OFEV 150mg Boehringer Treatment Treated patients with non -cell lung cancer, spontaneous pulmonary fibrosis (6 blisters x 10 tablets)

Dosage form Box of 6 blisters x 10 tablets
Specifications Nintedanib

Ingredient

Composition informationContent
Nintedanib150mg

Uses

Indication

ofev® is used in combination with Docetaxel to treat patients with small cell lung cancer (NSCLC) at the progressive, metastatic or recurrent NSCLC is a tissue tissue carcinoma after treatment.

ofev® is indicated for the treatment of spontaneous pulmonary fibrosis (IPF) and reduces disease progression.

Pharmacokinus

Medication group: Anti -cancer - Tyrosine Kinase inhibitors.

Code ATC: L01xe31

Mechanism of action

For NSCLC treatment:

Nintedanib is a third-order Angiokinase inhibitor that prevents the activity of the kinase enzymes of blood vascular growth factors (VEGFR 1-3), platelet-derived growth factors (PDGFR α and ß) and fibroblen growth factors (FGFR 1-3). Nintedanib binds competition to adenosine triphosphate (ATP) of these receptors and prevent the transmission of intracellular signals, this is the process of determining the growth and existence of endothelial blood tissue cells as well as cells around blood vessels and muscle cells. In addition, Tyrosine Protein Kinase is similar to FMS (FLT) -3, Tyrosine protein kinase specific of the lymphocyte (LCK) and Tyrosine -Protein Kinase SRC (SRC) of cancer -causing cancer gene are also inhibited.

For IPF treatment:

Nintedanib is a small molecular tyrosine kinase inhibitor including receptor inhibitors of platelet-derived growth factors (PDGFR) α and ß, fibrous plant growth factors (FGFR) 1-3 and receptors of endothelial growth factors (VEGFR 1-3). Nintedanib bonds to compete into the adenosine triphosphate (ATP) mounting drive of these receptors and prevent the transmission of intracellular signals, which is the process of deciding on the development, immigration and change of fibroblasts representing the main mechanism in spontaneous pulmonary fibrosis (IPF). In addition, Nintedanib also inhibits FLT-3 Kinase, LCK Kinase, Lyn Kinase and SRC Kinase.

Pharmacological effects

For NSCLC treatment:

Tumor hyperlike hyperlage is an essential characteristic that contributes to tumor growth, progression and metastasis and is mainly onset by the release of vascular precursor factors (i.e. VEGF and BFGF) secreted by tumor cells to attract the blood vascular cells of the host as well as non -vascular cells to facilitate the supply of oxygen and nourish the blood vessel system. In the model of disease in preclinical test, the Nintedanib therapy effectively intervenes on the formation and maintenance of the blood vessel system of the tumor, resulting in inhibiting tumor growth and stagnating blood flow in the tumor. In particular, the treatment of tumor is transplanted with an experiment with Nintedanib leads to rapid reduction in capillary density in the tumor, the Rouget cell covers the blood vessels and the perfusion in the tumor.

Magnetic resonance measurement (DCE - MRI) shows the anti -vascular hypertrophy effect of Nintedanib in humans. This effect is not clear depending on the dose, but most of the observation response at the dose ≥ 200 mg. Logistic regression analysis shows statistical significance between anti -vascular proliferation and Nintedanib levels. This DCE - MRI results were seen after taking the first dose of 24-48 hours and was maintained or even increased after continuous treatment for weeks. There is no correlation between DCE - MRI response and the results of the target lesions significantly decreased in terms of clinical, but the DCE - MRI response is associated with the stability of the disease.

For IPF treatment:

The activation of the signal waterfall of FGFR and PDGFR is the decisive factor to participate in the growth and migration of pulmonary fibroblasts/ muscle fibroids, and cells distinguished in spontaneous pulmonary fibrosis. Currently, the possible effects of VEGFR inhibitors on spontaneous pulmonary fibrosis have not been completely clarified. At the molecular level, Nintedanib is thought to inhibit the signal waterfall, which is intermediaries for the development and immigration of pulmonary fibroblasts by attaching the adenosine triphosphate (ATP) mounting of intracellular kinase receptors, thus interfering with cross -activation through automated phosphorylation of binary receptors. On Vitro, target receptors are inhibited by Nintedanib at low concentrations of nano levels. On spontaneous patients with pulmonary fibrosis, Nintedanib inhibits the proliferation of cells stimulated by PDGF, FGF and VEGF with EC50 values, equivalent to 11 nmol/l; 5.5 nmol/l and less than 1 nmol/l. At the concentration between 100 and 1000 nmol/l, Nintedanib also inhibits the immigration of the fibroblasts caused by PDGF, FGF and VEGF and inhibits the conversion of fibroids into muscle fibroblasts due to TGF-Beta 2 sensor. It is not clear the role of Nintedanib's anti -vascular activity in its mechanism of activity in pulmonary fibrosis. In In Vivo studies, Nintedanib shows anti -fiber and anti -inflammatory effects.

Dynamic pharmacokinetics

The pharmacokinetics (PK) of Nintedanib can be considered as linearly (ie single -dose data that can be extracted for multiple -doses of data). The accumulation of drugs when using multiple doses is 1.04 times for CMAX and 1.38 times for AUCT. Nintedanib's bottom concentration remains stable for more than a year.

absorption: Nintedanib reaches a maximum concentration in plasma about 2-4 hours after taking soft gelatin capsules in full eating conditions (from 0.5-8 hours). The absolute bioavailability of a 100 mg dose is 4.69% (KTC 90%: 3,615-6.078) in healthy volunteers. The absorption and bioavailability of the drug is reduced by the effects of transportation and the initial metabolism.

Calculate the proportional proportion of the dose is shown by the increased Nintedanib level (the dose range from 50-450 mg once daily and 150 - 300 mg twice daily). The concentration in plasma achieved stable state at least within a week of medication.

After eating, the Nintedanib concentration increased by about 20% compared to the drug in hunger (KTC: 95.3-152.5%) and the absorption was slowed (Tmax median when hungry: 2 hours; no: 3.98 hours).

Distribution

Nintedanib follows the dynamics of at least two stages distributed. After intravenous infusion, there was a large volume of drugs distributed (VSS: 1050 L, 45.0% GCV).

The ratio of protein cohesion in human plasma on Vitro in Nintedanib's in vitro is 97.8%. Albumin serum is considered a major bonding protein. Nintedanib is given priority in plasma ratios with plasma/plasma ratios of 0.869.

Metabolism

The common metabolic reaction to Nintedanib is the hydrolysis reaction by the esterase enzymes that make up the bibf 1202 free acid -based acid. BIBF 1202 is then linked to glucuronide by UGT enzymes, namely UGT 1A1, UGT 1A7, UGT 1A8, and UGT 1A10 to become BIBF 1202 Glucuronide. Only a small amount of Nintedanib has been biological transformation through the CYP metabolic path with CYP 3A4 as the main enzyme participating. In ADME research in humans, it is not possible to detect the main metabolites depending on CYP in plasma. On Vitro, metabolism depends on CYP, accounting for about 5% compared to about 25% through the ester hydrolysis reaction.

For NSCLC treatment:

In Vivo clinical experiments, BIBF 1202 does not record the effectiveness of BIBF 1202, although this substance is active at the target receptors of the active ingredient.

Elimination

The total clearance of plasma after intravenous infusion is high (Cl: 1390 ml/ min, 28.8% GCV). About 0.05% of the drug dose (31.5% GCV) is eliminated in urine in the unchanged form of the active ingredient within 48 hours after oral or about 1.4% of the dose (24.2% GCV) after intravenous infusion; The renal clearance is 20 ml/ minute (32.6% GCV). After taking Nintedanib mounted [14C], radioactive substances are excreted mainly through feces/ secretion of bile (93.4% dose, 2,61% GCV). The excretion through the kidneys contributes small to the total clearance (0.649%, 26.3% GCV). The entire recovery is considered completely (over 90%) within 4 days after taking the drug. Nintedanib's last waste sale time is about 10-15 hours (about 50% GCV).

concentration relationship - response

For NSCLC treatment:

In pharmacokinetic exploration analysis (PK)- a disadvantageous effect, the higher Nintedanib concentration tends to be associated with increased liver enzymes, but does not accompany adverse events on the gastrointestinal tract.

PK-effective analysis is not done for clinical final evaluation criteria. Logistic regression shows a statistical significance between Nintedanib levels and responds on DCE-MRI.

For IPF treatment:

The concentration-response analysis shows that the relationship is similar to the maximum efficiency between the concentration in the usage range in phase II and III and the annual fVC ratio with the EC50 is about 3-5 ng/ml (relative standard error: 54-67%).Safe, seems to have a weak relationship between Nintedanib levels in plasma and increase in ALT and/ or AST. The actual dosage may be a better predictive factor than the risk of diarrhea at any extent, even if it does not exclude the risk factor that determines the risk of drug concentration in plasma (see the warning and cautious part when taking the drug).

internal and external factors; Special populationNintedanib's PK characteristics are the same in healthy volunteers, spontaneous pulmonary fibrosis patients and cancer patients. Based on the results of the population pharmacokinetics analysis (poppk) and description studies, the Nintedanib concentration is not affected by gender (adjustable body weight), mild and medium renal failure (evaluated through creatinine clearance), liver metastas, state scales according to Ecog, alcohol level, or P-GP genotype. Popular pharmacokinetic analysis shows moderate effects on Nintedanib concentration depending on age, weight and race. Based on the high variation in individuals about the observed concentration in Lume-Lung 1 clinical trial, these effects are not considered clinical significance (see warning and caution when taking the drug).

Age

Nintedanib levels increase linearly by age. AUCT, SS decreased by 16% in a 45 -year -old patient (5th values) and an increase of 13% in a 76 -year -old patient (95th values) compared to a median patient of 62. About 5% of the population is greater than 75 years old.

has not conducted research in children's population.

Body weight

A correlation between body weight and Nintedanib level has been recorded. AUCT, SS increased by 25% in a patient weighing 50 kg (the 5th values) and decreased 19% in a patient weighing 100 kg (the 95th differential value) compared to a medium -weight patient 71.5 kg.

Race

The average of the population of Nintedanib concentration in Chinese, Taiwanese, and India patients is 33-50% higher and in Japanese patients, it is 16% higher while this value in Koreans is 16-22% lower than whites (corrected body weight). Data on black people are very limited but still in the same value as in white people.

For NSCLC treatment:

However, based on the high variation between individuals in terms of concentration, these effects are not considered clinical significance.

Liver failure

In a separate single -dose phase study and comparison with healthy patients. Nintedanib concentration is based on CMAX and AUC in mild liver volunteers than 2.2 times higher. (Child Pugh A; 90% CI respectes 1.3 - 3.7, respectively for cmax and 1.2 - 3.8 for AUC). In the average volunteer of liver failure (Child Pugh B), the concentration based on CMAX is 7.6 times higher (90% CI 4.4 - 13.2) and concentration based on AUC higher than 8.7 times (90% CI 5.7 - 13.1) compared to healthy volunteers. Do not study in patients with severe liver failure.

Use simultaneously with pirfenidone

For IPF treatment:

Researching the simultaneous use of Nintedanib with Pirfenidone has been conducted in a parallel group design study in Japanese patients with spontaneous pulmonary fibrosis. 24 patients were treated with Nintedanib 150mg twice daily for 28 days. In particular, 13 patients were further treated with Nintedanib while long -term use of Pirfenidone, 11 patients used for Nintedanib. Nintedanib concentration tends to be lower when treated simultaneously with Pirfenidone than using only Nintedanib. Nintedanib does not affect the pharmacokinetics of Pirfenidone. Due to the short time of use and the number of patients is small, it is impossible to draw conclusions about the safety and effectiveness of this coordination.

Ability to interact with drugs - drugs

Metabolism

Interaction between Nintedanib and the substrates of CYP, CYP inhibitors, or CYP induction substances are expected to occur, because Nintedanib, BIBF 1202, and BIBF 1202 glucuronide do not inhibit or stimulate CYP enzymes in clinical and clinical trials and Nintedanibs are also not transformed by CYP enzymes at a negative level.

Shipping

Nintedanib is a substrate of P-GP. About Nintedanib's interaction with this shipping, see the interaction section of the drug. Nintedanib has been shown not to be an OatP-1B1, OATP -1B3, OATP-2B1, OATP-2B1, OATP-OATP or MRP-2. Nintedanib is not a substrate of BCRP. Only record the ability to inhibit the low octel, BCRP, and P-GP on in vitro, which is considered to be less clinical significance. This record also applies the same to Nintedanib as a substrate of OCT-1.

Before taking OFEV 150mg Boehringer Treatment Treated patients with non -cell lung cancer, spontaneous pulmonary fibrosis (6 blisters x 10 tablets)

How to use

Ofev® capsules are used orally, should be used with food, swallow whole tablets with water, and should not chew or crush the pill.

Dosage

for NSCLC treatment:

Treatment with ofev® should be started and supervised by an experienced doctor in the use of anti -cancer therapy.

Regarding dosage, usage, and how to adjust the dosage of Docetaxel, please refer to the corresponding docetaxel product information.

The recommended dose of ofev® is 200 mg twice daily, about 12 hours apart, on the 2nd to 21th of the 21 -day standard treatment cycle with Docetaxel.

Do not use ofev® on the same day using docetaxel chemotherapy (= day 1).

Do not exceed the maximum daily recommendation of 400 mg.

Patients may continue treating with ofev® after stopping docetaxel when they still have clinical benefits or until unacceptable toxicity occurs.

For IPF treatment:

Should start treatment with ofev® because doctors have experience in IPF diagnosis and treatment.

Dosage recommended by ofev® is 150 mg twice daily use about 12 hours apart.

Do not exceed the maximum daily dose of 300 mg.

Dose adjustment

For NSCLC treatment:

To manage side effects (see Table 1 and 2 ), the first measure is to suspend treatment with ofev® until the significant adverse reaction has been restored to the extent that it allows to continue treatment (to degree 1 or initial level). It is possible to reuse ofev® with a decreased dose. It is recommended that each dose of about 100 mg per day (ie reduced 50 mg per dose) based on the safety and tolerance of each individual as described in Table 1 and Table 2 .

In case the adverse reactions still last for the patient when the patient does not tolerate the dose of 100 mg twice daily, it is necessary to stop treating with ofev® .

In case there is a significant increase in the enameled aminotransferase (AST) / Alanine Aminotransferase (ALT)> 3 times the normal limit on (ULN) in combination with total bilirubin tank ≥ 2 times ULN and Alkaline Phosphatase ALKP Table 2 ofev® . Should end permanently treatment with ofev® , unless detected for other reasons.

Table 1: Recommended the dose adjustment for ofev® In case of diarrhea, vomiting and adverse adverse reactions or not related to hematology except for liver enzyme hyper enzyme (see Table 2 ).

CTCAE adverse reaction*

or

diarrhea ≥ level 3 despite anti -diarrhea treatment **




After stopping the drug and recovering to degree 1 or initial level, reducing the dose from 200 mg twice daily to 150 mg twice daily and - if considered, it is necessary to reduce the dose twice - from 150 mg twice daily to 100 mg twice daily.

and/or

Nausea ≥ level 3 despite anti -vomiting treatment **

other adverse reactions related to hematology with a level of ≥ level 3.

** also see the section warning and caution when taking the drug.

Table 2: Recommended dose adjustment ofev® (Nintedanib) in the event of an increase in AST and/or Alt and Bilirubin. Increase AST/Alt and Bilirubin

Dosage adjustment

or

Increase AST and/or ALT values ​​to> 5 times ULN.

After stopping the drug and the value of the Transaminase enzyme recovers to ≤ 2.5 times Uln in combination with bilirubin to normal levels, reducing the dose from 200 mg twice a day to 150 mg twice daily and - if considered, it is necessary to reduce the dose twice - from 150 mg twice daily to 100 mg twice daily. Uln combined with total bilirubin increase to ≥ 2 times ULN and ALKP

alkp: alkaline phosphatase; Uln: Upper Limited Normal (above normal limit).

For IPF treatment:

In addition to treating more symptoms if needed, controlling side effects (see items warning and caution when taking the drug, the unwanted effect of the drug ) of ofev® may include reducing the dose and temporary suspension until the specific adverse reaction has recovered to the level of permission to continue treatment. Treatment with ofev® may continue with normal doses (150 mg twice daily) or a decrease doses (100 mg twice daily). If a patient is intolerant to a dose of 100 mg twice daily, it is recommended to stop treating with ofev® .

In case of stopping treatment due to increased transaminase enamel (AST or ALT)> 3 times ULN, when the Transaminase enamel returns to the initial limit, it may be started to re -treat with ofev® with normal doses (150 mg twice daily) or with a decrease doses (100 mg twice a day), then it can increase to normal doses (150 mg daily). (See the section warning and caution when taking the drug, the unwanted effect of the drug ).

Special population

Children

Safety and effectiveness of ofev® in children have not been studied in clinical trials.

Elderly patients (> 65 years old)

There is no overall difference in safety and effectiveness in elderly patients compared to patients under 65 years old. No need to adjust the starting dose according to the age of the patient (see section pharmacokinetic properties ).

Race

Based on the pharmacokinetic analysis of the population (-PK), do not need to adjust the dose ofev® before using (see the pharmacokinetic characteristics ). Safety data on black skin patients is limited.

Body weight

Based on the pharmacokinetic analysis of the population (-PK), do not need to adjust the dose ofev® before use (see the pharmacokinetic characteristics ).

kidney failure

less than 1% of the Nintedanib single dose is excreted through the kidneys (see the pharmacokinetic characteristics ). It is not necessary to adjust the starting dose in patients with mild to moderate renal failure. No safety, effectiveness, and pharmacokinetics of Nintedanib in patients with severe renal impairment (creatinine clearance

Hepatic failure

Nintedanib is excreted mainly through bile/ fertilizer (> 90%). The drug concentration in the body increases in patients with hepatic impairment (Child Pugh A, Child Pugh B; See section pharmacokinetic characteristics ).

Not studying the safety and effectiveness of Nintedanib in patients with liver failure Child Pugh B and C. It is not recommended to use ofev® to treat medium and severe patients (Child Pugh B), see the Dynamic characteristics .

For NSCLC treatment:

Based on clinical data, no need to adjust the starting dose in patients with mild liver impairment (Child Pugh A, see the section warning and caution when taking drugs ).

For IPF treatment:

In patients with mild liver failure (Child Pugh A), the recommended dose of ofev® is 100 mg twice daily about 12 hours apart.

In patients with mild liver failure (Child Pugh A), it is advisable to consider suspending or stopping treatment to control side effects.

What to do when overdose? The highest single dose of Nintedanib used in phase 1 studies is 450 mg once a day. In addition, there are 2 patients who have taken overdose to a maximum of 600 mg twice daily to 8 days. The disadvantageous events are in accordance with the known safety records of Nintedanib, which means increasing liver enzymes and digestive symptoms. Both patients recover from these adverse reactions.

In case of overdose, it is recommended to suspend treatment and start using appropriate general support measures.

For IPF treatment:

In Inpulsis tests, a patient accidentally taken a dose of 600mg in a total of 21 days. A non -serious disadvantage (nasopharyngitis) has occurred and resolved during the wrong dosage period, no events of the events have been reported.

What to do when you forget 1 dose? However, if the time to relax with the next dose is too short, skip the dose and continue the calendar of the drug. Do not use double doses to compensate for missed dose.

Side Effects

Summary of safety records.

To manage the selective adverse reactions, please see the warning and caution when taking the drug .

For NSCLC treatment:

Safety data provided by the following is based on the key study globally in phase 3, with a code of 1199.13 (Lume-Lung 1) with a double, random design, comparison of Nintedanib therapy combined with docetaxel with a placebo combination of Docetaxel in patients with NSCLC on the spot of progressive, metastatic, or NSCLC after treatment with treatment. The most common adverse reactions characterized by Nintedanib are diarrhea, increasing the values ​​of liver enzymes (ALT and AST) and vomiting. Table 3 Summary of adverse reactions according to the classification of the organ system (SOC).

Table 3: Classification of side effects based on adverse events in patients with NSCLC is tissue carcinoma.

The following terms are used to classify the side effects according to the frequency of encountered: Very common (≥ 1/10), popular (≥ 1/100 to

frequency

Agency system

Very popular

(≥ 1/10)

popular

(≥ 1/100

Not popular

(≥ 1/1000

Air-car.

infection 1.

electrolyte imbalance.

dehydration.

Losing weight.

Hypertension.

vomiting.

Nausea.

Abdominal pain.

stomatitis.

Pancreatitis.

Hepatogle disorders increase alanine aminotransferase, increase aspartate aminotransferase, increase blood phosphatase. Drugs.

Skin rashes.

2) The frequency does not increase in patients treated with Nintedanib in combination with Docetaxel compared to the placebo patient in combination with Docetaxel.

3) The pancreatitis events have been reported in patients using Nintedanib to treat IPF and NSCLC. Most of these events are reported in IPF patients.

Describe unwanted effects:

diarrhea

Diarrhea occurs at 43.4% (> level 3: 6.3%) Patients with glandular cancer patients in the Nintedanib group. Most of the side effects appear in a close relationship with the use of Docetaxel. Most patients recover diarrhea after stopping treatment, use anti -diarrhea therapy and reduce the dose of Nintedanib.

The recommended measures and adjusting the dose in case of diarrhea, see in turn in the warning and cautious section when taking the drug and the dosage, usage .

Hyper enzyme and hypoglycemia

Side effects related to the liver occur in 42.8% of patients treated with Nintedanib. Approximately one -third of these patients have severe side effects related to the liver ≥ level 3. In patients with rising liver indicators, the use of a diagram of a staircase has been established as appropriate measures and only need to stop treatment in 2.2% of patients. In most patients, increasing liver indicators can recover.

Information about special patient groups, recommended measures and adjust the dose in case of increased liver enzymes and bilirubin, see in turn in the warning and cautious when taking drugs and the dosage, usage .

Neutral leukemia, neutropenia fever and blood infection

Hemorrhage and neutropenia fever have been reported as complications of neutropenia. Hemorrhage infection rate (1.3%) and neutropenia fever (7.5%) increased when treated with Nitendanib compared to the placebo group. The monitoring of blood counts during treatment is important, especially in the treatment process in combination with docetaxel (see section warning and caution when taking drugs ).

Bleeding

In the post -circulating period, serious and non -serious bleeding events, some of which lead to deaths, including patients with or without anticoagulant treatments or drugs that may cause bleeding. The after -circulating hemorrhage events include but not limited to the digestive tract, the respiratory system and the central nervous organs, with the most common frequency of respiratory systems (see the warning and cautiousness when taking the drug ).

Gastrointestinal tract puncture

Based on the mechanism of action of the drug, the gastrointestinal perforation may occur in patients treated with Nintedanib. However, the frequency of patients perforation is low.

Peripheral neurological disorders

Peripheral neuropathy is also known to occur when treated with docetaxel. Peripheral neurological disorders are reported in 16.5% of patients treated with placebo and 19.1% of patients treated with Nintedanib.

For IPF treatment:

Nintedanib has been studied in clinical trials with 1529 patients with spontaneous pulmonary fibrosis (IPF).

Safety data provided by the following is based on two phase 3 studies, with random design, double blindness, verified by the placebo over 1061 patients, comparing the treatment group and Nintedanib 150 mg twice daily with the placebo group for 52 weeks (Inpulsis-1 and Inpulsis-2).

The most often reported events are most often related to the use of Nintedanib including diarrhea, nausea, vomiting, abdominal pain, decreased appetite, weight loss and increased liver enzymes.

Table 4: Summary of side effects classified by frequency in Patient IPF

The following terms are used to classify the side effects according to the frequency of encountered: Very common (≥ 1/10), popular (≥ 1/100 to

frequency


Agency system

Very popular

(≥ 1/10)

popular

(≥ 1/100

Not popular

(≥ 1/1000

Blood disorders and lymphatic system

Losing weight.

Nausea.

Abdominal pain.

vomit. Blood phosphatase alkaline.

2) Observed serious and non -serious bleeding events, some of which lead to death in the post -circulating period.

Describe unwanted effects:

diarrhea

Diarrhea has been reported at 62.4% of patients treated with Nintedanib. The event was reported as a severity of 3.3% of patients treated with Nintedanib. More than two -thirds of patients who have diarrhea report this side effect in the first three months of treatment. Diarrhea leads to permanent stop treatment in 4.4% of patients; Other events can be controlled by anti -diarrhea therapies, dose reduction or suspension of treatment (see section warning and caution when taking drugs ).

Liver enzyme

Increase liver enzymes (see the section warning and caution when taking drugs ) is reported in 13.6% of patients treated with Nintedanib. Hyper enzyme enzyme can be recovered and not related to liver disease with clinical manifestations. Other information about special patient groups, recommended measures and adjust the dose in case of diarrhea and increased liver enzymes, see in turn in the warning and cautious when taking drugs and dosage, usage .

Notice immediately to the doctor or pharmacist the harmful reactions encountered when using the drug.

Warnings

Before using the drug you need to read the instructions carefully and refer to the information below.

Contraindicated

contraindicated use ofev® in patients who have known sensitivity to Nintedanib, Lac, Soy or any excipients of the drug (see item ingredients formula ).

Contraindicated to use ofev® during pregnancy (see section fertility, pregnancy and nursing mothers ).

For NSCLS treatment:

For Docetaxel's contraindications, please refer to the corresponding docetaxel product information.

Caution when using

digestive disorders

For NSCLS treatment:

  • diarrhea:

    • Diarrhea is the most frequent gastrointestinal event and appears in the close relationship with the use of Docetaxel (see the item of the unwanted effect of the drug ). In Lume-Lung 1 clinical trial (see section clinical trial ), most patients have mild to medium mild diarrhea. 6.3% of patients with diarrhea ≥ degree 3 in combined treatment compared to 3.6% of patients are single treatment with Docetaxel. It is necessary to treat diarrhea when there are first signs by adequate rehydration and use of anti -diarrhea drugs such as Loperamid, and may have to be suspended, dose or stop therapeutic with ofev® (see section Dosage, usage ).

  • Nausea and vomiting:

    • Nausea and vomiting, mostly from mild to medium level, are the most frequent gastrointestinal adverse events (see items unwanted effects of the drug ). If prolonged symptoms have been taken care of properly (including anti -vomiting treatment), it may be necessary to reduce the dose, suspend, or stop therapeutic ofev® (see section dosage, usage ).

    In case of dehydration, infusion and electrolytes. Must monitor the concentration of electrolytes in plasma if other digestive adverse events occur.

    For IPF treatment:

  • diarrhea:

    • In Inpulsis tests (see section clinical trial ), diarrhea is the most frequent gastrointestinal event, equivalent to 62.4% compared to 18.4% in patients treated with ofev® compared to placebo (see item unwanted effects of drugs ). In most patients, this event has a mild to medium level and appears in the first 3 months of treatment. Diarrhea leads to a dose of over 10.7% of patients and stop using Nintedanib in 4.4% of patients.

    It is necessary to treat diarrhea when there are first signs by fully rehydration and anti -diarrhea, such as loopamid, and may have to stop treating. Can be treated again with ofev® with a reduction (100 mg twice daily) or with a normal dose (150 mg twice daily). It is advisable to stop using ofev® in case of severe, persistent diarrhea despite symptom treatment.

  • Nausea and vomiting:

    • Nausea and vomiting are the most commonly reported adverse events (see the unwanted effect of the drug ). In most patients with vomiting and nausea, the level is mild to moderate. Nausea leads to stop use of Nintedanib in 2.0% of patients. Vomiting leads to stopping use in 0.8% of patients.

    may have to reduce the dose or stop treatment if persistent symptoms, despite the appropriate supportive treatment (including treatment with anti -vomiting drugs). Can continue treatment with a decrease dosage (100 mg twice daily) or with a normal dose (150 mg twice daily). It should be stopped using ofev® in cases of severe, persistent symptoms.

    diarrhea and vomiting can lead to dehydration and/ or electrolyte imbalance.

    neutropenia and blood infection

    For NSCLC treatment:

    Frequency of neutropenia by CTCAE> Degree 3 is higher in patients with ofev® in combination with Docetaxel compared to Docetaxel treatment. The next complications such as hemorrhage or neutropenia also occur.

    Need to monitor blood formula during the treatment period, especially during the treatment period in combination with Docetaxel. The monitoring of blood formula regularly must be done from the beginning of each treatment cycle and around the time when the blood formula is at the lowest level (NADIR) with the patient who is being treated for Nintedanib in combination with the docetaxel and when clinically indicated after the final coordination treatment.

    Liver function

    Safety and effectiveness of ofev® has not been studied in patients with average liver failure (Child Pugh B) or severe (Child Pugh C). Therefore, it is not recommended for treatment ofev® in these patients (see section pharmacokinetic properties ).

    For NSCLC treatment:

    Due to the increased level of drug concentration in patients with mild liver failure, the risk of side effects may increase (Child Pugh A, see the dosage, how to use ).

    has recorded cases of liver damage caused by drugs when treated with Nintedanib.

    Using Nintedanib is often accompanied by increased liver enzymes (ALT, AST, ALKP (Alkalin Phosphathase)), gamma-glutamyltransferase (GGT) and Bilirubin. This increase can recover in most cases.

    Women and Asian patients are at higher risk of increasing liver enzymes.

    Nintedanib concentration increases linearly for patients, correlation inversely with weight can lead to a higher risk of increasing liver enzymes (see section pharmacokinetic characteristics ). Correct monitoring recommendations in patients with these risk factors.

    It is necessary to check the concentration of transaminase, alkp and bilirubin enzymes before starting a combination of ofev® with docetaxel. These values ​​must be monitored when clinical indicators or periodic monitoring during the treatment period, that is, in the period in combination with Docetaxel at the beginning of each treatment cycle and monthly, in the case of continuing to use ofev® as the treatment after the DOCETAXEL has stopped.

    If the liver enzymes increase, may need to be suspended, reduce the dose or stop treatment with ofev® (see the dosage, how to use/table 2 ). Need to find other causes of increased liver enzymes and have the corresponding solution if necessary.

    If there is a significant change in the values ​​of liver enzymes (AST/ALT increases> 3 times ULN) in combination with bilirubin increased ≥ 2 times ULN and ALKP ofev® . The permanent treatment should be terminated with ofev® , unless detected for other causes (see section dosage, usage/table 2 ).

    For IPF treatment:

    Due to the increased level of drug concentration in patients with mild liver failure, the risk of side effects may increase (Child Pugh A). Patients with mild liver failure (Child Pugh A) should be treated for the dose reduction ofev® (see section Dosage, usage and pharmacokinetic properties ).

    has recorded cases of liver damage caused by drugs when treated with Nintedanib.

    Using Nintedanib comes with the increase in liver enzymes (ALT, AST, ALKP, Gamma-Glutamyl-Transferase (GGT)) and Bilirubin. Increasing transaminase enamel is reversible when reducing the dose or suspension of treatment. Liver transaminase enzyme test should be tested and bilirubin levels before the beginning of treatment with ofev® , and then periodically tested (for example, at each patient examination) or when clinically indicated.

    Patients with low weight ( Nintedanib concentration increases linear with the age of patients who can lead to a higher risk of increasing liver enzymes (see section pharmacokinetic properties ).

    Advice closely monitoring in patients with these risk factors.

    If Men Transaminase (AST or ALT) increases> 3 times the normal limit (ULN), recommends reducing the dose or stopping treatment with ofev® and should closely monitor patients. When the transaminase enzymes return to the original value, it may increase back to normal doses (150 mg twice daily) or start treating with ofev® with a decrease dose (100 mg twice daily) and then may increase the normal dose (see item dosage, usage/recommended dose ). If the test shows that increased liver enzymes, there are additional clinical symptoms or signs of liver damage, such as jaundice, must end permanently treatment with ofev® . It is necessary to consider other causes of liver enzymes.

    Bleeding

    For NSCLC treatment:

    VEGFR inhibitor may be accompanied by an increased risk of bleeding. In clinical trial (Lume-Lung 1) with ofev® , the frequency of bleeding in both treatment groups is similar. Mild to moderate nosebleeds are the most common hemorrhage. There is no report on the imbalance on the respiratory tract or death or hemorrhage in the brain. The hemorrhagic events mainly lead to deaths related to tumors.

    In the post -circulating period, observing serious and non -serious bleeding events, some of which lead to death. In patients, there has been a 3/4 bleeding event, so carefully evaluate the benefits/risks when continuing to treat with ofev® and can consider stopping treatment with ofev® . If you continue treating with ofev® , recommend daily dose reduction (see section dose, usage/table 1 ).

    Patients with recent pulmonary bleeding (> 2.5 ml of bright red blood) as well as patients with tumors in the center with local invasive evidence of large blood vessels on X -rays or evidence of cave tumors or necrotic tumors on X -rays are excluded from clinical trials. Therefore, it is recommended not to treat ofev® for these patients.

  • Brain metastasis

    • Stable brain metastasis

    The frequency of cerebral hemorrhage does not increase in patients with brain metastases that have been properly treated but still stable ≥ 4 weeks before starting treatment with ofev® . However, it is necessary to closely monitor the signs and symptoms of cerebral hemorrhage in these patients.

    progressive brain metastasis

    Patients with progressive metastasis are excluded from clinical trials and are not recommended for treatment with ofev® .

  • anticoagulant treatment

    • There is no data on patients who tend to bleed by genetic or patients who have received a full dose of anticoagulant therapy before starting treatment with ofev® . There is no increase in the frequency of hemorrhage in patients who are using low molecular weight heparin or acetylsalicylic acidic acid. Patients with vascular thrombosis during treatment and those who need anticoagulants are still allowed to continue using ofev® and do not see increased frequency of bleeding. Regular monitoring of prothrombin, Inr or clinical hemorrhage for patients used in combination with anticoagulants such as warfarin or phenprocoumon.

    For IPF treatment:

    VEGFR inhibitor may be accompanied by an increased risk of bleeding. In the Inpulsis test with ofev® , the frequency of patients who have a slightly higher hemorrhage in the group uses ofev® (10.3%) than the placebo group (7.8%). Neonutoating bleeding is the most common hemorrhage. Serious hemorrhage events occur with low and similar frequency in two groups (placebo groups: 1.4%; groups used ofev® : 1.3%).

    Patients who have been known to have a risk of bleeding include patients who tend to bleed by genetics or patients who are taking adequate doses of anticoagulants are not selected in Inpulsis studies. Therefore, only ofev® for these patients when the prognostic benefits are out of potential risks. In the post -circulating period, observing serious and non -serious bleeding events, some of which lead to death.

    Aortic thrombolytic events

    Be cautious when treating in patients at higher risk of cardiovascular disease, including coronary artery disease. It is important to consider stopping the drug in patients with symptoms or signs of acute myocardial ischemia.

    For NSCLC treatment:

    The frequency of arterial thromboembolism events is the same between the two treatment groups in phase 3 of the study of 1199.13 (Lume-Lung 1). Patients with a recent history of myocardial infarction or stroke have been excluded from the study. However, there has been an increase in the frequency of arterial thromboembolism events on spontaneous pulmonary fibrosis (IPF) when using monomers with Nintedanib.

    For IPF treatment:

    Patients with a recent history of myocardial infarction or stroke have been excluded from Inpulsis tests. Aortic thrombolytic embolism is not regularly reported: over 0.7% of patients in the placebo group and 2.5% in patients in the Nintedanib treatment group.

    While adultery events reflect anemia on the heart are the same between Nintedanib and placebo groups, the proportion of patients with myocardial infarction in the Nintedanib group is higher (1.6%) than the placebo group (0.5%).

    Venous thrombosis

    For NSCLC treatment:

    Patients treated with ofev® have an increase in the risk of venous thrombosis including deep vein thrombosis. Need to closely monitor thrombolytic events in these patients. ofev® should stop using ofev® in patients with venous thrombosis reactions that are life -threatening.

    For IPF treatment:

    In Inpulsis tests, there is no observation of an increase in the risk of venous thrombosis in patients treated with Nintedanib. Based on the mechanism of action of Nintedanib, the patient may be increased at risk of thrombotic embolism.

    Gastrointestinal tract puncture

    Based on the mechanism of action of Nintedanib, the patient may have an increased risk of gastrointestinal perforation.

    For NSCLC treatment:

    The frequency of gastrointestinal perforation is the same between the treatment groups in Lume-Lung 1 research. It is necessary to be particularly cautious when treating patients with abdominal surgery before or a recent history of hollow organ perforation. Therefore, only ofev® should be started at least 4 weeks after a major surgery, including abdominal surgery. Treatment should be stopped ofev® permanently in patients with gastrointestinal perforation.

    For IPF treatment:

    In Inpulsis tests, there is no observation of an increase in the risk of gastrointestinal perforation in patients treated with Nintedanib. Cases of gastrointestinal perforation have been reported in the post -circulation period. It is necessary to be especially cautious when treating patients with abdominal surgery before or a recent history of empty organs, previous history of gastrointestinal ulcers, excess bags or simultaneous use with corticosteroids or NSAIDs. Therefore, only ofev® should be started at least 4 weeks after a major surgery, including abdominal surgery. Treatment should be stopped ofev® permanently in patients with gastrointestinal perforation.

    Hearing the healing of wounds

    Based on the mechanism of action of the drug, Nintedanib can reduce the healing of wounds. The frequency of slow healing of wounds is not increased in clinical trials. No studies have been conducted to survey the effects of Nintedanib on healing wounds. Therefore, treatment with ofev® should only be started or- in case of suspension due to surgery- re-use based on clinical evaluation of healing wounds adequately.

    soy lecithin

    Soft capsules ofev® contain soy lecithin (see section contraindicated ).

    Special population

    For NSCLC treatment:

    In the study of 1199.13 (Lume-Lung 1), the frequency of severe serious events in patients treated with Nintedanib and Docetaxel whose body weight is less than 50 kg than patients with body weight ≥ 50 kg; However, the number of patients with body weight is less than 50 kg. Therefore, it is recommended to closely monitor patients with body weight

    The effect of drugs on driving and operating machinery

    has not conducted research on the impact of the drug on the ability to drive and operate machinery.

    advise patients to be cautious when driving or using machines during treatment with ofev® .

    Using drugs for women during pregnancy and lactation

    fertility

    For NSCLC treatment:

    Based on preclinical studies, there is no evidence of reducing fertility in males. From semi -acute and prolonged toxicity studies, there is no evidence that the fertility in Cai mice is impaired at the body concentration corresponding to the maximum recommended dose in humans (MRHD) is 200 mg twice daily.

    For IPF treatment:

    Based on preclinical studies, there is no evidence of reducing fertility in males. From semi -acute and prolonged toxicity studies, there is no evidence that the fertility in Cai mice is impaired at the body concentration corresponding to the maximum recommended dose in humans (MRHD) is 150 mg twice daily.

    contraceptive

    Women who are likely to be pregnant under treatment with ofev® should be advised to use appropriate contraception in and at least 3 months after the last dose ofev® . It is recommended that women are likely to be pregnant during pregnancy while being treated with ofev® .

    pregnancy

    There is no information on the use of ofev® in pregnant women, but preclinical studies on animals have shown the toxicity of the drug on fertility (see section toxicity ). Because Nintedanib can also harm the fetus in humans, do not use this medication during pregnancy and have to test for pregnancy tests at least before treatment with ofev® .

    Women's patients need advice to notify their doctor or pharmacist if they are pregnant during treatment with ofev® .

    If the patient is pregnant while taking ofev® , the patient needs to be notified of the potential dangers for the fetus. Should consider stopping treatment.

    breastfeeding

    There is no information on the excretion of Nintedanib and metabolites into the mother's milk. Pre -clinical studies show that a small amount of Nintedanib and its metabolites (≤ 0.5 % of the dose) are excreted in the mother's milk.

    cannot rule out the risk of babies/ young children. Therefore, stop breastfeeding during treatment with ofev® .

    For NSCLC treatment:

    Regarding Docetaxel information related to fertility, pregnancy and lactation, please refer to the corresponding docetaxel product information.

    Drug interaction

    p-glycoprotein (P-GP)

    Nintedanib is a substrate of P-GP (see section pharmacokinetic properties ). In a study specializing in drug-drug interactions, simultaneous use with a strong P-GP inhibitor, Ketoconazole, has increased Nintedanib concentration to 1.61 times based on AUC and 1.83 times based on CMAX.

    In a drug-drug-medication-medication study study with Rifampicin, Nintedanib concentration has dropped to 50.3% based on AUC and 60.3% based on CMAX when using simultaneously with Rifampicin compared to when using Nintedanib alone.

    If used with ofev® , strong P-GP inhibitors (such as ketoconazol or erythromycin) may increase Nintedanib levels. In this case, it is necessary to monitor patients closely on the ability to tolerate Nintedanib. The suspension, dose reduction or therapeutic stops are required ofev® to control the side effects (see item dosage, how to use ).

    Strong P-GP touch substances (such as Rifampicin, Carbamazepin, Phenytoin, and St. John herbs) may reduce Nintedanib levels. It is advisable to consider the replacement of these drugs with non-P-GP induction drugs or induction at a minimum when used simultaneously with ofev® .

    Food

    Recommendation ofev® along with food (see section pharmacokinetic properties ).

    Cytochrome enzymes (CYP)

    Only a small amount of Nintedanib is transformed by biodegradable through the CYP path. Nintedanib and its metabolites are BIBF 1202 free acid root and its glucoronide complex is BIBF 1202 -Glucuronide does not inhibit or induce the CYP enzymes in preclinical studies (see pharmacokinetic properties ). Therefore, the ability to interact with drug-drugs of Nintedanib is based on the metabolism through CYP is considered low.

    Simultaneous use with other drugs

    The ability of Nintedanib to interact with unprocessed hormonal contraceptives.

    For NSCLC treatment:

    The use of Nintedanib along with Docetaxel (75 mg /m2) does not change the pharmacokinetics of both drugs to a meaningful level.

    Tyeum of drugs

    Not applicable.

    Storage

    Store in the refrigerator (2 ° C - 8 ° C). Store in the packaging to avoid moisture.

    Other drugs

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