Consumer medicine information

Ofev

Nintedanib

BRAND INFORMATION

Brand name

Ofev

Active ingredient

Nintedanib

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Ofev.

What is in this leaflet

This leaflet answers some common questions about Ofev.

It does not contain all the available information.

It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking Ofev against the benefits they expect it will have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

This leaflet was last updated on the date at the end of this leaflet. More recent information may be available. The latest Consumer Medicine Information is available from your pharmacist, doctor, or from www.medicines.org.au (Australia) and may contain important information about the medicine and its use of which you should be aware.

Keep this leaflet with the medicine. You may need to read it again.

What Ofev is used for

Ofev contains the active ingredient nintedanib (as esilate).

Nintedanib is a tyrosine kinase inhibitor that works by blocking the activity of a group of proteins which are involved in the building and the growth of blood vessels. These blood vessels are necessary to provide growing cancer cells with nutrients and oxygen. By blocking the activity of these proteins, nintedanib can inhibit the growth and the spread of cancer cells.

Ofev is used in combination with the chemotherapy docetaxel to treat a type of lung cancer called Non-Small Cell Lung Cancer (NSCLC). It is used in adult patients with a certain type of lung cancer called adenocarcinoma who have already received one treatment with another medicine to treat this cancer but whose tumour started to grow again.

Ofev is also used for the treatment of Idiopathic Pulmonary Fibrosis (IPF).

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.

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.

Ofev is also used for the treatment of Systemic Sclerosis associated Interstitial Lung Disease (SSc-ILD).

Systemic Sclerosis (SSc), also known as scleroderma, 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.

Ask your doctor if you have any questions about why this medicine has been prescribed for you. Your doctor may have prescribed it for another reason.

This medicine is available only with a doctor's prescription.

Before you take Ofev

When you must not take it

Do not take Ofev if you have an allergy to:

  • any medicine containing nintedanib esilate (the active ingredient)
  • soya or peanut (Ofev contains soya lecithin)
  • any of the other ingredients listed at the end of this leaflet.

Some of the symptoms of an allergic reaction may include:

  • shortness of breath
  • wheezing or difficulty breathing
  • swelling of the face, lips, tongue or other parts of the body
  • rash, itching or hives on the skin.

Do not take this medicine if you are pregnant, or think you may be pregnant or are planning to become pregnant. It may affect your developing baby if you take it during pregnancy (see section 'Before you start to take it' below).

Do not breastfeed if you are taking this medicine. The active ingredient in Ofev may pass into breast milk and there is a possibility that your baby might be affected.

Do not give this medicine to a child under the age of 18 years. Safety and effectiveness in children younger than 18 years has not been established.

Do not take this medicine after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering. If it has expired or is damaged, return it to your pharmacist for disposal.

If you are not sure whether you should start taking this medicine, talk to your doctor.

Before you start to take it

Tell your doctor if you have allergies to any other medicines, foods, preservatives or dyes.

Tell your doctor if you:

  • have or have had liver problems
  • have or have had problems with your kidneys or if an increased amount of protein has been detected in your urine
  • have or have had bleeding problems, particularly recent bleeding in the lung
  • take blood-thinning medicines (such as warfarin or heparin) to prevent blood clotting
  • have or have had cancer that has spread to the brain
  • have or have had heart problems (for example a heart attack)
  • have or have had an aneurysm (enlargement and weakening of a blood vessel wall) or a tear in a blood vessel (dissection)
  • have or have had a hole in the wall of your gut (gastrointestinal perforation)
  • have or have had peptic ulcers or diverticular disease (a condition which affects the wall of the large intestine)
  • take anti-inflammatory drugs (NSAIDs) (used for pain relief and to treat swelling) or steroids (used for inflammation and allergies).

Tell your doctor if you have had previous abdominal surgery or any other recent surgery. Ofev may affect the way your wounds heal. Your treatment with Ofev will usually be interrupted if you are having surgery. Your doctor will decide when to resume your treatment with this medicine.

If you have not told your doctor about any of the above, tell him/her before you start taking Ofev.

Before starting Ofev treatment, you must have a pregnancy test done to ensure you are not pregnant.

Talk to your doctor about effective methods of contraception.

You or your sexual partner must use a highly effective method of contraception to prevent pregnancy when starting Ofev treatment, during Ofev treatment and for at least 3 months after taking the last dose of Ofev.

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 you experience these, talk to your doctor to discuss an alternative more appropriate method of contraception.

Taking other medicines

Tell your doctor or pharmacist if you are taking any other medicines, including any that you get without a prescription from your pharmacy, supermarket or health food shop.

Some medicines and Ofev may interfere with each other. These include:

  • ketoconazole, a medicine used to treat fungal infections
  • erythromycin, a medicine used to treat bacterial infections
  • rifampicin, a medicine used to treat tuberculosis
  • carbamazepine or phenytoin, medicines used to treat fits or convulsions
  • herbal medicines derived from St John's Wort - (Hypericum perforatum).

These medicines may be affected by Ofev or may affect how well it works. You may need different amounts of your medicines, or you may need to take different medicines.

Your doctor and pharmacist have more information on medicines to be careful with or avoid while taking this medicine.

How to take Ofev

Follow all directions given to you by your doctor or pharmacist carefully. They may differ from the information contained in this leaflet.

If you do not understand the instructions on the box, ask your doctor or pharmacist for help.

How much to take

NON-SMALL CELL LUNG CANCER
The recommended dose of Ofev is two 100 mg capsules twice daily, about 12 hours apart (this is a total of 400 mg Ofev per day).

Your doctor may decrease your dose by 100 mg steps per day if you do not tolerate the dose prescribed.

IDIOPATHIC PULMONARY FIBROSIS, OTHER CHRONIC FIBROSING INTERSTITIAL LUNG DISEASES WITH A PROGRESSIVE PHENOTYPE, AND SYSTEMIC SCLEROSIS ASSOCIATED INTERSTITIAL LUNG DISEASE
The recommended dose of Ofev is one 150 mg capsule twice daily, about 12 hours apart (this is a total of 300 mg Ofev per day).

If you have problems with your liver or do not tolerate the dose prescribed, your doctor may decrease your dose to one 100 mg capsule twice daily.

If you get severe side effects, your doctor may interrupt your treatment and then re-start your treatment at a lower dose or may tell you to discontinue taking Ofev completely.

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

How to take it

Take the capsules with food.

Swallow the capsules whole with a full glass of water.

Do not chew, crush or open the capsules. If contact with the content of the capsule occurs, wash your hands immediately and thoroughly.

When to take it

NON-SMALL CELL LUNG CANCER

Ofev should be taken twice a day (about 12 hours apart) on days 2 to 21 of a standard 21-day docetaxel treatment cycle. Ofev must not be taken on the same day of docetaxel administration. That is, it should NOT be taken on day 1 of the treatment cycle.

IDIOPATHIC PULMONARY FIBROSIS, OTHER CHRONIC FIBROSING INTERSTITIAL LUNG DISEASES WITH A PROGRESSIVE PHENOTYPE, AND SYSTEMIC SCLEROSIS ASSOCIATED INTERSTITIAL LUNG DISEASE

Ofev should be taken twice a day (about 12 hours apart).

How long to take it

Continue taking your medicine for as long as your doctor tells you.

If you forget to take it

Do not take a double dose to make up for the dose that you missed. This may increase the chance of you getting an unwanted side effect.

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

If you are not sure what to do, ask your doctor or pharmacist.

If you have trouble remembering to take your medicine, ask your pharmacist for some hints.

If you take too much (overdose)

Immediately telephone your doctor or the Poisons Information Centre (telephone 13 11 26) for advice, or go to Emergency at the nearest hospital, if you think that you or anyone else may have taken too much Ofev. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

While you are taking Ofev

Things you must do

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are taking Ofev.

Tell any other doctors, dentists and pharmacists who treat you that you are taking this medicine.

If you go into hospital, tell the medical staff that you are taking this medicine.

If you or your partner becomes pregnant or if you think you or your partner may be pregnant while taking this medicine, tell your doctor immediately.

Keep all of your doctor's appointments so that your progress can be checked.

Things you must not do

Do not take Ofev to treat any other complaints unless your doctor tells you to.

Do not give your medicine to anyone else, even if they have the same condition as you.

Do not stop taking your medicine or lower the dosage without checking with your doctor.

If you do not take this medicine as prescribed by your doctor your cancer may resume growing again earlier.

Things to be careful of

Be careful driving or operating machinery until you know how Ofev affects you. No studies of the effects of Ofev on the ability to drive and operate machinery have been performed. You should not drive or operate machinery if you feel sick.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking Ofev.

All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical attention if you get some of the side effects.

Do not be alarmed by the following lists of side effects. You may not experience any of them.

Ask your doctor or pharmacist to answer any questions you may have.

Tell your doctor or pharmacist if you notice any of the following and they worry you:

  • nausea
  • vomiting
  • decreased appetite
  • weight decrease
  • abscesses (a swollen area containing pus)
  • mouth sores and inflammation
  • rash or itching
  • headache
  • hair loss.

Ofev may be associated with changes in your blood, urine or liver test results. Your doctor may want to perform tests from time to time to check on your progress and detect any unwanted side effects.

Tell your doctor immediately if you notice any of the following:

  • diarrhoea, treatment of diarrhoea at the first signs is important
  • any signs and symptoms of dehydration such as headache, dizziness, tiredness or decreased urine output
  • fever, chills, fast breathing or a fast heartbeat, these could be signs of infection or infection of the blood (sepsis)
  • severe pain in your stomach area, fever, chills, sickness, vomiting, or abdominal rigidity or bloating, this could be symptoms of a hole in the wall of your gut ('gastrointestinal perforation')
  • if you have a combination of severe pain or cramping in your stomach, red blood in your stool or diarrhoea as these could be symptoms of bowel inflammation from inadequate blood supply (ischaemic colitis)
  • passing little or no urine, swelling in your legs and feet or around your eyes, drowsiness, nausea, vomiting, breathlessness, loss of appetite and weakness. These could be signs or symptoms of kidney disease (renal failure) which could become serious and life threatening
  • pain, swelling, reddening, warmth of a limb, this could be symptoms of a blood clot in one of your veins (a type of blood vessel)
  • any major bleeding
  • severe upper stomach pain, often with nausea and vomiting, this could be symptoms of inflammation of the pancreas (pancreatitis)
  • bleeding or bruising more easily than normal, this could be signs of low blood platelet count (thrombocytopenia)
  • 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, this could be symptoms of a heart attack
  • any signs and symptoms of liver problems such as yellow skin or eyes and dark 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.

Diarrhoea is a very common side effect of Ofev and is sometimes severe. You may become dehydrated if you experience severe or persistent diarrhoea and this could become serious and life-threatening if untreated.

As soon as you notice any signs of diarrhoea, you should drink plenty of fluids and take anti-diarrhoeal medicine exactly as your doctor tells you to help treat your diarrhoea.

You must immediately ask your doctor for further advice if your diarrhoea becomes severe (with more than 4 bowel movements each day) or if your diarrhoea is not under control within 48 hours after taking the anti-diarrhoeal medicine.

Tell your doctor or pharmacist if you notice anything that is making you feel unwell.

Other side effects not listed above may also occur in some people.

After taking Ofev

Storage

Keep your capsules in the blister pack until it is time to take them to protect from moisture. If you take the capsules out of the pack they may not keep well.

Keep your capsules in a cool, dry place where the temperature stays below 25°C.

Do not store Ofev or any other medicine in the bathroom or near a sink. Do not leave it on a window sill or in the car. Heat and dampness can destroy some medicines.

Keep it where children cannot reach it. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Disposal

If your doctor tells you to stop taking this medicine or the expiry date has passed, ask your pharmacist what to do with any medicine that is left over.

Product description

What it looks like

Ofev is the brand name of your medicine.

Ofev is available in two strengths of capsules:

Ofev 100 mg - peach-coloured, opaque, oblong, soft gelatin capsules imprinted in black on one side with the Boehringer Ingelheim company logo and with "100". The capsules contain a bright yellow viscous suspension.

Ofev 150 mg - brown-coloured, opaque, oblong, soft gelatin capsules imprinted in black on one side with the Boehringer Ingelheim company logo and with "150". The capsules contain a bright yellow viscous suspension.

Ofev is available in blister packs of 60 capsules. Each pack contains 6 blister strips containing 10 capsules per strip.

Ingredients

Active ingredient:

Ofev 100 mg capsule contains 100 mg of nintedanib (as 120.40 mg nintedanib esilate).

Ofev 150 mg capsule contains 150 mg of nintedanib (as 180.60 mg nintedanib esilate).

Inactive ingredients:

Ofev capsules also contain the following ingredients:

  • medium chain triglycerides
  • hard fat
  • lecithin
  • gelatin
  • glycerol 85%
  • titanium dioxide
  • iron oxide red CI77491
  • iron oxide yellow CI77492.

Black printing ink containing:

  • iron oxide black CI77499
  • shellac
  • ethanol
  • propylene glycol.

Supplier

Ofev is supplied in Australia by:

Boehringer Ingelheim Pty Limited
ABN 52 000 452 308
Sydney, Australia
www.boehringer-ingelheim.com.au

This Consumer Medicine Information was updated in December 2021.

® Ofev is a registered trade mark of Boehringer Ingelheim.

© Boehringer Ingelheim Pty Limited 2021

Australian Registration Numbers:

Ofev 100 mg: AUST R 226065

Ofev 150 mg: AUST R 226068

Published by MIMS February 2022

BRAND INFORMATION

Brand name

Ofev

Active ingredient

Nintedanib

Schedule

S4

 

1 Name of Medicine

Nintedanib esilate.

2 Qualitative and Quantitative Composition

Ofev are soft gelatin capsules for oral administration containing 100 mg or 150 mg nintedanib (as nintedanib esilate).

Excipients with known effect.

Each Ofev 100 mg capsule contains 1.2 mg of soya lecithin.
Each Ofev 150 mg capsule contains 1.8 mg of soya lecithin.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Ofev 100 mg capsules are peach-coloured, opaque, oblong, soft gelatin capsules imprinted in black on one side with the Boehringer Ingelheim company logo and "100". The capsules contain a bright yellow viscous suspension.
Ofev 150 mg capsules are brown-coloured, opaque, oblong, soft gelatin capsules imprinted in black on one side with the Boehringer Ingelheim company logo and "150". The capsules contain a bright yellow viscous suspension.

4 Clinical Particulars

4.1 Therapeutic Indications

Ofev is indicated in combination with docetaxel for the treatment of patients with locally advanced, metastatic or recurrent non-small cell lung cancer (NSCLC) of adenocarcinoma tumour histology after failure of first line chemotherapy.
Ofev is indicated for the treatment of idiopathic pulmonary fibrosis (IPF).
Ofev is also indicated for the treatment of other chronic fibrosing interstitial lung diseases (ILDs) with a progressive phenotype.
Ofev is indicated for slowing the rate of decline in pulmonary function in patients with systemic sclerosis-associated interstitial lung disease (SSc-ILD).

4.2 Dose and Method of Administration

Method of administration.

Ofev capsules should be taken orally, preferably with food, swallowed whole with water, and should not be chewed.
If a dose is missed, administration should resume at the next scheduled time at the recommended dose. If a dose is missed, the patient should not be given an additional dose.
The capsule should not be opened or crushed. If contact with the content of the capsule occurs, hands should be washed immediately and thoroughly.

NSCLC.

Treatment with Ofev should be initiated and supervised by a physician experienced in the use of anticancer therapies.
The recommended dose of Ofev is 200 mg twice daily administered approximately 12 hours apart, on days 2 to 21 of a standard 21-day docetaxel treatment cycle.
Ofev must not be taken on the same day of docetaxel chemotherapy administration (= day 1).
The recommended maximum daily dose of 400 mg should not be exceeded.
Patients may continue therapy with Ofev after discontinuation of docetaxel for as long as clinical benefit is observed or until unacceptable toxicity occurs.
For dosage, method of administration and dose modifications of docetaxel, please refer to the corresponding product information for docetaxel.

IPF, other chronic fibrosing ILDs with a progressive phenotype, and SSc-ILD.

Treatment should be initiated by physicians experienced in the diagnosis and treatment of conditions for which Ofev is indicated.
The recommended dose of Ofev is 150 mg twice daily administered approximately 12 hours apart.
The recommended maximum daily dose of 300 mg should not be exceeded.

Dose adjustments.

NSCLC.

As initial measure for the management of adverse reactions (see Table 1 and Table 2) treatment with Ofev should be temporarily interrupted until the specific adverse reaction has resolved to levels that allow continuation of therapy (to grade 1 or baseline). Ofev treatment may be resumed at a reduced dose. Dose adjustments in 100 mg steps per day (i.e. a 50 mg reduction per dosing) based on individual safety and tolerability are recommended as described in Table 1 and Table 2.
In case of further persistence of the adverse reaction(s), i.e. if a patient does not tolerate 100 mg twice daily, treatment with Ofev should be permanently discontinued.
In case of specific elevations of AST/ALT values to > 3 x upper limit normal (ULN) in conjunction with an increase of total bilirubin to ≥ 2 x ULN and ALP < 2 x ULN (see Table 2) treatment with Ofev should be interrupted. Unless there is an alternative cause established, Ofev should be permanently discontinued (see Section 4.4 Special Warnings and Precautions for Use, Hepatic function).

IPF, other chronic fibrosing ILDs with a progressive phenotype, and SSc-ILD.

In addition to symptomatic treatment if applicable, the management of adverse reactions (see Section 4.4 Special Warnings and Precautions for Use; Section 4.8 Adverse Effects (Undesirable Effects)) of Ofev could include dose reduction and temporary interruption until the specific adverse reaction has resolved to levels that allow continuation of therapy. Ofev treatment may be resumed at the full dose (150 mg twice daily) or a reduced dose (100 mg twice daily). If a patient does not tolerate 100 mg twice daily, treatment with Ofev should permanently be discontinued.
In case of interruptions due to transaminase (AST or ALT) elevations > 3 x upper limit of normal (ULN), once transaminases have returned to baseline values, treatment with Ofev may be reintroduced at a reduced dose (100 mg twice daily) which subsequently may be increased to the full dose (150 mg twice daily) (see Section 4.4 Special Warnings and Precautions for Use; Section 4.8 Adverse Effects (Undesirable Effects)).

Special populations.

Paediatric population. The safety and efficacy of Ofev in paediatric patients have not been studied in clinical trials.
Elderly patients (≥ 65 years). No overall differences in safety and efficacy were observed for elderly patients compared to patients aged below 65 years. No adjustment of the initial dosing is required on the basis of a patient's age (see Section 5.2 Pharmacokinetic Properties).
Race. Based on population PK analyses, no a priori dose adjustments of Ofev are necessary (see Section 4.4 Special Warnings and Precautions for Use, Special populations; Section 5.2 Pharmacokinetic Properties). Safety data for Black patients are limited.
Body weight. Based on population PK analyses, no a priori dose adjustments of Ofev are necessary (see Section 5.2 Pharmacokinetic Properties).
Renal impairment. Less than 1% of a single dose of nintedanib is excreted via the kidney (see Section 5.2 Pharmacokinetic Properties). Adjustment of the starting dose in patients with mild to moderate renal impairment is not required. The safety, efficacy, and pharmacokinetics of nintedanib have not been studied in patients with severe renal impairment (< 30 mL/min CrCL).
Hepatic impairment. Nintedanib is predominantly eliminated via biliary/faecal excretion (> 90%). Exposure increased in patients with hepatic impairment (Child Pugh A, Child Pugh B; see Section 5.2 Pharmacokinetic Properties).
The safety and efficacy of nintedanib have not been investigated in patients with hepatic impairment classified as Child Pugh B and C. Treatment of patients with moderate (Child Pugh B) and severe (Child Pugh C) hepatic impairment with Ofev is not recommended (see Section 5.2 Pharmacokinetic Properties).

NSCLC.

No adjustment of the starting dose is needed for patients with mild hepatic impairment based on clinical data (Child Pugh A, see Section 4.4 Special Warnings and Precautions for Use).

IPF, other chronic fibrosing ILDs with a progressive phenotype, and SSc-ILD.

In patients with mild hepatic impairment (Child Pugh A), the recommended dose of Ofev is 100 mg twice daily approximately 12 hours apart. If adverse reactions occur, treatment interruption or treatment discontinuation should be considered.

4.3 Contraindications

Ofev is contraindicated in patients with known hypersensitivity to nintedanib, peanut or soya, or to any of the excipients.
Ofev is contraindicated during pregnancy (see Section 4.6 Fertility, Pregnancy and Lactation).

NSCLC.

For contraindications related to docetaxel please refer to the corresponding product information for docetaxel.

4.4 Special Warnings and Precautions for Use

Gastrointestinal disorders.

NSCLC.

Diarrhoea.

Diarrhoea was the most frequently reported gastrointestinal event (see Section 4.8 Adverse Effects (Undesirable Effects)). In the clinical trial LUME-Lung 1 (see Section 5.1 Pharmacodynamic Properties, Clinical trials), the majority of patients had mild to moderate diarrhoea. 6.3% of the patients had diarrhoea of grade ≥ 3 in combination treatment compared to 3.6% treated with docetaxel alone. Dehydration was reported in 1.9% of patients in the combination arm and in none of the patients treated with docetaxel alone. Diarrhoea should be treated at first signs with adequate hydration and anti-diarrhoeal medicinal products, e.g. loperamide, and may require interruption, dose reduction or discontinuation of therapy with Ofev (see Section 4.2 Dose and Method of Administration).

Nausea and vomiting.

Nausea and vomiting, mostly of mild to moderate severity, were frequently reported gastrointestinal adverse events (see Section 4.8 Adverse Effects (Undesirable Effects)). If symptoms persist despite appropriate supportive care (including anti-emetic therapy), dose reduction, treatment interruption or discontinuation of therapy with Ofev (see Section 4.2 Dose and Method of Administration) may be required.
Diarrhoea and vomiting may lead to dehydration with or without electrolyte disturbances which may progress to renal function impairment. In the event of dehydration, administration of electrolytes and fluids is required. Plasma levels of electrolytes should be monitored, if relevant gastrointestinal adverse events occur.
IPF, other chronic fibrosing ILDs with a progressive phenotype, and SSc-ILD.

Diarrhoea.

In the clinical trials (see Section 5.1 Pharmacodynamic Properties, Clinical trials), diarrhoea was the most frequent gastro-intestinal event reported. In most patients, the event was of mild to moderate intensity and occurred within the first 3 months of treatment. In the INPULSIS trials in patients with IPF, diarrhoea was reported in 62.4% versus 18.4% of patients treated with Ofev and placebo, respectively. Overall, adverse events led to dose reduction of Ofev in 15.8% of patients and to discontinuation of Ofev in 19.3% of patients. Diarrhoea led to dose reduction of Ofev in 10.7% of the patients and to discontinuation of Ofev in 4.4% of the patients. In the INBUILD trial in patients with other chronic fibrosing ILDs with a progressive phenotype, diarrhoea was reported in 66.9% versus 23.9% of patients treated with Ofev and placebo, respectively. Diarrhoea led to dose reduction of Ofev in 16.0% of the patients and to discontinuation of Ofev in 5.7% of the patients. In the SENSCIS trial in patients with SSc-ILD, diarrhoea was reported in 75.7% versus 31.6% of patients treated with Ofev and placebo, respectively. Overall, adverse events led to dose reduction of Ofev in 34.0% of patients and to discontinuation of Ofev in 16.0% of patients. Diarrhoea led to dose reduction of Ofev in 22.2% of the patients and to discontinuation of Ofev in 6.9% of the patients (see Section 4.8 Adverse Effects (Undesirable Effects)).
Diarrhoea should be treated at first signs with adequate hydration and anti-diarrhoeal medicinal products, e.g. loperamide, and may require dose reduction or treatment interruption. Ofev treatment may be resumed at a reduced dose (100 mg twice daily) or at the full dose (150 mg twice daily). In case of persisting severe diarrhoea despite symptomatic treatment, therapy with Ofev should be discontinued.

Nausea and vomiting.

Nausea and vomiting were frequently reported adverse events (see Section 4.8 Adverse Effects (Undesirable Effects)). In most patients with nausea and vomiting, the event was of mild to moderate intensity. In the INPULSIS trials, nausea led to discontinuation of Ofev in 2.0% of patients and vomiting led to discontinuation in 0.8% of the patients. In the INBUILD trial, the frequency of nausea and vomiting leading to Ofev discontinuation were 0.3% and 0.9%, respectively. In the SENSCIS trial, the frequency of nausea and vomiting leading to Ofev discontinuation were 2.1% and 1.4%, respectively.
If symptoms persist despite appropriate supportive care (including anti-emetic therapy), dose reduction or treatment interruption may be required. The treatment may be resumed at a reduced dose (100 mg twice daily) or at the full dose (150 mg twice daily). In case of persisting severe symptoms therapy with Ofev should be discontinued.
Diarrhoea and vomiting may lead to dehydration with or without electrolyte disturbances which may progress to renal function impairment.

Gastrointestinal perforations and ischaemic colitis.

Due to the mechanism of action nintedanib patients might have an increased risk of gastrointestinal perforations and ischaemic colitis. Cases of gastrointestinal perforations and cases of ischaemic colitis, some of which were fatal, have been reported in the post-marketing period. Particular caution should be exercised when treating patients with previous abdominal surgery, previous history of peptic ulceration, diverticular disease or receiving concomitant corticosteroids or NSAIDs. Ofev should only be initiated at least 4 weeks after abdominal surgery. Therapy with Ofev should be permanently discontinued in patients who develop gastrointestinal perforation or ischaemic colitis. Exceptionally, Ofev can be reintroduced after complete resolution of ischaemic colitis and careful assessment of patient's condition and other risk factors.

NSCLC.

The frequency of gastrointestinal perforation was comparable between the treatment arms in the LUME-Lung 1 study. Particular caution should be exercised when treating patients with previous abdominal surgery or a recent history of a hollow organ perforation.

IPF, other chronic fibrosing ILDs with a progressive phenotype, and SSc-ILD.

In the clinical trials no increased risk of gastrointestinal perforation was observed in Ofev treated patients. Particular caution should be exercised when treating patients with previous abdominal surgery, a recent history of a hollow organ perforation, previous history of peptic ulceration, diverticular disease or receiving concomitant corticosteroids or NSAIDs.

Renal function.

Cases of renal impairment/failure, in some cases with fatal outcome, have been reported with nintedanib use (see Section 4.8 Adverse Effects (Undesirable Effects)).
Patients should be monitored during nintedanib therapy, with particular attention to those patients exhibiting risk factors for renal impairment/failure. In case of renal impairment/failure, therapy adjustment should be considered (see Section 4.2 Dose and Method of Administration).

Neutropenia and sepsis.

NSCLC.

A higher frequency of neutropenia of CTCAE grade ≥ 3 was observed in patients treated with Ofev in combination with docetaxel as compared to treatment with docetaxel alone. Subsequent complications such as sepsis or febrile neutropenia have been observed. Febrile neutropenia was reported in 7.5% of patients in the combination arm compared to 4.5% of patients during treatment with docetaxel alone. Fatal sepsis was reported in 0.9% of patients treated with Ofev in combination with docetaxel. Fatal sepsis was not reported during treatment with docetaxel alone.
Blood counts should be monitored during therapy, in particular during the combination treatment with docetaxel. Frequent monitoring of complete blood counts should be performed at the beginning of each treatment cycle and around the nadir for patients receiving treatment with nintedanib in combination with docetaxel, and as clinically indicated after the administration of the last combination cycle.

Hepatic function.

Use in hepatic impairment. Subjects with baseline AST, ALT or bilirubin levels > 1.5 times the upper limit of normal were excluded from the pivotal studies. Based on increased exposure, the risk for adverse events may be increased in patients with mild hepatic impairment (Child Pugh A; see Section 4.2 Dose and Method of Administration; Section 5.2 Pharmacokinetic Properties). The safety and efficacy of Ofev has not been studied in patients with moderate (Child Pugh B) or severe (Child Pugh C) hepatic impairment. Therefore, treatment with Ofev is not recommended in such patients (see Section 5.2 Pharmacokinetic Properties).
Liver enzyme elevations and hyperbilirubinaemia. Cases of drug-induced liver injury have been observed with nintedanib treatment.

NSCLC.

In the post-marketing period, severe liver injury with fatal outcome has been reported. Administration of nintedanib was associated with an elevation of liver enzymes (ALT, AST, ALP) gamma-glutamyltransferase (GGT) and bilirubin. These increases were reversible upon dose reduction or interruption in the majority of cases. Liver related adverse events of grade ≥ 3 were reported in 15.3% of patients treated with the combination of Ofev and docetaxel compared to 1.8% of patients treated with docetaxel alone.
Transaminase, ALP and bilirubin levels should be investigated before the initiation of the combination treatment with Ofev plus docetaxel. The values should be monitored as clinically indicated or periodically during treatment, i.e. in the combination phase with docetaxel at the beginning of each treatment cycle and monthly in case Ofev is continued as monotherapy after discontinuation of docetaxel.
If relevant liver enzyme elevations are measured, interruption, dose reduction or discontinuation of the therapy with Ofev may be required (see Section 4.2 Dose and Method of Administration, Table 2). Alternative causes of the liver enzyme elevations should be investigated and respective action should be taken as necessary.
In case of specific changes in liver values (AST/ALT > 3 x ULN in conjunction with bilirubin ≥ 2 x ULN and ALP < 2 x ULN) treatment with Ofev should be interrupted. Unless there is an alternative cause established, Ofev should be permanently discontinued (see Section 4.2 Dose and Method of Administration, Table 2).
Female and Asian patients have a higher risk of elevations in liver enzymes. Nintedanib exposure increased linearly with patient age and was inversely correlated to weight which may also result in a higher risk of developing liver enzyme elevations (see Section 5.2 Pharmacokinetic Properties). Close monitoring is recommended in patients with these risk factors.

IPF, other chronic fibrosing ILDs with a progressive phenotype, and SSc-ILD.

Patients with mild hepatic impairment (Child Pugh A) should be treated with a reduced dose of Ofev (see Section 4.2 Dose and Method of Administration; Section 5.2 Pharmacokinetic Properties).
In the post-marketing period, non-serious and serious cases of drug-induced liver injury, including severe liver injury with fatal outcome, have been reported. Administration of nintedanib was associated with elevations of liver enzymes (ALT, AST, ALP, gamma-glutamyl-transferase (GGT)) and bilirubin. In the INPULSIS trials, liver enzyme elevations were reported in 13.6% versus 2.6% of nintedanib patients treated with Ofev and placebo, respectively. In the SENSCIS trial, liver enzyme elevations were reported in 13.2% versus 3.1% of patients treated with Ofev and placebo, respectively. Elevations of liver enzymes were reversible and not associated with clinically manifest liver disease. The majority of hepatic events occur within the first three months of treatment. Therefore, hepatic transaminase and bilirubin levels should be investigated before the initiation of treatment with Ofev, at regular intervals during the first three months of treatment and periodically thereafter (e.g. at each patient visit) or as clinically indicated.
Elevations of liver enzymes (ALT, AST, ALP, gamma-glutamyl-transferase (GGT)) and bilirubin were reversible upon dose reduction or interruption in the majority of cases. If transaminase (AST or ALT) elevations > 3 x upper limit of normal (ULN) are measured, dose reduction or interruption of the therapy with Ofev is recommended and the patient should be monitored closely. Once transaminases have returned to baseline values, treatment with Ofev may be re-increased to the full dose (150 mg twice daily) or reintroduced at a reduced dose (100 mg twice daily) which subsequently may be increased to the full dose (see Section 4.2 Dose and Method of Administration). If any liver test elevations are associated with clinical signs or symptoms of liver injury, e.g. jaundice, treatment with Ofev should be permanently discontinued. Alternative causes of the liver enzyme elevations should be investigated.
Patients with low body weight (< 65 kg), Asian and female patients have a higher risk of elevations in liver enzymes. Nintedanib exposure increased linearly with patient age, which may also result in a higher risk of developing liver enzyme elevations (see Section 5.2 Pharmacokinetic Properties). Close monitoring is recommended in patients with these risk factors.

Haemorrhage.

NSCLC. VEGFR inhibition might be associated with an increased risk of bleeding. In the clinical trial LUME-Lung 1 with Ofev, the frequency of bleeding in both treatment arms was comparable. Mild to moderate epistaxis represented the most frequent bleeding event. There were no imbalances of respiratory or fatal bleedings and no intracerebral bleeding was reported. The majority of fatal bleeding events were tumour-associated.
In the post-marketing period non-serious and serious bleeding events, some of which were fatal, have been observed. In patients who experience grade 3/4 bleeding events, the benefits and risks of continuing treatment with Ofev should be carefully weighed and discontinuation of Ofev may be considered. If treatment with Ofev is resumed, a reduced daily dose is recommended (see Section 4.2 Dose and Method of Administration, Table 1).
Patients with recent pulmonary bleeding (> 2.5 mL of red blood) as well as patients with centrally located tumours with radiographic evidence of local invasion of major blood vessels or radiographic evidence of cavitary or necrotic tumours have been excluded from clinical trials. Therefore, it is not recommended to treat these patients with Ofev.
Brain metastasis.

Stable brain metastasis.

No increased frequency of cerebral bleeding in patients with adequately pre-treated brain metastases which were stable for ≥ 4 weeks before start of treatment with Ofev was observed. However, such patients should be closely monitored for signs and symptoms of cerebral bleeding.

Active brain metastasis.

Patients with active brain metastasis were excluded from clinical trials and are not recommended for treatment with Ofev.
Therapeutic anticoagulation. There are no data available for patients with inherited predisposition to bleeding or for patients receiving a full dose of anticoagulative treatment prior to start of treatment with Ofev. In patients on chronic low dose therapy with low molecular weight heparins or acetylsalicylic acid, no increased frequency of bleeding was observed. Patients who developed thromboembolic events during treatment and who required anticoagulant treatment were allowed to continue Ofev and did not show an increased frequency of bleeding events. Patients taking concomitant anticoagulation, such as warfarin should be monitored regularly for changes in prothrombin time, INR, or clinical bleeding episodes.

IPF, other chronic fibrosing ILDs with a progressive phenotype, and SSc-ILD.

VEGFR inhibition might be associated with an increased risk of bleeding.
In the clinical trials with Ofev, the frequency of patients who experienced bleeding adverse events was slightly higher in patients treated with Ofev or comparable between the treatment arms (Ofev 10.3% versus placebo 7.8% for INPULSIS; Ofev 11.1% versus placebo 12.7% for INBUILD; Ofev 11.1% versus placebo 8.3% for SENSCIS). Non-serious epistaxis was the most frequent bleeding event reported. Serious bleeding events occurred with low frequencies in the 2 treatment groups (Ofev 1.3% versus placebo 1.4% for INPULSIS; Ofev 0.9% versus placebo 1.5% for INBUILD; Ofev 1.4% versus placebo 0.7% for SENSCIS).
Patients at known risk for bleeding including patients with inherited predisposition to bleeding or patients receiving a full dose of anticoagulative treatment were not included in clinical trials. Cases of haemorrhage have been reported in postmarketing period (including patients with or without anticoagulant therapy or other drugs that could cause bleeding). Therefore, these patients should only be treated with Ofev if the anticipated benefit outweighs the potential risk. In the post-marketing period non-serious and serious bleeding events, some of which were fatal, have been observed.

Arterial thromboembolic events.

Use caution when treating patients with a higher cardiovascular risk including known coronary artery disease. Treatment interruption should be considered in patients who develop signs or symptoms of acute myocardial ischaemia.

NSCLC.

The frequency of arterial thromboembolic events was comparable between the two treatment arms in the phase III study 1199.13 (LUME-Lung 1). Patients with a recent history of myocardial infarction or stroke were excluded from this study. However, an increased frequency of arterial thromboembolic events was observed in patients with IPF when treated with nintedanib monotherapy.

IPF, other chronic fibrosing ILDs with a progressive phenotype, and SSc-ILD.

Patients with a recent history of myocardial infarction or stroke were excluded from the clinical trials.
In the clinical trials, arterial thromboembolic events were infrequently reported (Ofev 2.5% versus placebo 0.7% for INPULSIS; Ofev 0.9% versus placebo 0.9% for INBUILD; Ofev 0.7% versus placebo 0.7% for SENSCIS). In the INPULSIS trials, a higher percentage of patients experienced myocardial infarctions in the Ofev group (1.6%) compared to the placebo group (0.5%), while adverse events reflecting ischaemic heart disease were balanced between the Ofev and placebo groups. In the INBUILD and the SENSCIS trial myocardial infarction was observed with low frequency: Ofev 0.9% versus placebo 0.9% for INBUILD; Ofev 0% versus placebo 0.7% for SENSCIS.

Aneurysms and artery dissections.

The use of VEGF pathway inhibitors in patients with or without hypertension may promote the formation of aneurysms and/or artery dissections. Before initiating nintedanib, this risk should be carefully considered in patients with risk factors such as hypertension or history of aneurysm.

Venous thromboembolism.

NSCLC.

Patients treated with Ofev have an increased risk of venous thromboembolism including deep vein thrombosis. Patients should be closely monitored for thromboembolic events. Ofev should be discontinued in patients with life-threatening venous thromboembolic reactions.

IPF, other chronic fibrosing ILDs with a progressive phenotype, and SSc-ILD.

In the clinical trials, no increased risk of venous thromboembolism was observed in Ofev treated patients. Due to the mechanism of action of nintedanib patients might have an increased risk of thromboembolic events.

Nephrotic range proteinuria.

Very few cases of nephrotic range proteinuria have been reported post-marketing. Histological findings in individual cases were consistent with glomerular microangiopathy with or without renal thrombi. Reversal of symptoms has been observed after Ofev was discontinued. Treatment interruption should be considered in patients who develop signs or symptoms of nephrotic syndrome.

Pulmonary hypertension.

Other chronic fibrosing ILDs with a progressive phenotype and SSc-ILD.

Data on the use of Ofev in patients with pulmonary hypertension is limited. Patients with significant pulmonary hypertension (cardiac index ≤ 2 L/min/m2, or parenteral epoprostenol/treprostinil, or significant right heart failure) were excluded from the INBUILD and SENSCIS trials. Ofev should not be used in patients with severe pulmonary hypertension. Close monitoring is recommended in patients with mild to moderate pulmonary hypertension.

Wound healing complication.

Based on the mechanism of action nintedanib may impair wound healing. No increased frequency of impaired wound healing was observed in the clinical trials. No dedicated studies investigating the effect of nintedanib on wound healing were performed. Treatment with Ofev should therefore only be initiated, or in case of perioperative interruption, resumed based on clinical judgement of adequate wound healing.

Soya lecithin.

Ofev soft capsules contain soya lecithin (see Section 4.3 Contraindications).

Special populations.

In study 1199.13 (LUME-Lung 1), there was a higher frequency of serious adverse events in patients treated with Ofev plus docetaxel with a body weight of less than 50 kg compared to patients with a weight ≥ 50 kg; however, the number of patients with a body weight of less than 50 kg was small. Therefore, close monitoring is recommended in patients weighing < 50 kg.

Docetaxel.

For precautions related to docetaxel please refer to the corresponding product information for docetaxel.

Use in the elderly.

See Section 4.2 Dose and Method of Administration, Special populations, Elderly patients (≥ 65 years); Section 5.2 Pharmacokinetic Properties, Intrinsic and extrinsic factors; special populations, Age.

Paediatric use.

See Section 4.2 Dose and Method of Administration, Special populations, Paediatric population; Section 5.2 Pharmacokinetic Properties, Intrinsic and extrinsic factors; special populations, Age.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

P-glycoprotein (P-gp).

Nintedanib is a substrate of P-gp (see Section 5.2 Pharmacokinetic Properties). Co-administration with the potent P-gp inhibitor ketoconazole increased exposure to nintedanib 1.61-fold based on AUC and 1.83-fold based on Cmax in a dedicated drug-drug interaction study.
In a drug-drug interaction study with the potent P-gp inducer rifampicin, exposure to nintedanib decreased by 50% based on AUC and by 40% based on Cmax upon co-administration with rifampicin compared to administration of nintedanib alone.
If co-administered with Ofev, potent P-gp inhibitors (e.g. ketoconazole or erythromycin) may increase exposure to nintedanib. In such cases, patients should be monitored closely for tolerability of nintedanib. Management of adverse reactions may require interruption, dose reduction, or discontinuation of therapy with Ofev (see Section 4.2 Dose and Method of Administration).
Potent P-gp inducers (e.g. rifampicin, carbamazepine, phenytoin, and St. John's wort) may decrease exposure to nintedanib. Selection of an alternate concomitant medication with no or minimal P-gp induction potential should be considered.

Food.

Ofev is recommended to be taken with food (see Section 5.2 Pharmacokinetic Properties).

Cytochrome (CYP)-enzymes.

Only a minor extent of the biotransformation of nintedanib consisted of CYP pathways. Nintedanib and its metabolites, the free acid moiety BIBF 1202 and its glucuronide BIBF 1202 glucuronide, did not inhibit or induce CYP enzymes in preclinical studies (see Section 5.2 Pharmacokinetic Properties). The likelihood of drug-drug interactions with nintedanib based on CYP metabolism is therefore considered to be low.

Co-administration with other drugs.

Co-administration of nintedanib with an oral hormonal contraceptive containing ethinylestradiol and levonorgestrel did not alter the pharmacokinetics of ethinylestradiol and levonorgestrel to a relevant extent in patients with SSc-ILD (see Section 5.2 Pharmacokinetic Properties).

NSCLC.

Co-administration of nintedanib with docetaxel (75 mg/m2) did not alter the pharmacokinetics of either drug to a relevant extent.

IPF, other chronic fibrosing ILDs with a progressive phenotype, and SSc-ILD.

For co-administration of nintedanib with pirfenidone (see Section 5.2 Pharmacokinetic Properties).
Co-administration of nintedanib with bosentan did not alter the pharmacokinetics of nintedanib (see Section 5.2 Pharmacokinetic Properties).

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Based on preclinical investigations, there is no evidence for impairment of male fertility. A study of male fertility and early embryonic development up to implantation in rats at 100 mg/kg/day did not reveal effects on the male reproductive tract and male fertility. In the same species, nintedanib reduced female fertility at 100 mg/kg/day (slightly above the clinical exposure on an AUC basis), and increased early resorptions at ≥ 20 mg/kg/day (below clinical exposure based on AUC). Ovarian follicles and corpora lutea (increased luteinised follicles and increased number and decreased size of corpora lutea) were adversely affected in mice and rats at subclinical exposures.
(Category D)
There is no information on the use of Ofev in pregnant women, but pre-clinical studies in animals have shown reproductive toxicity of this drug.
As nintedanib may cause fetal harm also in humans, it must not be used during pregnancy (see Section 4.3 Contraindications) and pregnancy testing must be conducted prior to treatment with Ofev and during treatment as appropriate. Female patients should be advised to notify their doctor or pharmacist if they become pregnant during therapy with Ofev. If the patient becomes pregnant while receiving Ofev treatment must be discontinued and the patient should be apprised of the potential hazard to the fetus.
Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with Ofev and to use highly effective contraceptive methods at initiation of, during and at least 3 months after the last dose of Ofev. Co-administration of nintedanib has no relevant effect on the plasma exposure of ethinylestradiol and levonorgestrel in patients with SSc-ILD (see Section 5.2 Pharmacokinetic Properties). The efficacy of oral hormonal contraceptives may be compromised by vomiting and/or diarrhoea or other conditions where the absorption may be affected. Women taking oral hormonal contraceptives experiencing these conditions should be advised to use an alternative highly effective contraceptive measure.

NSCLC.

In rats, embryo-fetal lethality and teratogenic effects were observed at an exposure significantly lower (below the level of quantification, at 2.5 mg/kg/day) than at the maximal recommended human dose (MRHD) of 200 mg twice daily.
In rabbits, embryo-fetal lethality and teratogenic effects were observed at 15 mg/kg/day with an exposure approximately 4 times higher than at the MHRD but equivocal effects on the embryo-fetal development of the axial skeleton and the heart were noted already at an exposure below than at the MRHD of 200 mg twice daily.

IPF, other chronic fibrosing ILDs with a progressive phenotype, and SSc-ILD.

In rats, embryo-fetal lethality and teratogenic effects were observed at an exposure significantly lower (below the level of quantification, at 2.5 mg/kg/day) than at the maximal recommended human dose (MRHD) of 150 mg twice daily.
In rabbits, embryo-fetal lethality and teratogenic effects were observed at 15 mg/kg/day with an exposure approximately 5 times higher than at the MHRD but equivocal effects on the embryo-fetal development of the axial skeleton and the heart were noted already at an exposure below that at the MRHD of 150 mg twice daily.
Fetal abnormalities included brachydactyly, major artery anomalies (missing, additional, altered position or size), abnormal heart shape, missing urogenital organs (kidneys, ureter, uterus, ductus deferens, ovaries), vertebral anomalies (missing, fused, displaced, cleft, asymmetrical ossification), and rib anomalies (flat, thickened, additional, fused).
 There is no information on the excretion of nintedanib and its metabolites in human milk. Pre-clinical studies showed that small amounts of nintedanib and/or its metabolites (≤ 0.5% of the administered dose) were secreted into milk of lactating rats.
Decreased postnatal viability during the first 4 postnatal days was observed in rats dosed with 10 mg/kg/day nintedanib from gestation day 6 to postnatal day 20 (exposure less than the clinical exposure based on AUC).
Because of the potential for serious adverse effects in breastfeeding infants, breastfeeding should be discontinued during treatment with Ofev.

4.7 Effects on Ability to Drive and Use Machines

No studies of the effects on the ability to drive and use machines have been performed.
Patients should be advised to be cautious when driving or using machines during treatment with Ofev.

4.8 Adverse Effects (Undesirable Effects)

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at http://www.tga.gov.au/reporting-problems.

Summary of the safety profile.

NSCLC.

The safety data provided below are based on the global, double-blind randomised pivotal phase III trial 1199.13 (LUME-Lung 1) comparing treatment with Ofev plus docetaxel against placebo plus docetaxel in patients with locally advanced, or metastatic, or recurrent NSCLC after first-line chemotherapy. Adverse events in all patients occurring in at least 10% of patients in either treatment arm in the pivotal trial LUME-Lung 1 are summarised in Table 3.
Table 4 summarises the frequencies of adverse drug reactions (ADRs) by System Organ Class (SOC) that were reported in the pivotal study LUME-Lung 1 for patients with NSCLC of adenocarcinoma tumour histology (n = 320) and based on data observed during the nintedanib post-marketing period. The following terms are used to rank the ADRs by frequency: very common (≥ 1/10), common (≥ 1/100 < 1/10), uncommon (≥ 1/1,000 < 1/100). Within each frequency grouping adverse reactions are presented in order of decreased seriousness. The most frequently reported adverse reactions specific for Ofev were diarrhoea, increased liver enzyme values (ALT and AST) and vomiting.

IPF, other chronic fibrosing ILDs with a progressive phenotype, and SSc-ILD.

Ofev has been studied in clinical trials including 1529 patients suffering from IPF, 663 patients with other chronic fibrosing interstitial lung disease (ILDs) with a progressive phenotype, and 576 patients with SSc-ILD.
The safety data provided in the following are based on:
Two phase III, randomised, double-blind, placebo-controlled trials comparing treatment with Ofev 150 mg twice daily to placebo for 52 weeks (INPULSIS-1 and INPULSIS-2) in 1061 patients with IPF.
One phase III randomised, double-blind, placebo-controlled trial comparing treatment with Ofev 150 mg twice daily to placebo for at least 52 weeks in 663 patients with other chronic fibrosing ILDs with a progressive phenotype (INBUILD).
One phase III randomised, double-blind, placebo-controlled trial comparing treatment with Ofev 150 mg twice daily to placebo for at least 52 weeks in 576 patients with SSc-ILD (SENSCIS).
In clinical trials, the most frequently reported adverse reactions associated with the use of Ofev included diarrhoea, nausea and vomiting, abdominal pain, decreased appetite, weight decreased and hepatic enzyme increased.
The safety profile of Ofev in a long term extension trial in patients with IPF, treated up to 5.7 years, was consistent with that observed in the phase III trials (see Section 5.1 Pharmacodynamic Properties, Clinical trials).
Adverse events occurring in at least 5% of patients in either treatment arm in the pivotal trials INPULSIS-1 and INPULSIS-2 are summarised in Table 5.
Adverse events occurring in at least 5% of patients in either treatment arm in the pivotal trial SENSCIS are summarised in Table 6.
Adverse events occurring in at least 5% of patients in either treatment arm in the pivotal trial INBUILD are summarised in Table 7.
Table 8 summarises the frequencies of ADRs by MedDRA SOC that were reported in the nintedanib group pooled from the two placebo-controlled Phase III clinical trials of 52 weeks duration in 638 IPF patients, the placebo-controlled Phase III clinical trial of 52 weeks duration in 663 patients with other chronic fibrosing ILDs with a progressive phenotype, the placebo-controlled Phase III clinical trial of 52 weeks duration in 288 SSc-ILD patients and data observed during the post-marketing experience.
Frequency categories are defined using the following convention: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), not known (cannot be estimated from the available data).
For the management of selected adverse reactions please also see Section 4.4 Special Warnings and Precautions for Use.

Post marketing experience.

GI disorders.

Colitis (frequency uncommon).

Renal and urinary disorders.

Renal failure (frequency unknown).

Vascular disorders.

Cases of aneurysms and artery dissections, sometimes fatal, have been reported with VEGFR pathway inhibitors.

4.9 Overdose

For information on the management of overdose, contact the Poison Information Centre on 13 11 26 (Australia).
There is no specific antidote or treatment for Ofev overdose. The highest single dose of nintedanib administered in phase I studies was 450 mg once daily. In addition, 2 patients in the oncology programme had an overdose of maximum 600 mg twice daily (b.i.d) up to eight days. Observed adverse events were consistent with the known safety profile of nintedanib, i.e. increased liver enzymes and gastrointestinal symptoms. Both patients recovered from these adverse reactions.
In the INPULSIS trials (IPF), one patient was inadvertently exposed to a dose of 600 mg daily for a total of 21 days. A non-serious adverse event (nasopharyngitis) occurred and resolved during the period of incorrect dosing, with no onset of other reported events.
In case of overdose, treatment should be interrupted and general supportive measures initiated as appropriate.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Antineoplastic agents - Protein-tyrosine kinase inhibitors.
ATC code: L01XE31.

Mechanism of action.

NSCLC.

Nintedanib is a triple angiokinase inhibitor blocking vascular endothelial growth factor receptors (VEGFR 1-3), platelet-derived growth factor receptors (PDGFR α and β) and fibroblast growth factor receptors (FGFR 1-3) kinase activity. Nintedanib binds competitively to the adenosine triphosphate (ATP) binding pocket of these receptors and blocks the intracellular signalling which is crucial for the proliferation and survival of endothelial as well as perivascular cells (pericytes and vascular smooth muscle cells). In addition, Fms-like tyrosine-protein kinase-3 (Flt-3), lymphocyte-specific tyrosine-protein kinase (Lck), tyrosine-protein kinase Lyn (Lyn) and proto-oncogene tyrosine-protein kinase Src (Src) are inhibited.

IPF, other chronic fibrosing ILDs with a progressive phenotype, and SSc-ILD.

Nintedanib is a small molecule tyrosine kinase inhibitor including the receptors platelet-derived growth factor receptor (PDGFR) α and β, fibroblast growth factor receptor (FGFR) 1-3, and vascular endothelial growth factor receptor (VEGFR) 1-3. In addition, nintedanib inhibits Lck, Lyn, Src, and CSF1R kinases. Nintedanib binds competitively to the ATP binding pocket of these kinases and blocks the intracellular signalling cascades, which have been demonstrated to be involved in the pathogenesis of fibrotic tissue remodelling in interstitial lung diseases.

Pharmacodynamic effects.

NSCLC.

Tumour angiogenesis is an essential feature contributing to tumour growth, progression and metastasis formation and is predominantly triggered by the release of pro-angiogenic factors secreted by the tumour cell (i.e. VEGF and bFGF) to attract host endothelial as well as perivascular cells to facilitate oxygen and nutrient supply through the host vascular system. In preclinical disease models nintedanib, as single agent, effectively interfered with the formation and maintenance of the tumour vascular system resulting in tumour growth inhibition and tumour stasis. Treatment of tumour xenografts with nintedanib led to a reduction in tumour microvessel density.
Dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) measurements showed an anti-angiogenic effect of nintedanib in humans. It was not clearly dose dependent, but most responses were seen at doses of ≥ 200 mg. Logistic regression revealed a statistically significant association of the anti-angiogenic effect to nintedanib exposure. DCE-MRI effects were seen 24-48 hours after the first intake of the medicinal product and were preserved or even increased after continuous treatment over several weeks. No correlation of the DCE-MRI response and subsequent clinically significant reduction in target lesion size was found, but DCE-MRI response was associated with disease stabilisation.

IPF, other chronic fibrosing ILDs with a progressive phenotype, and SSc-ILD.

In in vitro studies using human cells nintedanib has been shown to inhibit processes assumed to be involved in the initiation of the fibrotic pathogenesis, the release of pro-fibrotic mediators from peripheral blood monocytic cells and macrophage polarisation to alternatively activated macrophages. Nintedanib has been demonstrated to inhibit fundamental processes in organ fibrosis, proliferation and migration of fibroblasts and transformation to the active myofibroblast phenotype and secretion of extracellular matrix. In animal studies in multiple models of IPF, SSc/SSc-ILD, RA-ILD and other organ fibrosis, nintedanib has shown anti-inflammatory effects and anti-fibrotic effects in the lung, skin, heart, kidney, and liver. Nintedanib also exerted vascular activity. It reduced dermal microvascular endothelial cell apoptosis and attenuated pulmonary vascular remodelling by reducing the proliferation of vascular smooth muscle cells, the thickness of pulmonary vessel walls and percentage of occluded pulmonary vessels.

Clinical trials.

NSCLC.

Efficacy in the pivotal phase III trial LUME-Lung 1. The efficacy and safety of Ofev was investigated in 1314 patients with locally advanced, metastatic or recurrent NSCLC after one prior line of chemotherapy. The trial included 658 patients (50.1%) with adenocarcinoma, 555 patients (42.2%) with squamous cell carcinoma, and 101 patients (7.7%) with other tumour histologies.
Patients were randomised (1:1) to receive Ofev 200 mg orally twice daily in combination with 75 mg/m2 of i.v. docetaxel every 21 days (n = 655) or placebo orally twice daily in combination with 75 mg/m2 of docetaxel every 21 days (n = 659). Ofev was not given on day 1 of each cycle, i.e. the day when docetaxel was given. Randomisation was stratified according to Eastern Cooperative Oncology Group (ECOG) status (0 vs. 1), bevacizumab pre-treatment (yes vs. no), brain metastasis (yes vs. no) and tumour histology (squamous vs. non-squamous tumour histology).
Patient characteristics were balanced between treatment arms within the overall population and within the adenocarcinoma patients. In the overall population 72.7% of the patients were male. The majority of patients were non-Asian (81.6%), the median age was 60.0 years, the baseline ECOG performance status was 0 (28.6%) or 1 (71.3%); one patient had a baseline ECOG performance status of 2. 5.8% of the patients had stable brain metastasis at study entry and 3.8% had prior bevacizumab treatment.
The disease stage was determined at the time of diagnosis using Union Internationale Contre le Cancer (UICC)/ American Joint Committee on Cancer (AJCC) Edition 6 or Edition 7. In the overall population, 16.0% of the patients had disease stage < IIIB/IV, 22.4% had disease stage IIIB and 61.6% had disease stage IV. 9.2% of the patients entered the study with locally recurrent disease stage as had been evaluated at baseline. For patients with tumour of adenocarcinoma histology, 15.8% had disease stage < IIIB/IV, 15.2% had disease stage IIIB and 69.0% had disease stage IV. 5.8% of the adenocarcinoma patients entered the study with locally recurrent disease stage as had been evaluated at baseline. 'Locally recurrent' was defined as local re-occurrence of the tumour without metastases at study entry.
The primary endpoint was progression-free survival (PFS) as assessed by an independent review committee (IRC) based on the intent-to-treat (ITT) population and tested by histology. Overall survival (OS) was the key secondary endpoint. Other efficacy outcomes included objective response, disease control, change in tumour size and health-related quality of life.
As shown in Table 9, the addition of Ofev to docetaxel led to a statistically significant reduction in the risk of progression or death by 21% for the overall population (HR 0.79; 95% CI: 0.68 - 0.92; p = 0.0019) as determined by the IRC. This result was confirmed in the follow-up PFS analysis (HR 0.85; 95% CI: 0.75 - 0.96; p = 0.0070) which included all events collected at the time of the final OS analysis. OS analysis in the overall population did not reach statistical significance (HR 0.94; 95% CI: 0.83-1.05). Of note, pre-planned analyses according to histology showed statistically significant difference in OS between treatment arms in the adenocarcinoma population only.
The addition of Ofev to docetaxel led to a statistically significant reduction in the risk of progression or death by 23% for the adenocarcinoma population (HR 0.77; 95% CI: 0.62 - 0.96). In line with these observations, related study endpoints such as disease control and change in tumour size showed significant improvements.
A statistically significant improvement in OS favouring treatment with Ofev plus docetaxel was demonstrated in patients with adenocarcinoma with a 17% reduction in the risk of death (HR 0.83, p = 0.0359) and a median OS improvement of 2.3 months (10.3 vs. 12.6 months, see Figure 1).
A pre-specified evaluation was performed in the population of adenocarcinoma patients considered to have entered the study with a particularly poor treatment prognosis, namely, patients who progressed during or shortly after 1st line therapy prior to study entry. This population included those adenocarcinoma patients identified at baseline as having progressed and entered the study less than 9 months since start of their first-line therapy. Treatment of these patients with Ofev in combination with docetaxel reduced the risk of death by 25%, compared with placebo plus docetaxel (HR 0.75; 95% CI: 0.60 - 0.92; p = 0.0073). Median OS improved by 3 months (Ofev: 10.9 months; placebo: 7.9 months).
In a post hoc analysis in adenocarcinoma patients having progressed and entered the study ≥ 9 months since start of their first-line therapy the difference did not reach statistical significance (HR for OS: 0.89, 95% CI: 0.66 - 1.19).
The proportion of adenocarcinoma patients with stage < IIIB/IV at diagnosis was small and balanced across treatment arms (placebo: 54 patients (16.1%); Ofev: 50 patients, (15.5%)). The HR for these patients for PFS and OS was 1.24 (95% CI: 0.68, 2.28) and 1.09 (95% CI: 0.70, 1.70), respectively. However, the sample size was small, there was no significant interaction and the CI was wide and included the HR for OS of the overall adenocarcinoma population.

Quality of life.

Treatment with Ofev did not significantly change the time to deterioration of the pre-specified symptoms cough, dyspnoea and pain. Patients receiving Ofev plus docetaxel reported a statistically significant, small deterioration in the symptom assessment of diarrhoea used in the European Organization for Research and Treatment of Cancer (EORTC) core questionnaire QLQ-C30. This finding did not compromise patients' self-reported Global health status/Quality of life. Patients receiving Ofev plus docetaxel reported statistically significant improvements in other individual lung cancer symptoms (e.g. pain in chest and pain in arm and shoulder).

IPF.

The clinical efficacy of Ofev has been studied in patients with IPF in two phase III, randomised, double-blind, placebo-controlled studies with identical design (INPULSIS-1 and INPULSIS-2). The studies enrolled subjects with FVC ≥ 50% of predicted and DLCO corrected for haemoglobin 30-79% of predicted at baseline. Patients were randomised in a 3:2 ratio to treatment with Ofev 150 mg or placebo twice daily for 52 weeks.
The primary endpoint was the annual rate of decline in Forced Vital Capacity (FVC). The key secondary endpoints were change from baseline in Saint George's Respiratory Questionnaire (SGRQ) total score at 52 weeks and time to first acute IPF exacerbation.

Annual rate of decline in FVC.

The annual rate of decline of FVC (in mL) was significantly reduced in patients receiving Ofev compared to patients receiving placebo. The treatment effect was consistent in both trials. See Table 10 for individual and pooled study results.
The robustness of the effect of Ofev in reducing the annual rate of decline in FVC was confirmed in all pre-specified sensitivity analyses.
In addition, similar effects were observed on other lung function endpoints, e.g. change from baseline in FVC at week 52 and FVC responder analyses providing further substantiation of the effects of Ofev on slowing disease progression. See Figure 2 for the evolution of change from baseline over time in both treatment groups, based on the pooled analysis of studies (INPULSIS-1 and INPULSIS-2).

FVC responder analysis.

In both INPULSIS trials, the proportion of FVC responders, defined as patients with an absolute decline in FVC % predicted no greater than 5% (a threshold indicative of the increasing risk of mortality in IPF), was significantly higher in the Ofev group as compared to placebo. Similar results were observed in analyses using a conservative threshold of 10%. See Table 11 for individual and pooled study results.

Time to progression (≥ 10% absolute decline of FVC % predicted or death).

In both INPULSIS trials, the risk of progression was statistically significantly reduced for patients treated with Ofev compared with placebo. In the pooled analysis, the HR was 0.60 indicating a 40% reduction in the risk of progression for patients treated with Ofev compared with placebo, see Table 12.

Change from baseline in SGRQ total score at week 52.

SGRQ total score measuring health related quality of life (HRQoL) was analysed at 52 weeks. In INPULSIS-2, patients receiving placebo had a larger increase from baseline SGRQ total score as compared to patients receiving Ofev 150 mg bid. The deterioration of HRQoL was smaller in the nintedanib group; the difference between the treatment groups was modest, but statistically significant (-2.69; 95% CI: -4.95, -0.43; p = 0.0197). The clinical significance of this finding is unknown.
In INPULSIS-1, the increase from baseline in SGRQ total score at week 52 was comparable between Ofev and placebo (difference between treatment groups: -0.05; 95% CI: -2.50, 2.40; p = 0.9657). In the pooled analysis of the INPULSIS trials, the estimated mean change from baseline to week 52 in SGRQ total score was smaller in the Ofev group (3.53) than in the placebo group (4.96), with a difference between the treatment groups of -1.43 (95% CI: -3.09, 0.23; p = 0.0923). Overall, the effect of Ofev on health-related quality of life as measured by the SGRQ total score is modest, indicating less worsening compared to placebo. The clinical significance of this finding is unknown.

Time to first acute IPF exacerbation.

In the INPULSIS-2 trial, the risk of first acute IPF exacerbation over 52 weeks was significantly reduced in patients receiving Ofev compared to placebo, in the INPULSIS-1 trial there was no difference in between the treatment groups. In the pooled analysis of the INPULSIS trials, a numerically lower risk of first acute exacerbation was observed in patients receiving Ofev compared to placebo. See Table 13 for individual and pooled study results.
All adverse events of acute IPF exacerbation reported by the investigator were adjudicated by a blinded adjudication committee. A pre-specified sensitivity analysis of the time to first 'confirmed' or 'suspected' adjudicated acute IPF exacerbation was performed on the pooled data. The frequency of patients with at least 1 adjudicated exacerbation occurring within 52 weeks was lower in the Ofev group (1.9% of patients) than in the placebo group (5.7% of patients). Time to event analysis of the adjudicated exacerbation events using pooled data yielded an HR of 0.32 (95% CI: 0.16, 0.65; p = 0.0010). This indicates that the risk of having a first acute IPF exacerbation was statistically significantly lower in the Ofev group than in the placebo group at any time point.

Survival analysis.

The INPULSIS trials were not statistically powered for overall mortality. In a pre-specified pooled analysis, overall mortality over 52 weeks was numerically lower in the Ofev group (5.5%) compared with the placebo group (7.8%). The difference did not reach statistical significance. The analysis of time to death resulted in a HR of 0.70 (95% CI: 0.43, 1.12; p = 0.1399). The results of all survival endpoints (such as on-treatment mortality and respiratory mortality) showed a consistent numerical difference in favour of Ofev (see Table 14).

Supportive evidence from the phase II trial (1199.30) Ofev 150 mg twice daily results.

Additional evidence of efficacy is provided by the randomised, double-blind, placebo-controlled, dose finding phase II trial including a Ofev 150 mg bid dose group.
The primary endpoint, rate of decline in FVC over 52 weeks was lower in the Ofev arm (-0.060 L/year, N = 84) than the placebo arm (-0.190 L/year, N = 83). The estimated difference between the treatment groups was 0.131 L/year (95% CI: 0.027, 0.235). Although the difference between the treatments was not significant according to the primary analysis, it reached statistical significance (p = 0.0136) using a pre-specified sensitivity analysis.
The estimated mean change from baseline in SGRQ total score at 52 weeks was 5.46 for placebo, indicating worsening of the health-related quality of life and -0.66 for Ofev, indicating stable health-related quality of life. The estimated mean difference for Ofev compared with placebo was -6.12 (95% CI: -10.57, -1.67; p = 0.0071).
The number of patients with acute IPF exacerbations over 52 weeks was lower in the Ofev group (2.3%, N = 86) compared to placebo (13.8%, N = 87). The estimated hazard ratio of Ofev versus placebo was 0.16 (95% CI: 0.04, 0.71; p = 0.0054).

Long-term treatment with Ofev in patients with IPF (INPULSIS-ON).

An open-label extension trial of Ofev included 734 patients with IPF. Some patients were treated with Ofev for more than 5 years. 734 of 807 (91%) patients who completed the 52 week treatment period in an INPULSIS trial received open-label Ofev treatment in the extension trial INPULSIS-ON. Median exposure time for patients treated with Ofev in both the INPULSIS and INPULSIS-ON trials was 44.7 months (range 11.9-68.3). The adjusted annual rate of decline in FVC over 192 weeks was -135.1 (SE 5.8) mL/year in all patients treated and was consistent with the annual rate of FVC decline in patients treated with Ofev in the INPULSIS phase III trials (-113.6 mL per year). The adverse event profile of Ofev in INPULSIS-ON was similar to that in the INPULSIS phase III trials.

IPF patients with advanced lung function impairment (INSTAGE).

INSTAGE was a multicentre, multinational, prospective, randomised, double-blind, parallel group clinical trial in IPF patients with advanced lung function impairment (DLCO ≤ 35% predicted) for 24 weeks. 136 patients were treated with Ofev monotherapy. Primary endpoint result showed a reduction of St Georges Respiratory Questionnaire (SGRQ) total score by -0.77 units (95% CI -2.76, 1.22) at week W12, based on adjusted mean change from baseline. A post hoc comparison demonstrated that the decline in FVC in these patients was consistent with the decline in FVC in patients with less advanced disease and treated with Ofev in the INPULSIS phase III trials.

Additional data from the phase IV INJOURNEY trial with Ofev 150 mg twice daily and add-on pirfenidone.

Concomitant treatment with nintedanib and pirfenidone has been investigated in an exploratory open-label, randomised trial of nintedanib 150 mg twice daily with add-on pirfenidone titrated to 801 mg three times a day (n = 53) compared to nintedanib 150 mg twice daily alone (n = 52) in 105 randomised patients for 12 weeks. The primary endpoint was the percentage of patients with gastrointestinal adverse events from baseline to week 12. Analyses were descriptive and exploratory. Gastrointestinal adverse events were frequent and in line with the established safety profile of each component. Diarrhoea, nausea and vomiting were the most frequent adverse events reported in 20 (37.7%) versus 16 (31.4%), in 22 (41.5%) versus 6 (11.8%) and in 15 (28.3%) versus 6 (11.8%) patients, treated with pirfernidone added to nintedanib versus nintedanib alone, respectively.

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

The clinical efficacy of Ofev has been studied in patients with chronic fibrosing ILDs with a progressive phenotype in a double-blind, randomised, placebo-controlled phase III trial (INBUILD). Patients with IPF were excluded. Patients with a clinical diagnosis of chronic fibrosing ILD were selected if they had relevant fibrosis (> 10% fibrotic features) on high resolution computed tomography (HRCT) and presented with clinical signs of progression (defined as FVC decline ≥ 10%, FVC decline ≥ 5% and < 10% with worsening symptoms or imaging, or worsening symptoms and worsening imaging all in the 24 months prior to screening). Patients were required to have an FVC greater than or equal to 45% of predicted and a DLCO 30% to less than 80% of predicted. Patients were required to have progressed despite management deemed appropriate in clinical practice for the patient's relevant ILD. A total of 663 patients were randomised in a 1:1 ratio to receive either Ofev 150 mg bid or matching placebo for at least 52 weeks. The median Ofev exposure over the whole trial was 17.4 months and the mean Ofev exposure over the whole trial was 15.6 months. Randomisation was stratified based on HRCT fibrotic pattern as assessed by central readers. 412 patients with HRCT with usual interstitial pneumonia (UIP)-like fibrotic pattern and 251 patients with other HRCT fibrotic patterns were randomised. There were 2 co-primary populations defined for the analyses in this trial: all patients (the overall population) and patients with HRCT with UIP-like fibrotic pattern. Patients with other HRCT fibrotic patterns represented the 'complementary' population.
The primary endpoint was the annual rate of decline in Forced Vital Capacity (FVC) (in mL) over 52 weeks. Main secondary endpoints were absolute change from baseline in King's Brief Interstitial Lung Disease Questionnaire (K-BILD) total score at week 52, time to first acute ILD exacerbation or death over 52 weeks, and time to death over 52 weeks.
Patients had a mean (standard deviation [SD, Min-Max]) age of 65.8 (9.8, 27-87) years and a mean FVC percent predicted of 69.0% (15.6, 42-137). The underlying clinical ILD diagnoses in groups represented in the trial were hypersensitivity pneumonitis (26.1%), autoimmune ILDs (25.6%), idiopathic nonspecific interstitial pneumonia (18.9%), unclassifiable idiopathic interstitial pneumonia (17.2%), and other ILDs (12.2%).

Annual rate of decline in FVC.

The annual rate of decline in FVC (in mL) over 52 weeks was significantly reduced by 107.0 mL in patients receiving Ofev compared to patients receiving placebo (Table 15) corresponding to a relative treatment effect of 57.0%.
Similar results were observed in the co-primary population of patients with HRCT with UIP-like fibrotic pattern: the annual rate of decline in FVC was -211.1 mL/year in the placebo group (n=206) and -82.9 mL/year in the Ofev group (n=206). The difference between the treatment groups was 128.2 mL/year (95% CI: 70.8, 185.6; p < 0.0001). Further, the treatment effect of annual rate of decline in FVC (mL) over 52 weeks was consistent in the complementary population of patients with other HRCT fibrotic patterns. (Figure 3.)
The effect of Ofev in reducing the annual rate of decline in FVC was confirmed in all pre-specified sensitivity analyses and consistent results were observed in all pre-specified subgroups (e.g. gender, age group, race, baseline FVC % predicted, and original underlying clinical ILD diagnosis in groups). The trial was not designed or powered to provide evidence for a benefit of nintedanib in specific diagnostic subgroups.
Figure 4 shows the evolution of change in FVC from baseline over time in the treatment groups.
The adjusted mean absolute change from baseline to week 52 in FVC % predicted was lower in the nintedanib group (-2.62%) than in the placebo group (-5.86%). The adjusted mean difference between the treatment groups was 3.24 (95% CI: 2.09, 4.40).

FVC responder analysis.

The proportion of FVC responders, defined as patients with a relative decline in FVC % predicted no greater than 5%, was higher in the Ofev group as compared to placebo. Similar results were observed in analyses using a threshold of 10% (Table 16).

Time to first acute ILD exacerbation or death.

The proportion of patients with at least one event of first acute ILD exacerbation or death over 52 weeks was 7.8% in the Ofev group and 9.7% in the placebo group. When analysing data over the whole trial, the risk of first acute ILD exacerbation or death further decreased in the Ofev group compared with the placebo group: the HR was 0.67 (95% CI: 0.46, 0.98 (Figure 5)).

Survival analysis.

The proportion of patients who died over 52 weeks was 4.8% in the Ofev group compared to 5.1% in the placebo group. In the analysis of data over the whole trial, the risk of death was lower in the Ofev group compared to the placebo group. The HR was 0.78 (95% CI: 0.50, 1.21).

Time to progression (≥ 10% absolute decline of FVC % predicted) or death.

In the INBUILD trial, the risk of progression (≥ 10% absolute decline of FVC % predicted) or death was reduced for patients treated with Ofev. The proportion of patients who died or progressed over 52 weeks was 25.6% in the Ofev group compared to 37.5% in the placebo group.
In the analysis of data over the whole trial, the risk of death or progression was lower in the Ofev group compared to the placebo group. The HR was 0.66 (95% CI: 0.53, 0.83).

Quality of life.

In the INBUILD trial health related quality of life at 52 weeks was measured using the:
Absolute change from baseline in King's Brief Interstitial Lung Disease Questionnaire (K-BILD) total score (range from 0-100, higher scores indicate a better health status).
Absolute change from baseline in Living with Pulmonary Fibrosis (L-PF) Symptoms dyspnoea domain score (range from 0-100, the higher the score the greater the impairment).
Absolute change from baseline in Living with Pulmonary Fibrosis (L-PF) Symptoms cough domain score (range from 0-100, the higher the score the greater the impairment).
The adjusted mean change from baseline in K-BILD total score at week 52 was -0.79 units in the placebo group and 0.55 in the Ofev group. The difference between the treatment groups was 1.34 (95% CI: -0.31, 2.98).
The adjusted mean absolute change from baseline in Living with Pulmonary Fibrosis (L-PF) Symptoms dyspnoea domain score at week 52 was 4.28 in the Ofev group compared with 7.81 in the placebo group. The adjusted mean difference between the groups in favour of Ofev was -3.53 (95% CI: -6.14, -0.92). The adjusted mean absolute change from baseline in L-PF Symptoms cough domain score at week 52 was -1.84 in the Ofev group compared with 4.25 in the placebo group. The adjusted mean difference between the groups in favour of Ofev was -6.09 (95% CI: -9.65, -2.53).

SSc-ILD.

The clinical efficacy of Ofev has been studied in patients with SSc-ILD in a double-blind, randomised, placebo-controlled phase III trial (SENSCIS). Patients were diagnosed with SSc-ILD based upon the 2013 American College of Rheumatology/ European League Against Rheumatism classification criteria for SSc and a chest high resolution computed tomography (HRCT) scan conducted within the previous 12 months. A total of 580 patients were randomised in a 1:1 ratio to receive either Ofev 150 mg bid or matching placebo for at least 52 weeks, of which 576 patients were treated. Randomisation was stratified by Antitopoisomerase Antibody status (ATA). Individual patients stayed on blinded trial treatment for up to 100 weeks (median Ofev exposure 15.4 months; mean Ofev exposure 14.5 months).
The primary endpoint was the annual rate of decline in forced vital capacity (FVC) over 52 weeks. Key secondary endpoints were absolute change from baseline in the modified Rodnan Skin Score (mRSS) at week 52 and absolute change from baseline in the Saint George's Respiratory Questionnaire (SGRQ) total score at week 52.
In the overall population, 75.2% of the patients were female. The mean (standard deviation [SD, Min-Max]) age was 54.0 (12.2, 20-79) years. Overall, 51.9% of patients had diffuse cutaneous systemic sclerosis (SSc) and 48.1% had limited cutaneous SSc. The mean (SD) time since first onset of a non-Raynaud symptom was 3.49 (1.7) years. 49.0% of patients were on stable therapy with mycophenolate at baseline (46.5% mycophenolate mofetil, 1.9% mycophenolate sodium, 0.5% mycophenolic acid). The safety profile in patients with or without mycophenolate at baseline was comparable.

Annual rate of decline in FVC.

The annual rate of decline of FVC (in mL) over 52 weeks was significantly reduced by 41.0 mL in patients receiving Ofev compared to patients receiving placebo (Table 17) corresponding to a relative treatment effect of 43.8%.
The effect of Ofev in reducing the annual rate of decline in FVC was similar across pre-specified sensitivity analyses and no heterogeneity was detected in pre-specified subgroups (e.g. by age, gender, and mycophenolate use). The exploratory subgroup analysis of the annual rate of decline in FVC by mycophenolate use at baseline is presented in Table 18.
In addition, similar effects were observed on other lung function endpoints, e.g. absolute change from baseline in FVC in mL at week 52 (Figure 6 and Table 19) and rate of decline in FVC in % predicted over 52 weeks (Table 20) providing further substantiation of the effects of Ofev on slowing progression of SSc-ILD. Furthermore, fewer patients in the Ofev group had an absolute FVC decline > 5% predicted (20.6% in the Ofev group vs. 28.5% in the placebo group, OR = 0.65, p = 0.0287). The relative FVC decline in mL > 10% was comparable between both groups (16.7% in the Ofev group vs. 18.1% in the placebo group, OR = 0.91, p = 0.6842). In these analyses, missing FVC values at week 52 were imputed with the patient's worst value on treatment.
An exploratory analysis of data up to 100 weeks (maximum treatment duration in SENSCIS) suggested that the on treatment effect of Ofev on slowing progression of SSc-ILD persisted beyond 52 weeks.

Change from baseline in modified Rodnan skin score (mRSS) at week 52.

The adjusted mean absolute change from baseline in mRSS at week 52 was comparable between the Ofev group (-2.17 (95% CI -2.69, -1.65)) and the placebo group (-1.96 (95% CI -2.48, -1.45)). The adjusted mean difference between the treatment groups was -0.21 (95% CI -0.94, 0.53; p = 0.5785).

Change from baseline in St. George's respiratory questionnaire (SGRQ) total score at week 52.

The adjusted mean absolute change from baseline in SGRQ total score at week 52 was comparable between the Ofev group (0.81 (95% CI -0.92, 2.55)) and the placebo group (-0.88 (95% CI -2.58, 0.82)). The adjusted mean difference between the treatment groups was 1.69 (95% CI -0.73, 4.12; p = 0.1711).

Survival analysis.

Mortality over the whole trial was comparable between the Ofev group (N = 10; 3.5%) and the placebo group (N = 9; 3.1%). The analysis of time to death over the whole trial resulted in a HR of 1.16 (95% CI 0.47, 2.84; p = 0.7535).

Effect on QT interval.

QT/QTc measurements were recorded and analysed from a dedicated study comparing nintedanib monotherapy against sunitinib monotherapy in patients with renal cell carcinoma. In this study single oral doses of 200 mg nintedanib as well as multiple oral doses of 200 mg nintedanib administered twice daily for 15 days did not prolong the QTcF interval.

NSCLC.

No thorough QT-trial of nintedanib administered in combination with docetaxel was conducted.

Paediatric population.

No clinical trials have been conducted in children and adolescents.

5.2 Pharmacokinetic Properties

The pharmacokinetics (PK) of nintedanib can be considered linear with respect to time (i.e. single-dose data can be extrapolated to multiple-dose data). Accumulation upon multiple administrations was 1.04-fold for Cmax and 1.38-fold for AUCT. Nintedanib trough concentrations remained stable for more than one year.

Absorption.

Nintedanib reached maximum plasma concentrations approximately 2 - 4 hours after oral administration as soft gelatin capsule under fed conditions (range 0.5 - 8 hours). The absolute bioavailability of a 100 mg dose was 4.69% (90% CI: 3.615 - 6.078) in healthy volunteers. Absorption and bioavailability are decreased by transporter effects and substantial first-pass metabolism.
Dose proportionality was shown by increase of nintedanib exposure (dose range 50 - 450 mg once daily and 150 - 300 mg twice daily). Steady state plasma concentrations were achieved within one week of dosing at the latest.
After food intake, nintedanib exposure increased by approximately 20% compared to administration under fasted conditions (CI: 0.953 - 1.525) and absorption was delayed (median tmax fasted: 2.00 hours; fed: 3.98 hours).

Distribution.

Nintedanib follows at least bi-phasic disposition kinetics. After intravenous infusion, a high volume of distribution (Vss: 1050 L, 45.0% gCV) was observed.
The in vitro protein binding of nintedanib in human plasma was high, with a bound fraction of 97.8%. Serum albumin is considered to be the major binding protein. Nintedanib is preferentially distributed in plasma with a blood to plasma ratio of 0.869.

Metabolism.

The prevalent metabolic reaction for nintedanib is hydrolytic cleavage by esterases resulting in the free acid moiety BIBF 1202. BIBF 1202 is subsequently glucuronidated by UGT enzymes, namely UGT1A1, UGT1A7, UGT1A8, and UGT1A10 to BIBF 1202 glucuronide.
Only a minor extent of the biotransformation of nintedanib consisted of CYP pathways, with CYP3A4 being the predominant enzyme involved. The major CYP-dependent metabolite could not be detected in plasma in the human ADME (absorption, distribution, metabolism and excretion) study. In vitro, CYP-dependent metabolism accounted for about 5% compared to about 25% ester cleavage.

Excretion.

Total plasma clearance after intravenous infusion was high (CL: 1390 mL/min, 28.8% gCV). Urinary excretion of the unchanged active substance within 48 hours was about 0.05% of the dose (31.5% gCV) after oral and about 1.4% of the dose (24.2% gCV) after intravenous administration; the renal clearance was 20 mL/min (32.6% gCV). The major route of elimination of drug related radioactivity after oral administration of [14C]-nintedanib was via faecal/biliary excretion (93.4% of dose, 2.61% gCV). The contribution of renal excretion to the total clearance was low (0.649% of dose, 26.3% gCV). The overall recovery was considered complete (above 90%) within 4 days after dosing. The terminal half-life of nintedanib was between 10 and 15 hours (gCV % approximately 50%).

Exposure-response relationship.

NSCLC.

In exploratory PK-adverse event analyses, higher exposure to nintedanib tended to be associated with liver enzyme elevations, but not with gastrointestinal adverse events.
PK-efficacy analyses were not performed for clinical endpoints. Logistic regression revealed a statistically significant association between nintedanib exposure and DCE-MRI response.

IPF, other chronic fibrosing ILDs with a progressive phenotype, and SSc-ILD.

Exposure-response analyses of patients with IPF, other chronic fibrosing ILDs with a progressive phenotype, and SSc-ILD indicated an Emax-like relationship between exposure and the annual rate of decline in FVC with an EC50 of around 3 nanogram/mL (relative standard error: around 55%). For comparison, median observed nintedanib trough concentrations for 150 mg bid Ofev were about 10 nanogram/mL.
With respect to safety, there seemed to be a weak relationship between nintedanib plasma exposure and ALT and/or AST elevations. Actual administered dose might be the better predictor for the risk of developing diarrhoea of any intensity, even if plasma exposure as risk determining factor could not be ruled out (see Section 4.4 Special Warnings and Precautions for Use).

Intrinsic and extrinsic factors; special populations.

The PK properties of nintedanib were similar in healthy volunteers, patients with IPF, patients with other chronic fibrosing ILDs with a progressive phenotype, patients with SSc-ILD and cancer patients. Based on results of population PK analyses and descriptive investigations, exposure to nintedanib was not influenced by gender (body weight corrected), mild and moderate renal impairment (estimated by creatinine clearance), liver metastases, ECOG performance score, alcohol consumption, or P-gp genotype. Population PK analyses indicated moderate effects on exposure to nintedanib depending on the intrinsic and extrinsic factors age, body weight, and race which are described in the following. Based on the high inter-individual variability of exposure observed in the clinical trials these effects are not considered clinically relevant (see Section 4.4 Special Warnings and Precautions for Use).
Age. Exposure to nintedanib increased linearly with age. AUCT,ss decreased by 16% for a 45-year old patient (5th percentile) and increased by 13% for a 76-year old patient (95th percentile) relative to a patient with the median age of 62 years. The age range covered by the analysis was 29 to 85 years; approximately 5% of the population was older than 75 years. Studies in paediatric populations have not been performed.
Body weight. An inverse correlation between bodyweight and exposure to nintedanib was observed. AUCT,ss increased by 25% for a 50 kg patient (5th percentile) and decreased by 19% for a 100 kg patient (95th percentile) relative to a patient with the median weight of 71.5 kg.
Race. The population mean exposure to nintedanib was 33 - 50% higher in Chinese, Taiwanese, and Indian patients and 16% higher in Japanese patients while it was 16 - 22% lower in Koreans compared to Caucasians (body weight corrected).
Data from black individuals was very limited but in the same range as for Caucasians.
Hepatic impairment. In a dedicated single dose phase I study and compared to healthy subjects, exposure to nintedanib based on Cmax and AUC was 2.2-fold higher in volunteers with mild hepatic impairment (Child Pugh A; 90% CI: 1.3 - 3.7 for Cmax and 1.2 - 3.8 for AUC, respectively). In volunteers with moderate hepatic impairment (Child Pugh B), exposure was 7.6-fold higher based on Cmax (90% CI: 4.4 - 13.2) and 8.7-fold higher (90% CI: 5.7 - 13.1) based on AUC, respectively, compared to healthy volunteers. Subjects with severe hepatic impairment (Child Pugh C) have not been studied.
Concomitant treatment with pirfenidone.

IPF.

In a dedicated pharmacokinetic study, concomitant treatment of Ofev with pirfernidone was investigated in patients with IPF. Group 1 received a single dose of 150 mg Ofev before and after up-titration to 801 mg pirfenidone three times a day at steady state. Group 2 received steady state treatment of 801 mg pirfenidone three times a day and had a PK profiling before and after at least 7 days of co-treatment with 150 mg Ofev twice daily. In group 1, the adjusted geometric mean ratios (90% confidence interval (CI)) were 93% (57% - 151%) and 96% (70% - 131%) for Cmax and AUC0-tz of nintedanib, respectively (N = 12). In group 2, the adjusted geometric mean ratios (90% CI) were 97% (86% - 110%) and 95% (86% - 106%) for Cmax,ss and AUCT,ss of pirfenidone, respectively (N = 12).
Due to the wide confidence intervals of the PK parameters, statistically a pharmacokinetic drug-drug interaction cannot be ruled out but there is no evidence of a relevant pharmacokinetic drug-drug interaction between nintedanib and pirfenidone when administered in combination.
Concomitant treatment with bosentan. In a dedicated pharmacokinetic study, concomitant treatment of Ofev with bosentan was investigated in healthy volunteers. Subjects received a single dose of 150 mg Ofev before and after multiple dosing of 125 mg bosentan twice daily at steady state. The adjusted geometric mean ratios (90% confidence interval (CI)) were 103% (86% - 124%) and 99% (91% - 107%) for Cmax and AUC0-tz of nintedanib, respectively (n = 13), indicating that co-administration of nintedanib with bosentan did not alter the pharmacokinetics of nintedanib.
Concomitant treatment with oral hormonal contraceptives. In a dedicated pharmacokinetic study, 15 female patients with SSc-ILD received a single dose of a combination of 30 microgram ethinylestradiol and 150 microgram levonorgestrel before and after twice daily dosing of 150 mg nintedanib for at least 10 days. The adjusted geometric mean ratios (90% confidence interval (CI)) were 117% (108% - 127%; Cmax) and 101% (93% - 111%; AUC0-tz) for ethinylestradiol and 101% (90% - 113%; Cmax) and 96% (91% - 102%; AUC0-tz) for levonorgestrel, respectively, indicating that co-administration of nintedanib has no relevant effect on the plasma exposure of ethinylestradiol and levonorgestrel.

Drug-drug interaction potential.

Metabolism.

Drug-drug interactions between nintedanib and CYP substrates, CYP inhibitors, or CYP inducers are not expected, since nintedanib, BIBF 1202, and BIBF 1202 glucuronide did not inhibit or induce CYP enzymes preclinically nor was nintedanib metabolised by CYP enzymes to a relevant extent.

Transport.

Nintedanib is a substrate of P-gp. For the interaction potential of nintedanib with this transporter, see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions. Nintedanib was shown not to be a substrate or inhibitor of OATP-1B1, OATP-1B3, OATP-2B1, OCT-2 or MRP-2 in vitro. Nintedanib was also not a substrate of BCRP. Only a weak inhibitory potential on OCT-1, BCRP, and P-gp was observed in vitro which is considered to be of low clinical relevance. In vitro studies also showed that nintedanib was a substrate of OCT-1, which is of low clinical relevance.

5.3 Preclinical Safety Data

Genotoxicity.

Nintedanib was not genotoxic in the bacterial reverse mutation assay, in vitro mouse lymphoma cell forward mutation assay, and in vivo rat micronucleus assay.

Carcinogenicity.

There was no evidence of carcinogenicity in a 103-week study in mice at oral doses of nintedanib up to 30 mg/kg/day, or in a 104-week study in rats at oral doses up to 10 mg/kg/day, resulting in approximately 2.5 and 0.15 times the human exposure (AUC) at the maximum recommended human dose (MRHD) of 200 mg twice daily, respectively.

6 Pharmaceutical Particulars

6.1 List of Excipients

Each Ofev capsule also contains medium chain triglycerides, hard fat and lecithin.
The capsule shell contains gelatin, glycerol 85%, titanium dioxide, iron oxide red (CI 77491), iron oxide yellow (CI 77492).
The black printing ink (Opacode Type S-1-17823) contains shellac, ethanol, propylene glycol, and iron oxide black (CI 77499).

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 25°C. Store in the original package in order to protect from moisture.

6.5 Nature and Contents of Container

Ofev 100 mg capsules are packaged in aluminium/aluminium blisters containing 10 capsules per blister. Ofev 100 mg are supplied in packs of 60 capsules.
Ofev 150 mg capsules are packaged in aluminium/aluminium blisters containing 10 capsules per blister. Ofev 150 mg are supplied in packs of 60 capsules.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Nintedanib esilate is a bright yellow powder. The octanol-water partition coefficient (log Pow) for nintedanib esilate free base was determined to be 3.6, which demonstrates the lipophilic character of the molecule. Due to the ionisable groups in nintedanib esilate, the lipophilicity profile is strongly pH dependent. At physiological pH (pH = 7.4), the apparent partition coefficient (log D) was calculated to 3.0. The molecule is less lipophilic in the acidic pH range (log D ≤ 1 for pH < 5).
Nintedanib esilate is soluble in water. A saturated solution in water was found to have a concentration of 2.8 mg/mL and exhibited an intrinsic pH of 5.7. The solubility of nintedanib esilate is strongly pH dependent with an increased solubility at acidic pH, particularly for pH < 3. The highest solubility of nintedanib esilate in organic solvents is observed in methanol and N-methylpyrrolidone. The best solubility in pharmaceutically relevant co-solvents is observed in propylene glycol.

Chemical structure.

Chemical name: 1H-Indole-6-carboxylic acid, 2,3-dihydro-3-[[[4-[methyl[-(4-methyl-1-piperazinyl) acetyl]amino]phenyl]amino] phenylmethylene]-2-oxo-, methyl ester, (3Z)-, ethanesulfonate (1:1).
Molecular formula: C31H33N5O4.C2H6O3S.
Molecular weight: 649.76.
Structural formula:

CAS number.

656247-18-6.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription Only Medicine.

Summary Table of Changes