Ofev

OFEV- nintedanib esylate capsule
Boehringer Ingelheim Pharmaceuticals, Inc.

1 INDICATIONS AND USAGE

1.1 Idiopathic Pulmonary Fibrosis

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

1.2 Chronic Fibrosing Interstitial Lung Diseases with a Progressive Phenotype

OFEV is indicated for the treatment of adults with chronic fibrosing interstitial lung diseases (ILDs) with a progressive phenotype [see Clinical Studies (14.2)].

1.3 Systemic Sclerosis-Associated Interstitial Lung Disease

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

2 DOSAGE AND ADMINISTRATION

2.1 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 (5.2, 5.4)].

2.2 Recommended Dosage

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

Administration Information

OFEV capsules should be taken with food [see Clinical Pharmacology (12.3)] and swallowed whole with liquid. OFEV capsules should not be chewed because of a bitter taste.

OFEV capsules should not be opened or crushed. If contact with the content of the capsule occurs, wash hands immediately and thoroughly. The effect of chewing or crushing of the capsule on the pharmacokinetics of nintedanib is not known.

Information for Missed Dose

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.

2.3 Recommended Dosage for Patients with Hepatic Impairment

Mild Hepatic Impairment

In patients with mild hepatic impairment (Child Pugh A), the recommended dosage of OFEV is 100 mg orally twice daily approximately 12 hours apart taken with food [see Use in Specific Populations (8.6)].

Moderate or Severe Hepatic Impairment

Treatment with OFEV is not recommended [see Warnings and Precautions (5.1) and Use in Specific Populations (8.6)].

2.4 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 (5.2, 5.3, 5.5, 5.7) and Adverse Reactions (6.1)].

Elevated Liver Enzymes

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 (5.2) and Adverse Reactions (6.1)].

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

3 DOSAGE FORMS AND STRENGTHS

Capsules:

  • 150 mg, brown, opaque, oblong, soft capsules imprinted in black with the Boehringer Ingelheim company symbol and “150”.
  • 100 mg, peach, opaque, oblong, soft capsules imprinted in black with the Boehringer Ingelheim company symbol and “100”.

4 CONTRAINDICATIONS

None

5 WARNINGS AND PRECAUTIONS

5.1 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 (8.6) and Clinical Pharmacology (12.3)]. Patients with mild hepatic impairment (Child Pugh A) can be treated with a reduced dose of OFEV [see Dosage and Administration (2.3)].

5.2 Elevated Liver Enzymes and Drug-Induced Liver Injury

Cases of drug-induced liver injury (DILI) have been observed with OFEV treatment. In the clinical trials and postmarketing period, non-serious and serious cases of DILI were reported. Cases of severe liver injury with fatal outcome have been reported in the postmarketing period. 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. In IPF studies (Study 1, Study 2, and Study 3), the majority (94%) of patients with ALT and/or AST elevations had elevations less than 5 times ULN and the majority (95%) of patients with bilirubin elevations had elevations less than 2 times ULN. In the chronic fibrosing ILDs with a progressive phenotype study (Study 5), the majority (95%) of patients with ALT and/or AST elevations had elevations less than 5 times ULN and the majority (94%) of patients with bilirubin elevations had elevations less than 2 times ULN. In the SSc-ILD study (Study 4), a maximum ALT and/or AST greater than or equal to 3 times ULN was observed for 4.9% of patients in the OFEV group and for 0.7% of patients in the placebo group [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)]. 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 (12.3)].

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 (2.1, 2.4)].

5.3 Gastrointestinal Disorders

Diarrhea

In clinical trials, diarrhea was the most frequent gastrointestinal event reported. In most patients, the event was of mild to moderate intensity and occurred within the first 3 months of treatment. In IPF studies (Study 1, Study 2, and Study 3), diarrhea was reported in 62% versus 18% of patients treated with OFEV and placebo, respectively [see Adverse Reactions (6.1)]. 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. In the chronic fibrosing ILDs with a progressive phenotype study (Study 5), diarrhea was reported in 67% versus 24% of patients treated with OFEV and placebo, respectively [see Adverse Reactions (6.1)]. Diarrhea led to permanent dose reduction in 16% of patients treated with OFEV compared to less than 1% of placebo-treated patients. Diarrhea led to discontinuation of OFEV in 6% of the patients compared to less than 1% of placebo-treated patients. In the SSc-ILD study (Study 4), diarrhea was reported in 76% versus 32% of patients treated with OFEV and placebo, respectively [see Adverse Reactions (6.1)]. Diarrhea led to permanent dose reduction in 22% of patients treated with OFEV compared to 1% of placebo-treated patients. Diarrhea led to discontinuation of OFEV in 7% of the patients compared to 0.3% 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 dose reduction or treatment interruption if diarrhea continues [see Dosage and Administration (2.4)]. 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

In IPF studies (Study 1, Study 2, and Study 3), nausea was reported in 24% versus 7% and vomiting was reported in 12% versus 3% of patients treated with OFEV and placebo, respectively. In the chronic fibrosing ILDs with a progressive phenotype study (Study 5), nausea was reported in 29% versus 9% and vomiting was reported in 18% versus 5% of patients treated with OFEV and placebo, respectively. In the SSc-ILD study (Study 4), nausea was reported in 32% versus 14% and vomiting was reported in 25% versus 10% of patients treated with OFEV and placebo, respectively [see Adverse Reactions (6.1)]. In most patients, these events were of mild to moderate intensity. In IPF studies (Study 1, Study 2, and Study 3), nausea led to discontinuation of OFEV in 2% of patients and vomiting led to discontinuation of OFEV in 1% of the patients. In the chronic fibrosing ILDs with a progressive phenotype study (Study 5), nausea led to discontinuation of OFEV in less than 1% of patients and vomiting led to discontinuation of OFEV in 1% of the patients. In the SSc-ILD study (Study 4), nausea led to discontinuation of OFEV in 2% of patients and 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 (2.4)]. 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.

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