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What is OFEV and how is it used?

  • OFEV is a prescription medicine used:
    • to treat people with a lung disease called idiopathic pulmonary fibrosis (IPF).
    • to treat people with a chronic (long lasting) interstitial lung disease in which lung fibrosis continues to worsen (progress).
    • to slow the rate of decline in lung function in people with systemic sclerosis-associated interstitial lung disease (SSc-ILD) (also known as scleroderma-associated ILD).
  • It is not known if OFEV is safe and effective in children.

What are the possible side effects of OFEV?

OFEV may cause serious side effects, including:

  • See “What is the most important information I should know about OFEV?”
  • liver problems. Call your doctor right away if you have unexplained symptoms such as yellowing of your skin or the white part of your eyes (jaundice), dark or brown (tea colored) urine, pain on the upper right side of your stomach area (abdomen), bleeding or bruising more easily than normal, feeling tired, or loss of appetite. Your doctor will do blood tests to check how well your liver is working before starting and during your treatment with OFEV.
  • diarrhea, nausea, and vomiting. While you are taking OFEV, your doctor may recommend that you drink fluids or take medicine to treat these side effects. Tell your doctor if you have diarrhea, nausea, or vomiting or if these symptoms do not go away or become worse. Tell your doctor if you are taking over-the-counter laxatives, stool softeners, and other medicines or dietary supplements that can cause diarrhea.
  • heart attack. Tell your doctor right away if you have symptoms of a heart problem. These symptoms may include chest pain or pressure, pain in your arms, back, neck or jaw, or shortness of breath.
  • stroke. Tell your doctor right away if you have symptoms of a stroke. These symptoms may include numbness or weakness on 1 side of your body, trouble talking, headache, or dizziness.
  • bleeding problems. OFEV may increase your chances of having bleeding problems. Tell your doctor if you have unusual bleeding, bruising, or wounds that do not heal. Tell your doctor if you are taking a blood thinner, including prescription blood thinners and over-the-counter aspirin.
  • tear in your stomach or intestinal wall (perforation). OFEV may increase your chances of having a tear in your stomach or intestinal wall. Tell your doctor if you have pain or swelling in your stomach area.

The most common side effects of OFEV are diarrhea, nausea, stomach pain, vomiting, liver problems, decreased appetite, headache, weight loss, and high blood pressure.

These are not all the possible side effects of OFEV. For more information, ask your doctor or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

DESCRIPTION

OFEV capsules contain nintedanib, a kinase inhibitor [see Mechanism Of Action]. Nintedanib is presented as the ethanesulfonate salt (esylate), with the 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). Its structural formula is:

OFEV® (nintedanib) Structural Formula - Illustration

Nintedanib esylate is a bright yellow powder with an empirical formula of C31H33N5O4·C2H6O3S and a molecular weight of 649.76 g/mol.

OFEV capsules for oral administration are available in 2 dose strengths containing 100 mg or 150 mg of nintedanib (equivalent to 120.40 mg or 180.60 mg nintedanib ethanesulfonate, respectively). The inactive ingredients of OFEV are the following: Fill Material: triglycerides, hard fat, lecithin. Capsule Shell: gelatin, glycerol, titanium dioxide, red ferric oxide, yellow ferric oxide, black ink.

INDICATIONS

Idiopathic Pulmonary Fibrosis

OFEV is indicated for the treatment of idiopathic pulmonary fibrosis (IPF).

Chronic Fibrosing Interstitial Lung Diseases with A Progressive Phenotype

OFEV is indicated for the treatment of chronic fibrosing interstitial lung diseases (ILDs) with a progressive phenotype [see Clinical Studies].

Systemic Sclerosis-Associated Interstitial Lung Disease

OFEV is indicated to slow the rate of decline in pulmonary function in patients with systemic sclerosis-associated interstitial lung disease (SSc-ILD).

DOSAGE AND ADMINISTRATION

Testing Prior To OFEV Administration

Conduct liver function tests in all patients and a pregnancy test in females of reproductive potential prior to initiating treatment with OFEV [see WARNINGS AND PRECAUTIONS].

Recommended Dosage

The recommended dosage of OFEV is 150 mg twice daily administered approximately 12 hours apart.

OFEV capsules should be taken with food [see CLINICAL PHARMACOLOGY] and swallowed whole with liquid. OFEV capsules should not be chewed or crushed because of a bitter taste. The effect of chewing or crushing of the capsule on the pharmacokinetics of nintedanib is not known.

If a dose of OFEV is missed, the next dose should be taken at the next scheduled time. Advise the patient to not make up for a missed dose. Do not exceed the recommended maximum daily dosage of 300 mg.

In patients with mild hepatic impairment (Child Pugh A), the recommended dosage of OFEV is 100 mg twice daily approximately 12 hours apart taken with food.

Dosage Modification Due To Adverse Reactions

In addition to symptomatic treatment, if applicable, the management of adverse reactions of OFEV may require dose reduction or temporary interruption until the specific adverse reaction resolves to levels that allow continuation of therapy. OFEV treatment may be resumed at the full dosage (150 mg twice daily), or at the reduced dosage (100 mg twice daily), which subsequently may be increased to the full dosage. If a patient does not tolerate 100 mg twice daily, discontinue treatment with OFEV [see WARNINGS AND PRECAUTIONS and ADVERSE REACTIONS].

Dose modifications or interruptions may be necessary for liver enzyme elevations. Conduct liver function tests (aspartate aminotransferase (AST), alanine aminotransferase (ALT), and bilirubin) prior to initiation of treatment with OFEV, at regular intervals during the first three months of treatment, and periodically thereafter or as clinically indicated. Measure liver tests promptly in patients who report symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice. Discontinue OFEV in patients with AST or ALT greater than 3 times the upper limit of normal (ULN) with signs or symptoms of liver injury and for AST or ALT elevations greater than 5 times the upper limit of normal. For AST or ALT greater than 3 times to less than 5 times the ULN without signs of liver damage, interrupt treatment or reduce OFEV to 100 mg twice daily. Once liver enzymes have returned to baseline values, treatment with OFEV may be reintroduced at a reduced dosage (100 mg twice daily), which subsequently may be increased to the full dosage (150 mg twice daily) [see WARNINGS AND PRECAUTIONS and ADVERSE REACTIONS ].

In patients with mild hepatic impairment (Child Pugh A), consider treatment interruption, or discontinuation for management of adverse reactions.

HOW SUPPLIED

Dosage Forms And Strengths

150 mg capsules: brown, opaque, oblong, soft capsules imprinted in black with the Boehringer Ingelheim company symbol and "150".

100 mg capsules: peach, opaque, oblong, soft capsules imprinted in black with the Boehringer Ingelheim company symbol and "100".

Storage And Handling

150 mg: brown, opaque, oblong, soft capsules imprinted in black with the Boehringer Ingelheim company symbol and "150". They are packaged in HDPE bottles with a child-resistant closure, available as follows: Bottles of 60 - NDC: 0597-0145-60

100 mg: peach, opaque, oblong, soft capsules imprinted in black with the Boehringer Ingelheim company symbol and "100". They are packaged in HDPE bottles with a child-resistant closure, available as follows: Bottles of 60 - NDC: 0597-0143-60

Storage

Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Protect from exposure to high humidity and avoid excessive heat. If repackaged, use USP tight container. Keep out of reach of children.

SIDE EFFECTS

The following adverse reactions are discussed in greater detail in other sections of the labeling:

  • Elevated Liver Enzymes and Drug-Induced Liver Injury [see WARNINGS AND PRECAUTIONS]
  • Gastrointestinal Disorders [see WARNINGS AND PRECAUTIONS]
  • Embryo-Fetal Toxicity [see WARNINGS AND PRECAUTIONS]
  • Arterial Thromboembolic Events [see WARNINGS AND PRECAUTIONS]
  • Risk of Bleeding [see WARNINGS AND PRECAUTIONS]
  • Gastrointestinal Perforation [see WARNINGS AND PRECAUTIONS]

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety of OFEV was evaluated in over 1000 IPF patients, 332 patients with chronic fibrosing ILDs with a progressive phenotype, and over 280 patients with SSc-ILD. Over 200 IPF patients were exposed to OFEV for more than 2 years in clinical trials.

Idiopathic Pulmonary Fibrosis

OFEV was studied in three randomized, double-blind, placebo-controlled, 52-week trials. In the phase 2 (Study 1) and phase 3 (Study 2 and Study 3) trials, 723 patients with IPF received OFEV 150 mg twice daily and 508 patients received placebo. The median duration of exposure was 10 months for patients treated with OFEV and 11 months for patients treated with placebo. Subjects ranged in age from 42 to 89 years (median age of 67 years). Most patients were male (79%) and Caucasian (60%).

The most frequent serious adverse reactions reported in patients treated with OFEV, more than placebo, were bronchitis (1.2% vs. 0.8%) and myocardial infarction (1.5% vs. 0.4%). The most common adverse events leading to death in patients treated with OFEV, more than placebo, were pneumonia (0.7% vs. 0.6%), lung neoplasm malignant (0.3% vs. 0%), and myocardial infarction (0.3% vs. 0.2%). In the predefined category of major adverse cardiovascular events (MACE) including MI, fatal events were reported in 0.6% of OFEV-treated patients and 1.8% of placebo-treated patients.

Adverse reactions leading to permanent dose reductions were reported in 16% of OFEV-treated patients and 1% of placebo-treated patients. The most frequent adverse reaction that led to permanent dose reduction in the patients treated with OFEV was diarrhea (11%).

Adverse reactions leading to discontinuation were reported in 21% of OFEV-treated patients and 15% of placebo-treated patients. The most frequent adverse reactions that led to discontinuation in OFEV-treated patients were diarrhea (5%), nausea (2%), and decreased appetite (2%).

DRUG INTERACTIONS

P-Glycoprotein (P-gp) And CYP3A4 Inhibitors And Inducers

Nintedanib is a substrate of P-gp and, to a minor extent, CYP3A4 [see CLINICAL PHARMACOLOGY]. Coadministration with oral doses of a P-gp and CYP3A4 inhibitor, ketoconazole, increased exposure to nintedanib by 60%. Concomitant use of P-gp and CYP3A4 inhibitors (e.g., erythromycin) with OFEV may increase exposure to nintedanib [see CLINICAL PHARMACOLOGY] In such cases, patients should be monitored closely for tolerability of OFEV. Management of adverse reactions may require interruption, dose reduction, or discontinuation of therapy with OFEV [see DOSAGE AND ADMINISTRATION].

Coadministration with oral doses of a P-gp and CYP3A4 inducer, rifampicin, decreased exposure to nintedanib by 50%. Concomitant use of P-gp and CYP3A4 inducers (e.g., carbamazepine, phenytoin, and St. John’s wort) with OFEV should be avoided as these drugs may decrease exposure to nintedanib [see CLINICAL PHARMACOLOGY].

Anticoagulants

Nintedanib is a VEGFR inhibitor and may increase the risk of bleeding. Monitor patients on full anticoagulation therapy closely for bleeding and adjust anticoagulation treatment as necessary [see WARNINGS AND PRECAUTIONS]

Pirfenidone

In a multiple-dose study conducted to assess the pharmacokinetic effects of concomitant treatment with nintedanib and pirfenidone, the coadministration of nintedanib with pirfenidone did not alter the exposure of either agent [see CLINICAL PHARMACOLOGY]. Therefore, no dose adjustment is necessary during concomitant administration of nintedanib with pirfenidone.

Bosentan

Coadministration of nintedanib with bosentan did not alter the pharmacokinetics of nintedanib [see CLINICAL PHARMACOLOGY].

PRECAUTIONS

Hepatic Impairment

Treatment with OFEV is not recommended in patients with moderate (Child Pugh B) or severe (Child Pugh C) hepatic impairment [see Use In Specific Populations and CLINICAL PHARMACOLOGY]. Patients with mild hepatic impairment (Child Pugh A) can be treated with a reduced dose of OFEV [see DOSAGE AND ADMINISTRATION].

Elevated Liver Enzymes And Drug-Induced Liver Injury

Cases of drug-induced liver injury (DILI) have been observed with OFEV treatment. In the postmarketing period, non-serious and serious cases of DILI, including severe liver injury with fatal outcome, have been reported. The majority of hepatic events occur within the first three months of treatment. In clinical trials, administration of OFEV was associated with elevations of liver enzymes (ALT, AST, ALKP, GGT) and bilirubin. Liver enzyme and bilirubin increases were reversible with dose modification or interruption in the majority of cases. The majority (94%) of patients with ALT and/or AST elevations had elevations less than 5 times ULN. The majority (95%) of patients with bilirubin elevations had elevations less than 2 times ULN [see Use In Specific Populations and CLINICAL PHARMACOLOGY]. Patients with a low body weight (less than 65 kg), Asian, and female patients may have a higher risk of elevations in liver enzymes. Nintedanib exposure increased with patient age, which may also result in a higher risk of increased liver enzymes [see CLINICAL PHARMACOLOGY].

Conduct liver function tests (ALT, AST, and bilirubin) prior to initiation of treatment with OFEV, at regular intervals during the first three months of treatment, and periodically thereafter or as clinically indicated. Measure liver tests promptly in patients who report symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice. Dosage modifications or interruption may be necessary for liver enzyme elevations [see DOSAGE AND ADMINISTRATION].

Gastrointestinal Disorders

Diarrhea

Diarrhea was the most frequent gastrointestinal event reported in 62% versus 18% of patients treated with OFEV and placebo, respectively [see ADVERSE REACTIONS]. In most patients, the event was of mild to moderate intensity and occurred within the first 3 months of treatment. Diarrhea led to permanent dose reduction in 11% of patients treated with OFEV compared to 0 placebo-treated patients. Diarrhea led to discontinuation of OFEV in 5% of the patients compared to less than 1% of placebo-treated patients.

Dosage modifications or treatment interruptions may be necessary in patients with adverse reactions of diarrhea. Treat diarrhea at first signs with adequate hydration and antidiarrheal medication (e.g., loperamide), and consider treatment interruption if diarrhea continues [see DOSAGE AND ADMINISTRATION]. OFEV treatment may be resumed at the full dosage (150 mg twice daily), or at the reduced dosage (100 mg twice daily), which subsequently may be increased to the full dosage. If severe diarrhea persists despite symptomatic treatment, discontinue treatment with OFEV.

Nausea And Vomiting

Nausea was reported in 24% versus 7% and vomiting was reported in 12% versus 3% of patients treated with OFEV and placebo, respectively [see ADVERSE REACTIONS]. In most patients, these events were of mild to moderate intensity. Nausea led to discontinuation of OFEV in 2% of patients. Vomiting led to discontinuation of OFEV in 1% of the patients.

For nausea or vomiting that persists despite appropriate supportive care including anti-emetic therapy, dose reduction or treatment interruption may be required [see DOSAGE AND ADMINISTRATION]. OFEV treatment may be resumed at the full dosage (150 mg twice daily), or at the reduced dosage (100 mg twice daily), which subsequently may be increased to the full dosage. If severe nausea or vomiting does not resolve, discontinue treatment with OFEV.

Embryo-Fetal Toxicity

Based on findings from animal studies and its mechanism of action, OFEV can cause fetal harm when administered to a pregnant woman. Nintedanib caused embryo-fetal deaths and structural abnormalities in rats and rabbits when administered during organogenesis at less than (rats) and approximately 5 times (rabbits) the maximum recommended human dose (MRHD) in adults. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to avoid becoming pregnant while receiving treatment with OFEV and to use effective contraception during treatment and at least 3 months after the last dose of OFEV. Verify pregnancy status prior to treatment with OFEV [see Use In Specific Populations and CLINICAL PHARMACOLOGY].

Arterial Thromboembolic Events

Arterial thromboembolic events have been reported in patients taking OFEV. In clinical trials, arterial thromboembolic events were reported in 2.5% of patients treated with OFEV and 0.8% of placebo-treated patients. Myocardial infarction was the most common adverse reaction under arterial thromboembolic events, occurring in 1.5% of OFEV-treated patients compared to 0.4% of placebo-treated patients.

Use caution when treating patients at higher cardiovascular risk including known coronary artery disease. Consider treatment interruption in patients who develop signs or symptoms of acute myocardial ischemia.

Risk Of Bleeding

Based on the mechanism of action (VEGFR inhibition), OFEV may increase the risk of bleeding. In clinical trials, bleeding events were reported in 10% of patients treated with OFEV and in 7% of patients treated with placebo. In the postmarketing period non-serious and serious bleeding events, some of which were fatal, have been observed.

Use OFEV in patients with known risk of bleeding only if the anticipated benefit outweighs the potential risk.

Gastrointestinal Perforation

Based on the mechanism of action, OFEV may increase the risk of gastrointestinal perforation. In clinical trials, gastrointestinal perforation was reported in 0.3% of patients treated with OFEV, compared to 0 cases in the placebo-treated patients. In the postmarketing period, cases of gastrointestinal perforations have been reported, some of which were fatal. Use caution when treating patients who have had recent abdominal surgery, previous history of diverticular disease or receiving concomitant corticosteroids or NSAIDs.

Discontinue therapy with OFEV in patients who develop gastrointestinal perforation. Only use OFEV in patients with known risk of gastrointestinal perforation if the anticipated benefit outweighs the potential risk.

Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (PATIENT INFORMATION).

Elevated Liver Enzymes And Drug-Induced Liver Injury

Advise patients that they will need to undergo liver function testing periodically. Advise patients to immediately report any symptoms of a liver problem (e.g., skin or the whites of eyes turn yellow, urine turns dark or brown (tea colored), pain on the right side of stomach, bleed or bruise more easily than normal, lethargy, loss of appetite) [see WARNINGS AND PRECAUTIONS].

Gastrointestinal Disorders

Inform patients that gastrointestinal disorders such as diarrhea, nausea, and vomiting were the most commonly reported gastrointestinal events occurring in patients who received OFEV. Advise patients that their healthcare provider may recommend hydration, antidiarrheal medications (e.g., loperamide), or anti-emetic medications to treat these side effects. Temporary dosage reductions or discontinuations may be required. Instruct patients to contact their healthcare provider at the first signs of diarrhea or for any severe or persistent diarrhea, nausea, or vomiting [see WARNINGS AND PRECAUTIONS and ADVERSE REACTIONS].

Embryo-Fetal Toxicity

Counsel patients on pregnancy prevention and planning. Advise females of reproductive potential of the potential risk to a fetus and to avoid becoming pregnant while receiving treatment with OFEV. Advise females of reproductive potential to use effective contraception during treatment, and for at least 3 months after taking the last dose of OFEV. Advise female patients to notify their doctor if they become pregnant during therapy with OFEV [see WARNINGS AND PRECAUTIONS and Use In Specific Populations].

Arterial Thromboembolic Events

Advise patients about the signs and symptoms of acute myocardial ischemia and other arterial thromboembolic events and the urgency to seek immediate medical care for these conditions [see WARNINGS AND PRECAUTIONS].

Risk Of Bleeding

Bleeding events have been reported. Advise patients to report unusual bleeding [see WARNINGS AND PRECAUTIONS].

Gastrointestinal Perforation

Serious gastrointestinal perforation events have been reported. Advise patients to report signs and symptoms of gastrointestinal perforation [see WARNINGS AND PRECAUTIONS].

Lactation

Advise patients that breastfeeding is not recommended while taking OFEV [see Use In Specific Populations].

Smokers

Encourage patients to stop smoking prior to treatment with OFEV and to avoid smoking when using OFEV [see CLINICAL PHARMACOLOGY].

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OFEV 150 MG 60 KP


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Description of product

What is OFEV and how is it used?

  • OFEV is a prescription medicine used:
    • to treat people with a lung disease called idiopathic pulmonary fibrosis (IPF).
    • to treat people with a chronic (long lasting) interstitial lung disease in which lung fibrosis continues to worsen (progress).
    • to slow the rate of decline in lung function in people with systemic sclerosis-associated interstitial lung disease (SSc-ILD) (also known as scleroderma-associated ILD).
  • It is not known if OFEV is safe and effective in children.

What are the possible side effects of OFEV?

OFEV may cause serious side effects, including:

  • See “What is the most important information I should know about OFEV?”
  • liver problems. Call your doctor right away if you have unexplained symptoms such as yellowing of your skin or the white part of your eyes (jaundice), dark or brown (tea colored) urine, pain on the upper right side of your stomach area (abdomen), bleeding or bruising more easily than normal, feeling tired, or loss of appetite. Your doctor will do blood tests to check how well your liver is working before starting and during your treatment with OFEV.
  • diarrhea, nausea, and vomiting. While you are taking OFEV, your doctor may recommend that you drink fluids or take medicine to treat these side effects. Tell your doctor if you have diarrhea, nausea, or vomiting or if these symptoms do not go away or become worse. Tell your doctor if you are taking over-the-counter laxatives, stool softeners, and other medicines or dietary supplements that can cause diarrhea.
  • heart attack. Tell your doctor right away if you have symptoms of a heart problem. These symptoms may include chest pain or pressure, pain in your arms, back, neck or jaw, or shortness of breath.
  • stroke. Tell your doctor right away if you have symptoms of a stroke. These symptoms may include numbness or weakness on 1 side of your body, trouble talking, headache, or dizziness.
  • bleeding problems. OFEV may increase your chances of having bleeding problems. Tell your doctor if you have unusual bleeding, bruising, or wounds that do not heal. Tell your doctor if you are taking a blood thinner, including prescription blood thinners and over-the-counter aspirin.
  • tear in your stomach or intestinal wall (perforation). OFEV may increase your chances of having a tear in your stomach or intestinal wall. Tell your doctor if you have pain or swelling in your stomach area.

The most common side effects of OFEV are diarrhea, nausea, stomach pain, vomiting, liver problems, decreased appetite, headache, weight loss, and high blood pressure.

These are not all the possible side effects of OFEV. For more information, ask your doctor or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

DESCRIPTION

OFEV capsules contain nintedanib, a kinase inhibitor [see Mechanism Of Action]. Nintedanib is presented as the ethanesulfonate salt (esylate), with the 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). Its structural formula is:

OFEV® (nintedanib) Structural Formula - Illustration

Nintedanib esylate is a bright yellow powder with an empirical formula of C31H33N5O4·C2H6O3S and a molecular weight of 649.76 g/mol.

OFEV capsules for oral administration are available in 2 dose strengths containing 100 mg or 150 mg of nintedanib (equivalent to 120.40 mg or 180.60 mg nintedanib ethanesulfonate, respectively). The inactive ingredients of OFEV are the following: Fill Material: triglycerides, hard fat, lecithin. Capsule Shell: gelatin, glycerol, titanium dioxide, red ferric oxide, yellow ferric oxide, black ink.

INDICATIONS

Idiopathic Pulmonary Fibrosis

OFEV is indicated for the treatment of idiopathic pulmonary fibrosis (IPF).

Chronic Fibrosing Interstitial Lung Diseases with A Progressive Phenotype

OFEV is indicated for the treatment of chronic fibrosing interstitial lung diseases (ILDs) with a progressive phenotype [see Clinical Studies].

Systemic Sclerosis-Associated Interstitial Lung Disease

OFEV is indicated to slow the rate of decline in pulmonary function in patients with systemic sclerosis-associated interstitial lung disease (SSc-ILD).

DOSAGE AND ADMINISTRATION

Testing Prior To OFEV Administration

Conduct liver function tests in all patients and a pregnancy test in females of reproductive potential prior to initiating treatment with OFEV [see WARNINGS AND PRECAUTIONS].

Recommended Dosage

The recommended dosage of OFEV is 150 mg twice daily administered approximately 12 hours apart.

OFEV capsules should be taken with food [see CLINICAL PHARMACOLOGY] and swallowed whole with liquid. OFEV capsules should not be chewed or crushed because of a bitter taste. The effect of chewing or crushing of the capsule on the pharmacokinetics of nintedanib is not known.

If a dose of OFEV is missed, the next dose should be taken at the next scheduled time. Advise the patient to not make up for a missed dose. Do not exceed the recommended maximum daily dosage of 300 mg.

In patients with mild hepatic impairment (Child Pugh A), the recommended dosage of OFEV is 100 mg twice daily approximately 12 hours apart taken with food.

Dosage Modification Due To Adverse Reactions

In addition to symptomatic treatment, if applicable, the management of adverse reactions of OFEV may require dose reduction or temporary interruption until the specific adverse reaction resolves to levels that allow continuation of therapy. OFEV treatment may be resumed at the full dosage (150 mg twice daily), or at the reduced dosage (100 mg twice daily), which subsequently may be increased to the full dosage. If a patient does not tolerate 100 mg twice daily, discontinue treatment with OFEV [see WARNINGS AND PRECAUTIONS and ADVERSE REACTIONS].

Dose modifications or interruptions may be necessary for liver enzyme elevations. Conduct liver function tests (aspartate aminotransferase (AST), alanine aminotransferase (ALT), and bilirubin) prior to initiation of treatment with OFEV, at regular intervals during the first three months of treatment, and periodically thereafter or as clinically indicated. Measure liver tests promptly in patients who report symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice. Discontinue OFEV in patients with AST or ALT greater than 3 times the upper limit of normal (ULN) with signs or symptoms of liver injury and for AST or ALT elevations greater than 5 times the upper limit of normal. For AST or ALT greater than 3 times to less than 5 times the ULN without signs of liver damage, interrupt treatment or reduce OFEV to 100 mg twice daily. Once liver enzymes have returned to baseline values, treatment with OFEV may be reintroduced at a reduced dosage (100 mg twice daily), which subsequently may be increased to the full dosage (150 mg twice daily) [see WARNINGS AND PRECAUTIONS and ADVERSE REACTIONS ].

In patients with mild hepatic impairment (Child Pugh A), consider treatment interruption, or discontinuation for management of adverse reactions.

HOW SUPPLIED

Dosage Forms And Strengths

150 mg capsules: brown, opaque, oblong, soft capsules imprinted in black with the Boehringer Ingelheim company symbol and "150".

100 mg capsules: peach, opaque, oblong, soft capsules imprinted in black with the Boehringer Ingelheim company symbol and "100".

Storage And Handling

150 mg: brown, opaque, oblong, soft capsules imprinted in black with the Boehringer Ingelheim company symbol and "150". They are packaged in HDPE bottles with a child-resistant closure, available as follows: Bottles of 60 - NDC: 0597-0145-60

100 mg: peach, opaque, oblong, soft capsules imprinted in black with the Boehringer Ingelheim company symbol and "100". They are packaged in HDPE bottles with a child-resistant closure, available as follows: Bottles of 60 - NDC: 0597-0143-60

Storage

Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Protect from exposure to high humidity and avoid excessive heat. If repackaged, use USP tight container. Keep out of reach of children.

SIDE EFFECTS

The following adverse reactions are discussed in greater detail in other sections of the labeling:

  • Elevated Liver Enzymes and Drug-Induced Liver Injury [see WARNINGS AND PRECAUTIONS]
  • Gastrointestinal Disorders [see WARNINGS AND PRECAUTIONS]
  • Embryo-Fetal Toxicity [see WARNINGS AND PRECAUTIONS]
  • Arterial Thromboembolic Events [see WARNINGS AND PRECAUTIONS]
  • Risk of Bleeding [see WARNINGS AND PRECAUTIONS]
  • Gastrointestinal Perforation [see WARNINGS AND PRECAUTIONS]

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety of OFEV was evaluated in over 1000 IPF patients, 332 patients with chronic fibrosing ILDs with a progressive phenotype, and over 280 patients with SSc-ILD. Over 200 IPF patients were exposed to OFEV for more than 2 years in clinical trials.

Idiopathic Pulmonary Fibrosis

OFEV was studied in three randomized, double-blind, placebo-controlled, 52-week trials. In the phase 2 (Study 1) and phase 3 (Study 2 and Study 3) trials, 723 patients with IPF received OFEV 150 mg twice daily and 508 patients received placebo. The median duration of exposure was 10 months for patients treated with OFEV and 11 months for patients treated with placebo. Subjects ranged in age from 42 to 89 years (median age of 67 years). Most patients were male (79%) and Caucasian (60%).

The most frequent serious adverse reactions reported in patients treated with OFEV, more than placebo, were bronchitis (1.2% vs. 0.8%) and myocardial infarction (1.5% vs. 0.4%). The most common adverse events leading to death in patients treated with OFEV, more than placebo, were pneumonia (0.7% vs. 0.6%), lung neoplasm malignant (0.3% vs. 0%), and myocardial infarction (0.3% vs. 0.2%). In the predefined category of major adverse cardiovascular events (MACE) including MI, fatal events were reported in 0.6% of OFEV-treated patients and 1.8% of placebo-treated patients.

Adverse reactions leading to permanent dose reductions were reported in 16% of OFEV-treated patients and 1% of placebo-treated patients. The most frequent adverse reaction that led to permanent dose reduction in the patients treated with OFEV was diarrhea (11%).

Adverse reactions leading to discontinuation were reported in 21% of OFEV-treated patients and 15% of placebo-treated patients. The most frequent adverse reactions that led to discontinuation in OFEV-treated patients were diarrhea (5%), nausea (2%), and decreased appetite (2%).

DRUG INTERACTIONS

P-Glycoprotein (P-gp) And CYP3A4 Inhibitors And Inducers

Nintedanib is a substrate of P-gp and, to a minor extent, CYP3A4 [see CLINICAL PHARMACOLOGY]. Coadministration with oral doses of a P-gp and CYP3A4 inhibitor, ketoconazole, increased exposure to nintedanib by 60%. Concomitant use of P-gp and CYP3A4 inhibitors (e.g., erythromycin) with OFEV may increase exposure to nintedanib [see CLINICAL PHARMACOLOGY] In such cases, patients should be monitored closely for tolerability of OFEV. Management of adverse reactions may require interruption, dose reduction, or discontinuation of therapy with OFEV [see DOSAGE AND ADMINISTRATION].

Coadministration with oral doses of a P-gp and CYP3A4 inducer, rifampicin, decreased exposure to nintedanib by 50%. Concomitant use of P-gp and CYP3A4 inducers (e.g., carbamazepine, phenytoin, and St. John’s wort) with OFEV should be avoided as these drugs may decrease exposure to nintedanib [see CLINICAL PHARMACOLOGY].

Anticoagulants

Nintedanib is a VEGFR inhibitor and may increase the risk of bleeding. Monitor patients on full anticoagulation therapy closely for bleeding and adjust anticoagulation treatment as necessary [see WARNINGS AND PRECAUTIONS]

Pirfenidone

In a multiple-dose study conducted to assess the pharmacokinetic effects of concomitant treatment with nintedanib and pirfenidone, the coadministration of nintedanib with pirfenidone did not alter the exposure of either agent [see CLINICAL PHARMACOLOGY]. Therefore, no dose adjustment is necessary during concomitant administration of nintedanib with pirfenidone.

Bosentan

Coadministration of nintedanib with bosentan did not alter the pharmacokinetics of nintedanib [see CLINICAL PHARMACOLOGY].

PRECAUTIONS

Hepatic Impairment

Treatment with OFEV is not recommended in patients with moderate (Child Pugh B) or severe (Child Pugh C) hepatic impairment [see Use In Specific Populations and CLINICAL PHARMACOLOGY]. Patients with mild hepatic impairment (Child Pugh A) can be treated with a reduced dose of OFEV [see DOSAGE AND ADMINISTRATION].

Elevated Liver Enzymes And Drug-Induced Liver Injury

Cases of drug-induced liver injury (DILI) have been observed with OFEV treatment. In the postmarketing period, non-serious and serious cases of DILI, including severe liver injury with fatal outcome, have been reported. The majority of hepatic events occur within the first three months of treatment. In clinical trials, administration of OFEV was associated with elevations of liver enzymes (ALT, AST, ALKP, GGT) and bilirubin. Liver enzyme and bilirubin increases were reversible with dose modification or interruption in the majority of cases. The majority (94%) of patients with ALT and/or AST elevations had elevations less than 5 times ULN. The majority (95%) of patients with bilirubin elevations had elevations less than 2 times ULN [see Use In Specific Populations and CLINICAL PHARMACOLOGY]. Patients with a low body weight (less than 65 kg), Asian, and female patients may have a higher risk of elevations in liver enzymes. Nintedanib exposure increased with patient age, which may also result in a higher risk of increased liver enzymes [see CLINICAL PHARMACOLOGY].

Conduct liver function tests (ALT, AST, and bilirubin) prior to initiation of treatment with OFEV, at regular intervals during the first three months of treatment, and periodically thereafter or as clinically indicated. Measure liver tests promptly in patients who report symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice. Dosage modifications or interruption may be necessary for liver enzyme elevations [see DOSAGE AND ADMINISTRATION].

Gastrointestinal Disorders

Diarrhea

Diarrhea was the most frequent gastrointestinal event reported in 62% versus 18% of patients treated with OFEV and placebo, respectively [see ADVERSE REACTIONS]. In most patients, the event was of mild to moderate intensity and occurred within the first 3 months of treatment. Diarrhea led to permanent dose reduction in 11% of patients treated with OFEV compared to 0 placebo-treated patients. Diarrhea led to discontinuation of OFEV in 5% of the patients compared to less than 1% of placebo-treated patients.

Dosage modifications or treatment interruptions may be necessary in patients with adverse reactions of diarrhea. Treat diarrhea at first signs with adequate hydration and antidiarrheal medication (e.g., loperamide), and consider treatment interruption if diarrhea continues [see DOSAGE AND ADMINISTRATION]. OFEV treatment may be resumed at the full dosage (150 mg twice daily), or at the reduced dosage (100 mg twice daily), which subsequently may be increased to the full dosage. If severe diarrhea persists despite symptomatic treatment, discontinue treatment with OFEV.

Nausea And Vomiting

Nausea was reported in 24% versus 7% and vomiting was reported in 12% versus 3% of patients treated with OFEV and placebo, respectively [see ADVERSE REACTIONS]. In most patients, these events were of mild to moderate intensity. Nausea led to discontinuation of OFEV in 2% of patients. Vomiting led to discontinuation of OFEV in 1% of the patients.

For nausea or vomiting that persists despite appropriate supportive care including anti-emetic therapy, dose reduction or treatment interruption may be required [see DOSAGE AND ADMINISTRATION]. OFEV treatment may be resumed at the full dosage (150 mg twice daily), or at the reduced dosage (100 mg twice daily), which subsequently may be increased to the full dosage. If severe nausea or vomiting does not resolve, discontinue treatment with OFEV.

Embryo-Fetal Toxicity

Based on findings from animal studies and its mechanism of action, OFEV can cause fetal harm when administered to a pregnant woman. Nintedanib caused embryo-fetal deaths and structural abnormalities in rats and rabbits when administered during organogenesis at less than (rats) and approximately 5 times (rabbits) the maximum recommended human dose (MRHD) in adults. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to avoid becoming pregnant while receiving treatment with OFEV and to use effective contraception during treatment and at least 3 months after the last dose of OFEV. Verify pregnancy status prior to treatment with OFEV [see Use In Specific Populations and CLINICAL PHARMACOLOGY].

Arterial Thromboembolic Events

Arterial thromboembolic events have been reported in patients taking OFEV. In clinical trials, arterial thromboembolic events were reported in 2.5% of patients treated with OFEV and 0.8% of placebo-treated patients. Myocardial infarction was the most common adverse reaction under arterial thromboembolic events, occurring in 1.5% of OFEV-treated patients compared to 0.4% of placebo-treated patients.

Use caution when treating patients at higher cardiovascular risk including known coronary artery disease. Consider treatment interruption in patients who develop signs or symptoms of acute myocardial ischemia.

Risk Of Bleeding

Based on the mechanism of action (VEGFR inhibition), OFEV may increase the risk of bleeding. In clinical trials, bleeding events were reported in 10% of patients treated with OFEV and in 7% of patients treated with placebo. In the postmarketing period non-serious and serious bleeding events, some of which were fatal, have been observed.

Use OFEV in patients with known risk of bleeding only if the anticipated benefit outweighs the potential risk.

Gastrointestinal Perforation

Based on the mechanism of action, OFEV may increase the risk of gastrointestinal perforation. In clinical trials, gastrointestinal perforation was reported in 0.3% of patients treated with OFEV, compared to 0 cases in the placebo-treated patients. In the postmarketing period, cases of gastrointestinal perforations have been reported, some of which were fatal. Use caution when treating patients who have had recent abdominal surgery, previous history of diverticular disease or receiving concomitant corticosteroids or NSAIDs.

Discontinue therapy with OFEV in patients who develop gastrointestinal perforation. Only use OFEV in patients with known risk of gastrointestinal perforation if the anticipated benefit outweighs the potential risk.

Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (PATIENT INFORMATION).

Elevated Liver Enzymes And Drug-Induced Liver Injury

Advise patients that they will need to undergo liver function testing periodically. Advise patients to immediately report any symptoms of a liver problem (e.g., skin or the whites of eyes turn yellow, urine turns dark or brown (tea colored), pain on the right side of stomach, bleed or bruise more easily than normal, lethargy, loss of appetite) [see WARNINGS AND PRECAUTIONS].

Gastrointestinal Disorders

Inform patients that gastrointestinal disorders such as diarrhea, nausea, and vomiting were the most commonly reported gastrointestinal events occurring in patients who received OFEV. Advise patients that their healthcare provider may recommend hydration, antidiarrheal medications (e.g., loperamide), or anti-emetic medications to treat these side effects. Temporary dosage reductions or discontinuations may be required. Instruct patients to contact their healthcare provider at the first signs of diarrhea or for any severe or persistent diarrhea, nausea, or vomiting [see WARNINGS AND PRECAUTIONS and ADVERSE REACTIONS].

Embryo-Fetal Toxicity

Counsel patients on pregnancy prevention and planning. Advise females of reproductive potential of the potential risk to a fetus and to avoid becoming pregnant while receiving treatment with OFEV. Advise females of reproductive potential to use effective contraception during treatment, and for at least 3 months after taking the last dose of OFEV. Advise female patients to notify their doctor if they become pregnant during therapy with OFEV [see WARNINGS AND PRECAUTIONS and Use In Specific Populations].

Arterial Thromboembolic Events

Advise patients about the signs and symptoms of acute myocardial ischemia and other arterial thromboembolic events and the urgency to seek immediate medical care for these conditions [see WARNINGS AND PRECAUTIONS].

Risk Of Bleeding

Bleeding events have been reported. Advise patients to report unusual bleeding [see WARNINGS AND PRECAUTIONS].

Gastrointestinal Perforation

Serious gastrointestinal perforation events have been reported. Advise patients to report signs and symptoms of gastrointestinal perforation [see WARNINGS AND PRECAUTIONS].

Lactation

Advise patients that breastfeeding is not recommended while taking OFEV [see Use In Specific Populations].

Smokers

Encourage patients to stop smoking prior to treatment with OFEV and to avoid smoking when using OFEV [see CLINICAL PHARMACOLOGY].

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