2.1 Testing Prior to OFEV Administration

Conduct liver function tests prior to initiating treatment with OFEV [see Warnings and Precautions (5.1)].

2.2 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 (12.3)] 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.

2.3 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 (5.1, 5.2, 5.4, 5.6) and Adverse Reactions (6.1)].

Dose modifications or interruptions may be necessary for liver enzyme elevations. For aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >3 times to <5 times the upper limit of normal (ULN) without signs of severe 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 (5.1) and Adverse Reactions (6.1)]. Discontinue OFEV for AST or ALT elevations >5 times ULN or >3 times ULN with signs or symptoms of severe liver damage.

5.1 Elevated Liver Enzymes

The safety and efficacy of OFEV has not been studied in patients with moderate (Child Pugh B) or severe (Child Pugh C) hepatic impairment. Treatment with OFEV is not recommended in patients with moderate or severe hepatic impairment [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].

In clinical trials, administration of OFEV was associated with elevations of liver enzymes (ALT, AST, ALKP, GGT). Liver enzyme increases were reversible with dose modification or interruption and not associated with clinical signs or symptoms of liver injury. The majority (94%) of patients with ALT and/or AST elevations had elevations <5 times ULN. Administration of OFEV was also associated with elevations of bilirubin. The majority (95%) of patients with bilirubin elevations had elevations <2 times ULN [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].

Conduct liver function tests (ALT, AST, and bilirubin) prior to treatment with OFEV, monthly for 3 months, and every 3 months thereafter, and as clinically indicated. Dosage modifications or interruption may be necessary for liver enzyme elevations [see Dosage and Administration (2.1, 2.3)].

5.2 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 (6.1)]. 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 <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 (2.3)]. 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 (6.1)]. 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 (2.3)]. 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.

5.3 Embryofetal Toxicity

OFEV can cause fetal harm when administered to a pregnant woman. Nintedanib was teratogenic and embryofetocidal in rats and rabbits at less than and approximately 5 times the maximum recommended human dose (MRHD) in adults (on an AUC basis at oral doses of 2.5 and 15 mg/kg/day in rats and rabbits, respectively). If OFEV is used during pregnancy, or if the patient becomes pregnant while taking OFEV, the patient should be advised of the potential hazard to a fetus. Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with OFEV and to use adequate contraception during treatment and at least 3 months after the last dose of OFEV [see Use in Specific Populations (8.1)].

5.4 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.

5.5 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.

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

5.6 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.

Use caution when treating patients who have had recent abdominal surgery. 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.

 6.1 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 eva luated in over 1000 IPF patients with over 200 patients exposed to OFEV for more than 2 years in clinical trials.

OFEV was studied in three randomized, double-blind, placebo-controlled, 52-week trials. In the phase 2 (Study 1) and phase 3 (Studies 2 and 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%).

The most common adverse reactions with an incidence of ≥5% and more frequent in the OFEV than placebo treatment group are listed in Table 1.

In addition, hypothyroidism was reported in patients treated with OFEV, more than placebo (1.1% vs. 0.6%).

 7.1 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 (12.3)]. 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 (12.3)]. 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 (2.3)].

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 (12.3)].

 7.2 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 (5.5)].

 8.1 Pregnancy

Pregnancy Category D. [See Warnings and Precautions (5.3)]

OFEV can cause fetal harm when administered to a pregnant woman. If OFEV is used during pregnancy, or if the patient becomes pregnant while taking OFEV, the patient should be apprised of the potential hazard to a fetus. Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with OFEV.

In animal reproduction toxicity studies, nintedanib caused embryofetal deaths and teratogenic effects in rats and rabbits at less than and approximately 5 times the maximum recommended human dose (MRHD) in adults (on a plasma AUC basis at maternal oral doses of 2.5 and 15 mg/kg/day in rats and rabbits, respectively). Malformations included abnormalities in the vasculature, urogenital, and skeletal systems. Vasculature anomalies included missing or additional major blood vessels. Skeletal anomalies included abnormalities in the thoracic, lumbar, and caudal vertebrae (e.g., hemivertebra, missing, or asymmetrically ossified), ribs (bifid or fused), and sternebrae (fused, split, or unilaterally ossified). In some fetuses, organs in the urogenital system were missing. In rabbits, a significant change in sex ratio was observed in fetuses (female:male ratio of approximately 71%:29%) at approximately 15 times the MRHD in adults (on an AUC basis at a maternal oral dose of 60 mg/kg/day). Nintedanib decreased post-natal viability of rat pups during the first 4 post-natal days when dams were exposed to less than the MRHD (on an AUC basis at a maternal oral dose of 10 mg/kg/day).

 8.3 Nursing Mothers

Nintedanib and/or its metabolites are excreted into the milk of lactating rats. Milk and plasma of lactating rats have similar concentrations of nintedanib and its metabolites. Excretion of nintedanib and/or its metabolites into human milk is probable. There are no human studies that have investigated the effects of OFEV on breast-fed infants. Because of the potential for serious adverse reactions in nursing infants from OFEV, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

 8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

 8.5 Geriatric Use

Of the total number of subjects in phase 2 and 3 clinical studies of OFEV, 60.8% were 65 and over, while 16.3% were 75 and over. In phase 3 studies, no overall differences in effectiveness were observed between subjects who were 65 and over and younger subjects; no overall differences in safety were observed between subjects who were 65 and over or 75 and over and younger subjects, but greater sensitivity of some older individuals cannot be ruled out.

 8.6 Hepatic Impairment

Nintedanib is predominantly eliminated via biliary/fecal excretion (>90%) [see Clinical Pharmacology (12.3)]. No dedicated pharmacokinetic (PK) study was performed in patients with hepatic impairment. Monitor for adverse reactions and consider dose modification or discontinuation of OFEV as needed for patients with mild hepatic impairment (Child Pugh A). The safety and efficacy of nintedanib has not been investigated in patients with hepatic impairment classified as Child Pugh B or C. Therefore, treatment of patients with moderate (Child Pugh B) and severe (Child Pugh C) hepatic impairment with OFEV is not recommended [see Warnings and Precautions (5.1)].

 8.7 Renal Impairment

Based on a single-dose study, less than 1% of the total dose of nintedanib is excreted via the kidney [see Clinical Pharmacology (12.3)]. Adjustment of the starting dose in patients with mild to moderate renal impairment is not required. The safety, efficacy, and pharmacokinetics of nintedanib have not been studied in patients with severe renal impairment (<30 mL/min CrCl) and end-stage renal disease.

 8.8 Smokers

Smoking was associated with decreased exposure to OFEV [see Clinical Pharmacology (12.3)], which may alter the efficacy profile of OFEV. Encourage patients to stop smoking prior to treatment with OFEV and to avoid smoking when using OFEV.