
Boehringer Ingelheim Pharma GmbH & Co. KG
Tel: +49 (0) 800 77 90 900
Nederland
Boehringer Ingelheim B.V.
Tel: +31 (0) 800 22 55 889

Eesti
Boehringer Ingelheim RCV GmbH & Co KG
Eesti filiaal
Tel: +372 612 8000

Norge
Boehringer Ingelheim Danmark A/S NUF
Tlf: +47 66 76 13 00

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

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

France
Boehringer Ingelheim France S.A.S.
Tél: +33 3 26 50 45 33

Portugal
Boehringer Ingelheim Portugal, Lda.
Tel: +351 21 313 53 00

Hrvatska
Boehringer Ingelheim Zagreb d.o.o.
Tel: +385 1 2444 600

România
Boehringer Ingelheim RCV GmbH & Co KG
Viena - Sucursala Bucureşti
Tel: +40 21 302 2800

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

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

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

Κύπρος
Boehringer Ingelheim Ελλάς Μονοπρόσωπη A.E.
Tηλ: +30 2 10 89 06 300

Sverige
Boehringer Ingelheim AB
Tel: +46 8 721 21 00

Latvija
Boehringer Ingelheim RCV GmbH & Co KG
Latvijas filiāle
Tel: +371 67 240 011

This leaflet was last revised in

Detailed information on this medicine is available on the European Medicines Agency web site:
https://www.ema.europa.eu.

Vargatef capsules contain the active substance nintedanib. Nintedanib blocks the activity of a group of proteins which are involved in the development of new blood vessels that cancer cells need to supply them with food and oxygen. By blocking the activity of these proteins, nintedanib can help stop the growth and spread of the cancer.

This medicine is used in combination with another cancer medicine (docetaxel) to treat a cancer of the lung called non-small cell lung cancer (NSCLC). It is for adult patients whose NSCLC is of a certain type (“adenocarcinoma”) and who had already received one treatment with another medicine to treat this cancer but whose tumour started to grow again.

Do not take Vargatef
- if you are allergic to nintedanib, to peanut or soya, 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 had liver problems, if you have or had bleeding problems, particularly recent bleeding in the lung
- if you have or have had problems with your kidneys or if an increased amount of protein has been detected in your urine
- if you take blood-thinning medicines (such as warfarin, phenprocoumon, heparin or acetylsalicylic acid) to prevent blood clotting. Treatment with Vargatef may lead to a higher risk of bleeding
- if you have recently had a surgery or plan to have a surgery. Nintedanib may affect the way your wounds heal. Therefore treatment with Vargatef will usually be interrupted if you are having surgery. Your doctor will decide when to resume your 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 a blood vessel wall) or a tear in a blood vessel wall

Based on this information your doctor may carry out some blood tests, for example to check your liver function and to determine how fast your blood can clot. Your doctor will discuss the results of these tests with you and decide whether you can be given Vargatef.

Inform your doctor immediately while taking this medicine
- if you get diarrhoea. Treatment of diarrhoea at the first signs is important (see section 4)
- if you vomit or feel sick (nausea)
- if you have unexplained symptoms such as yellowing of your skin or the white part of your eyes (jaundice), dark or brown (tea coloured) urine, pain on the upper right side of your stomach area (abdomen), bleeding or bruising more easily than normal, or feeling tired. This could be symptoms of serious liver problems
- if you develop fever, chills, fast breathing or a fast heartbeat. These could be signs of infection or infection of the blood (sepsis) (see section 4)
- if you experience severe pain in your stomach area, fever, chills, sickness, vomiting, or abdominal rigidity or bloating, as these could be symptoms of a hole in the wall of your gut (‘gastrointestinal perforation’)
- if you experience a combination of some or all of the symptoms thereafter: sudden severe abdominal pain or cramping, red blood in your stool, diarrhea or constipation, nausea and vomiting as these could be symptoms of a bowel inflammation from reduced blood flow (‘ischaemic colitis’)
- if you experience pain, swelling, reddening, warmth of a limb or if you experience chest pain and difficulty to breathe as these could be symptoms of a blood clot in one of your veins
- if you have any major bleeding
- if you experience chest pressure or pain, typically on the left side of the body, pain in the neck, jaw, shoulder or arm, a fast heartbeat, shortness of breath, nausea, vomiting, as this could be symptoms of a heart attack
- if you experience symptoms such as headache, vision changes, confusion, seizure or other neurologic disturbances such as weakness in an arm or a leg, with or without high blood pressure. This could be symptoms of a brain condition called posterior reversible encephalopathy syndrome (PRES)
- if any side effect(s) you may get (see section 4) becomes serious

Children and adolescents
This medicine has not been studied in children or adolescents to treat a cancer of the lung (NSCLC) and is therefore not to be taken by children and adolescents below the age of 18 years.

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 can interact with certain other medicines. The following medicines may increase the blood levels of nintedanib, the active substance of Vargatef, and hence may increase the risk for side effects (see section 4):
- Ketoconazole (used to treat fungal infections)
- Erythromycin (used to treat bacterial infections)
The following medicines may decrease the blood levels of nintedanib and thus may lead to reduction of the effectiveness of Vargatef:
- Rifampicin (an antibiotic used to treat tuberculosis)
- Carbamazepine, phenytoin (used to treat seizures)
- St. John’s Wort (a herbal medicine to treat depression)

Pregnancy and breast-feeding
If you are pregnant or breast-feeding, 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 can harm your unborn baby and cause birth defects.

Contraception
▪
Women who can become pregnant must use a highly effective method of birth control to prevent pregnancy, when they start taking Vargatef, while they are taking Vargatef and for at least 3 months after stopping treatment.
▪
You should discuss the most appropriate methods of contraception for you with your doctor.
▪
Vomiting and/or diarrhoea or other gastrointestinal conditions can affect the absorption of oral hormonal contraceptives, such as birth control pills, and may reduce their effectiveness.
Therefore, if experiencing these, talk to your doctor to discuss an alternative more appropriate method of contraception.
▪
Tell your doctor or pharmacist immediately if you become pregnant or think you may be pregnant during treatment with Vargatef.

Breast-feeding
It is not known if the medicine passes into breast milk and could cause harm to a breast-fed child.
Therefore, women should not breast-feed during treatment with Vargatef.

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

Driving and using machines
Vargatef may have minor influence on your ability to drive and use machines. You should not drive or use machines if you feel sick.

Vargatef contains soya
The capsules contain soya lecithin. If you are allergic to peanut or soya, do not use this medicine.

Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor or pharmacist if you are not sure.

Do not take Vargatef on the same day as your chemotherapy treatment with docetaxel.

Swallow the capsules whole with water and do not chew them. It is recommended to take the capsules with food, i.e. during or immediately before or after a meal.
Do not open or crush the capsule (see section 5).

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

This daily dose should be split into two doses of two capsules about 12 hours apart, for example two capsules in the morning and two capsules in the evening. These two doses should be taken at around the same time each day. Taking the medicine this way ensures that a steady amount of nintedanib is maintained in the body.

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

Your doctor may reduce your recommended dose to 300 mg per day (two capsules of 150 mg). In this

case your doctor will prescribe Vargatef 150 mg soft capsules for your treatment.

If necessary, your doctor may further reduce your daily dose to 200 mg per day (two capsules of 100 mg). You will be prescribed the appropriate capsule strength by your doctor if this happens.

In both cases, you should take one capsule of the appropriate strength twice daily approximately 12 hours apart with food (for example in the morning and in the evening) at about the same time of the day.

In case your doctor has stopped your chemotherapy with docetaxel you should continue to take 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 a forgotten dose. Take your next dose of Vargatef as planned at the next scheduled time and at the dose recommended by your doctor or pharmacist.

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

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

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

You need to pay special attention if you get the following side effects during treatment with Vargatef:

▪
Diarrhoea (very common, may affect more than 1 in 10 people)
Diarrhoea may lead to a loss of fluid and important salts (electrolytes, such as sodium or potassium) in your body. At the first signs of diarrhoea drink plenty of fluids and contact your doctor immediately.
Start appropriate anti-diarrhoeal treatment, e.g. with loperamide, as soon as possible after having contacted your doctor.

▪
Febrile neutropenia and sepsis (common, may affect up to 1 in 10 people)
Treatment with Vargatef may lead to a reduced number of a type of your white blood cells (neutropenia) which are important for the body’s reaction against bacterial or fungal infections. As a consequence of neutropenia, fever (febrile neutropenia) and blood infection (sepsis) may occur. Tell your doctor immediately if you develop fever, chills, fast breathing or a fast heartbeat.
During treatment with Vargatef your doctor will regularly monitor your blood cells and examine you for signs of infection, such as inflammation, fever or tiredness.

The following side effects were observed under treatment with this medicine:

Very common side effects (may affect more than 1 in 10 people)
▪
Diarrhoea – please see above
▪
Painful, numb and/or tingling feeling in fingers and toes (peripheral neuropathy) ▪ Feeling sick (nausea) ▪ Throwing up (vomiting) ▪ Pain in the stomach (abdomen) ▪ 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 ▪ Decreased appetite ▪ Electrolyte imbalance ▪ Increased liver enzyme values (alanine aminotransferase, aspartate aminotransferase, blood alkaline phosphatase) in the blood as seen from blood tests ▪ Hair loss (alopecia)

Common side effects (may affect up to 1 in 10 people)
▪
Blood poisoning (sepsis) – please 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 of a limb), which may travel through blood vessels to the lungs causing chest pain and difficulty in breathing (if you notice any of these symptoms, seek medical advice immediately) ▪ High blood pressure (hypertension) ▪ Fluid loss (dehydration) ▪ Abscesses ▪ Low platelet count (thrombocytopenia) ▪ Jaundice (hyperbilirubinaemia) ▪ Increased liver enzyme values (gamma-glutamyltransferase) in the blood as seen from blood tests ▪ Weight loss ▪ Itching ▪ Headache ▪ Increased amount of protein in your urine (proteinuria)

Uncommon side effects (may affect up to 1 in 100 people)
▪
Occurrence of holes in the wall of your gut (gastrointestinal perforation)
▪
Serious liver problems
▪
Inflammation of the pancreas (pancreatitis)
▪
Myocardial infarction
▪
Renal failure

Not known (cannot be estimated from the available data)
▪
Inflammation of the large bowel
▪
An enlargement and weakening of a blood vessel wall or a tear in a blood vessel wall (aneurysms and artery dissections) ▪ A brain condition with symptoms such as headache, vision changes, confusion, seizure or other neurologic disturbances such as weakness in an arm or a leg, with or without high blood pressure (posterior reversible encephalopathy syndrome)

Reporting of side effects
If you get 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 via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine.

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, wrapper and blisters. The expiry date refers to the last day of that month.

Do not store above 25 °C.
Store in the original package in order to protect from moisture.

Do not use this medicine if you notice that the blister containing the capsules is opened or a capsule is broken.
If you are in contact with the content of the capsule, wash off your hands immediately with plenty of water (see section 3).

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.

What Vargatef contains
The active substance is nintedanib. Each soft capsule contains 100 mg nintedanib (as esilate).

The excipients are:
Capsule content: Triglycerides medium-chain, hard fat, soya lecithin (E322)
Capsule shell:
Gelatin, glycerol (85%), titanium dioxide (E171), iron oxide red (E172), iron oxide yellow (E172)

What Vargatef looks like and contents of the pack
Vargatef 100 mg soft capsules (capsules) are peach-coloured, opaque, oblong capsules (approx. 16 x 6 mm) marked on one side with the Boehringer Ingelheim company symbol and the figure “100”.

Three pack-sizes of Vargatef 100 mg soft capsules are available:
▪
One box containing 60 capsules (6 aluminium blisters of 10 capsules each).
▪
One box containing 120 capsules (12 aluminium blisters of 10 capsules each).
▪
A multipack containing 120 capsules (2 boxes of 60 capsules each, bundled together by a wrapping foil).

Not all pack sizes of Vargatef 100 mg soft capsules may be marketed.

Marketing Authorisation 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 any information about this medicine, please contact the local representative of the Marketing Authorisation Holder:

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

България
Бьорингер Ингелхайм РЦВ ГмбХ и Ко. КГ - клон България
Тел: +359 2 958 79 98

Luxembourg/Luxemburg
Boehringer Ingelheim SComm
Tél/Tel: +32 2 773 33 11

Česká republika
Boehringer Ingelheim spol. s r.o.
Tel: +420 234 655 111

Magyarország
Boehringer Ingelheim RCV GmbH & Co KG
Magyarországi Fióktelepe
Tel: +36 1 299 89 00

Danmark
Boehringer Ingelheim Danmark A/S
Tlf.: +45 39 15 88 88

Malta
Boehringer Ingelheim Ireland Ltd.
Tel: +353 1 295 9620
Deutschland
Boehringer Ingelheim Pharma GmbH & Co. KG
Tel: +49 (0) 800 77 90 900
Nederland
Boehringer Ingelheim B.V.
Tel: +31 (0) 800 22 55 889

Eesti
Boehringer Ingelheim RCV GmbH & Co KG
Eesti filiaal
Tel: +372 612 8000

Norge
Boehringer Ingelheim Danmark A/S NUF
Tlf: +47 66 76 13 00

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

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

France
Boehringer Ingelheim France S.A.S.
Tél: +33 3 26 50 45 33

Portugal
Boehringer Ingelheim Portugal, Lda.
Tel: +351 21 313 53 00

Hrvatska
Boehringer Ingelheim Zagreb d.o.o.
Tel: +385 1 2444 600

România
Boehringer Ingelheim RCV GmbH & Co KG
Viena - Sucursala Bucureşti
Tel: +40 21 302 2800

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

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

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

Κύπρος
Boehringer Ingelheim Ελλάς Μονοπρόσωπη A.E.
Tηλ: +30 2 10 89 06 300

Sverige
Boehringer Ingelheim AB
Tel: +46 8 721 21 00

Latvija
Boehringer Ingelheim RCV GmbH & Co KG
Latvijas filiāle
Tel: +371 67 240 011

This leaflet was last revised in

Detailed information on this medicine is available on the European Medicines Agency web site:
https://www.ema.europa.eu/.

Vargatef capsules contain the active substance nintedanib. Nintedanib blocks the activity of a group of proteins which are involved in the development of new blood vessels that cancer cells need to supply them with food and oxygen. By blocking the activity of these proteins, nintedanib can help stop the growth and spread of the cancer.

This medicine is used in combination with another cancer medicine (docetaxel) to treat a cancer of the lung called non-small cell lung cancer (NSCLC). It is for adult patients whose NSCLC is of a certain type (“adenocarcinoma”) and who had already received one treatment with another medicine to treat this cancer but whose tumour started to grow again.

Do not take Vargatef
- if you are allergic to nintedanib, to peanut or soya, 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 had liver problems, if you have or had bleeding problems, particularly recent bleeding in the lung
- if you have or have had problems with your kidneys or if an increased amount of protein has been detected in your urine
- if you take blood-thinning medicines (such as warfarin, phenprocoumon, heparin or acetylsalicylic acid) to prevent blood clotting. Treatment with Vargatef may lead to a higher risk of bleeding
- if you have recently had a surgery or plan to have a surgery. Nintedanib may affect the way your wounds heal. Therefore treatment with Vargatef will usually be interrupted if you are having surgery. Your doctor will decide when to resume your 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 a blood vessel wall) or a tear in a blood vessel wall

Based on this information your doctor may carry out some blood tests, for example to check your liver function and to determine how fast your blood can clot. Your doctor will discuss the results of these tests with you and decide whether you can be given Vargatef.

Inform your doctor immediately while taking this medicine
- if you get diarrhoea. Treatment of diarrhoea at the first signs is important (see section 4)
- if you vomit or feel sick (nausea)
- if you have unexplained symptoms such as yellowing of your skin or the white part of your eyes (jaundice), dark or brown (tea coloured) urine, pain on the upper right side of your stomach area (abdomen), bleeding or bruising more easily than normal, or feeling tired. This could be symptoms of serious liver problems
- if you develop fever, chills, fast breathing or a fast heartbeat. These could be signs of infection or infection of the blood (sepsis) (see section 4)
- if you experience severe pain in your stomach area, fever, chills, sickness, vomiting, or abdominal rigidity or bloating, as these could be symptoms of a hole in the wall of your gut (‘gastrointestinal perforation’)
- if you experience a combination of some or all of the symptoms thereafter: sudden severe abdominal pain or cramping, red blood in your stool, diarrhea or constipation, nausea and vomiting as these could be symptoms of a bowel inflammation from reduced blood flow (‘ischaemic colitis’)
- if you experience pain, swelling, reddening, warmth of a limb or if you experience chest pain and difficulty to breathe as these could be symptoms of a blood clot in one of your veins
- if you have any major bleeding
- if you experience chest pressure or pain, typically on the left side of the body, pain in the neck, jaw, shoulder or arm, a fast heartbeat, shortness of breath, nausea, vomiting, as this could be symptoms of a heart attack
- if you experience symptoms such as headache, vision changes, confusion, seizure or other neurologic disturbances such as weakness in an arm or a leg, with or without high blood pressure. This could be symptoms of a brain condition called posterior reversible encephalopathy syndrome (PRES)
- if any side effect(s) you may get (see section 4) becomes serious

Children and adolescents
This medicine has not been studied in children or adolescents to treat a cancer of the lung (NSCLC) and is therefore not to be taken by children and adolescents below the age of 18 years.

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 can interact with certain other medicines. The following medicines may increase the blood levels of nintedanib, the active substance of Vargatef, and hence may increase the risk for side effects (see section 4):
- Ketoconazole (used to treat fungal infections)
- Erythromycin (used to treat bacterial infections)
The following medicines may decrease the blood levels of nintedanib and thus may lead to reduction of the effectiveness of Vargatef:
- Rifampicin (an antibiotic used to treat tuberculosis)
- Carbamazepine, phenytoin (used to treat seizures)
- St. John’s Wort (a herbal medicine to treat depression)

Pregnancy and breast-feeding
If you are pregnant or breast-feeding, 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 can harm your unborn baby and cause birth defects.

Contraception
▪
Women who can become pregnant must use a highly effective method of birth control to prevent pregnancy, when they start taking Vargatef, while they are taking Vargatef and for at least 3 months after stopping treatment.
▪
You should discuss the most appropriate methods of contraception for you with your doctor.
▪
Vomiting and/or diarrhoea or other gastrointestinal conditions can affect the absorption of oral hormonal contraceptives, such as birth control pills, and may reduce their effectiveness.
Therefore, if experiencing these, talk to your doctor to discuss an alternative more appropriate method of contraception.
▪
Tell your doctor or pharmacist immediately if you become pregnant or think you may be pregnant during treatment with Vargatef.

Breast-feeding
It is not known if the medicine passes into breast milk and could cause harm to a breast-fed child.
Therefore, women should not breast-feed during treatment with Vargatef.

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

Driving and using machines
Vargatef may have minor influence on your ability to drive and use machines. You should not drive or use machines if you feel sick.

Vargatef contains soya
The capsules contain soya lecithin. If you are allergic to peanut or soya, do not use this medicine.

Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor or pharmacist if you are not sure.

Do not take Vargatef on the same day as your chemotherapy treatment with docetaxel.

Swallow the capsules whole with water and do not chew them. It is recommended to take the capsule with food, i.e. during or immediately before or after a meal.
Do not open or crush the capsule (see section 5).

The recommended dose is two capsules per day (this is a total of 300 mg nintedanib per day). Do not take more than this dose.

This daily dose should be split into two doses of one capsule about 12 hours apart, for example one capsule in the morning and one capsule in the evening. The two doses should be taken at around the same time each day. Taking the medicine this way ensures that a steady amount of nintedanib is maintained in the body.

Dose reduction
If you cannot tolerate the recommended dose of 300 mg per day because of side effects (see section 4), your doctor may reduce your recommended daily dose of Vargatef to 200 mg per day (two capsules of 100 mg). In this case your doctor will prescribe Vargatef 100 mg soft capsules for your treatment.
You should take one capsule of this strength twice daily approximately 12 hours apart with food (for example in the morning and in the evening) at about the same time of the day.

Do not reduce the dose or stop the treatment yourself without consulting your doctor first.

In case your doctor has stopped your chemotherapy with docetaxel you should continue to take 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 a forgotten dose. Take your next dose of Vargatef as planned at the next scheduled time and at the dose recommended by your doctor or pharmacist.

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

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

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

You need to pay special attention if you get the following side effects during treatment with Vargatef:

▪
Diarrhoea (very common, may affect more than 1 in 10 people)
Diarrhoea may lead to a loss of fluid and important salts (electrolytes, such as sodium or potassium) in your body. At the first signs of diarrhoea drink plenty of fluids and contact your doctor immediately.
Start appropriate anti-diarrhoeal treatment, e.g. with loperamide, as soon as possible after having contacted your doctor.

▪
Febrile neutropenia and sepsis (common, may affect up to 1 in 10 people)
Treatment with Vargatef may lead to a reduced number of a type of your white blood cells (neutropenia) which are important for the body’s reaction against bacterial or fungal infections. As a consequence of neutropenia, fever (febrile neutropenia) and blood infection (sepsis) may occur. Tell your doctor immediately if you develop fever, chills, fast breathing or a fast heartbeat.
During treatment with Vargatef your doctor will regularly monitor your blood cells and examine you for signs of infection, such as inflammation, fever or tiredness.

The following side effects were observed under treatment with this medicine:

Very common side effects (may affect more than 1 in 10 people)
▪
Diarrhoea – please see above
▪
Painful, numb and/or tingling feeling in fingers and toes (peripheral neuropathy) ▪ Feeling sick (nausea) ▪ Throwing up (vomiting) ▪ Pain in the stomach (abdomen) ▪ 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 ▪ Decreased appetite ▪ Electrolyte imbalance ▪ Increased liver enzyme values (alanine aminotransferase, aspartate aminotransferase, blood

alkaline phosphatase) in the blood as seen from blood tests
▪
Hair loss (alopecia)

Common side effects (may affect up to 1 in 10 people)
▪
Blood poisoning (sepsis) – please 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 of a limb), which may travel through blood vessels to the lungs causing chest pain and difficulty in breathing (if you notice any of these symptoms, seek medical advice immediately) ▪ High blood pressure (hypertension) ▪ Fluid loss (dehydration) ▪ Abscesses ▪ Low platelet count (thrombocytopenia) ▪ Jaundice (hyperbilirubinaemia) ▪ Increased liver enzyme values (gamma-glutamyltransferase) in the blood as seen from blood tests ▪ Weight loss ▪ Itching ▪ Headache ▪ Increased amount of protein in your urine (proteinuria)

Uncommon side effects (may affect up to 1 in 100 people)
▪
Occurrence of holes in the wall of your gut (gastrointestinal perforation)
▪
Serious liver problems
▪
Inflammation of the pancreas (pancreatitis)
▪
Myocardial infarction
▪
Renal failure

Not known (cannot be estimated from the available data)
▪
Inflammation of the large bowel
▪
An enlargement and weakening of a blood vessel wall or a tear in a blood vessel wall (aneurysms and artery dissections) ▪ A brain condition with symptoms such as headache, vision changes, confusion, seizure or other neurologic disturbances such as weakness in an arm or a leg, with or without high blood pressure (posterior reversible encephalopathy syndrome)

Reporting of side effects
If you get 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 via the national reporting system listed in Appendix V. By reporting side effects you can help provide more information on the safety of this medicine.

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 and blisters. The expiry date refers to the last day of that month.

Do not store above 25 °C.
Store in the original package in order to protect from moisture.

Do not use this medicine if you notice that the blister containing the capsules is opened or a capsule is broken.
If you are in contact with the content of the capsule, wash off your hands immediately with plenty of

water (see section 3).

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.

What Vargatef contains
The active substance is nintedanib. Each soft capsule contains 150 mg nintedanib (as esilate).

The excipients are:
Capsule content: Triglycerides medium-chain, hard fat, soya lecithin (E322)
Capsule shell:
Gelatin, glycerol (85%), titanium dioxide (E171), iron oxide red (E172), iron oxide yellow (E172)

What Vargatef looks like and contents of the pack
Vargatef 150 mg soft capsules (capsules) are brown-coloured, opaque, oblong capsules (approx. 18 x 7 mm) marked on one side with the Boehringer Ingelheim company symbol and the figure “150”.

One box contains 60 capsules (6 aluminium blisters of 10 capsules each).

Marketing Authorisation 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 any information about this medicine, please contact the local representative of the Marketing Authorisation Holder:

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

България
Бьорингер Ингелхайм РЦВ ГмбХ и Ко. КГ - клон България
Тел: +359 2 958 79 98

Luxembourg/Luxemburg
Boehringer Ingelheim SComm
Tél/Tel: +32 2 773 33 11

Česká republika
Boehringer Ingelheim spol. s r.o.
Tel: +420 234 655 111

Magyarország
Boehringer Ingelheim RCV GmbH & Co KG
Magyarországi Fióktelepe
Tel: +36 1 299 89 00

Danmark
Boehringer Ingelheim Danmark A/S
Tlf.: +45 39 15 88 88

Malta
Boehringer Ingelheim Ireland Ltd.
Tel: +353 1 295 9620
Deutschland
Boehringer Ingelheim Pharma GmbH & Co. KG
Tel: +49 (0) 800 77 90 900
Nederland
Boehringer Ingelheim B.V.
Tel: +31 (0) 800 22 55 889

Eesti
Boehringer Ingelheim RCV GmbH & Co KG
Eesti filiaal
Tel: +372 612 8000

Norge
Boehringer Ingelheim Danmark A/S NUF
Tlf: +47 66 76 13 00

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

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

France
Boehringer Ingelheim France S.A.S.
Tél: +33 3 26 50 45 33

Portugal
Boehringer Ingelheim Portugal, Lda.
Tel: +351 21 313 53 00

Hrvatska
Boehringer Ingelheim Zagreb d.o.o.
Tel: +385 1 2444 600

România
Boehringer Ingelheim RCV GmbH & Co KG
Viena - Sucursala Bucureşti
Tel: +40 21 302 2800

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

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

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

Κύπρος
Boehringer Ingelheim Ελλάς Μονοπρόσωπη A.E.
Tηλ: +30 2 10 89 06 300

Sverige
Boehringer Ingelheim AB
Tel: +46 8 721 21 00

Latvija
Boehringer Ingelheim RCV GmbH & Co KG
Latvijas filiāle
Tel: +371 67 240 011

This leaflet was last revised in

Detailed information on this medicine is available on the European Medicines Agency web site:
https://www.ema.europa.eu/.