Drug Safety-related Labeling Changes (SrLC)

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Drug Safety-related Labeling Changes (SrLC) Database

ANDA	Abbreviated New Drug Application
BLA	Biologics License Application
CDER	Center for Drug Evaluation and Research
MG	Medication Guide
NDA	New Drug Application
PCI	Patient Counseling Information
PI	Patient Information
PLR	Physician Labeling Rule
PLLR	Pregnancy and Lactation Labeling Rule
Italics	For the most part, italics indicate an FDA comment such as: Additions and/or revisions underlined These italics usually appear at the beginning of the section. In some cases, italics may be an inherent part of the label, and will most often appear in the body of the section.
Underlines	Any text that is underlined indicates text that has been added or revised. There are exceptions where underlining occurs in a section subtitle or heading. This is the case when there is just one word underlined in the body of the text.

Sections

BW	Box Warning
WP	Warnings and Precautions all in one section (PLR-format) Warnings as one section (pre-PLR format) Precautions as one section (pre-PLR format)
AR	Adverse Reactions (in pre-PLR format, this may be a subheading under precautions).
DI	Drug Interactions (in pre-PLR format, this may be a subheading under precautions).
USP	Use in Specific Populations (Inclusive on one or more of the following: Pregnancy; Lactation (PLLR- format); Nursing Mothers (pre-PLLR format); Females and Males of Reproductive Potential (PLLR format only); Pediatric Use, Geriatric Use, Renal Impairment, Hepatic Impairment, Sex, Race (these last six may be a subheading of precautions if label in pre-PLLR format.
PCI/PI/MG	Patient Counseling Information (PLR format only) - summarizes the information that a health care provider should convey to a patient (or caregiver when applicable) when a counseling discussion is taking place (e.g., a physician prescribing a drug during an office visit, a nurse providing discharge instructions at a hospital, or a pharmacist conveying information at a pharmacy). Patient Information - FDA approved patient labeling. Medication Guide - paper handouts that come with many prescription medicines. The guides address issues that are specific to particular drugs and drug classes, and they contain FDA-approved information that can help patients avoid serious adverse events.

Only NDAs and CDER regulated BLAs are included in this database. ANDAs are not included.

Applications that remain active, even if the product has been discontinued, undergo safety-related labeling changes.

OFEV (NDA-205832)

(NINTEDANIB ESYLATE)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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10/11/2024 (SUPPL-28)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Postmarketing Experience

Additions and/or revisions underlined:

…

Blood and Lymphatic System Disorders: Thrombocytopenia

Gastrointestinal Disorders: Pancreatitis

Hepatobiliary Disorders: Drug-induced liver injury

Nervous System Disorders: Posterior reversible encephalopathy syndrome

Renal and Urinary Disorders: Proteinuria

Skin and Subcutaneous Tissue Disorders: Pruritus, rash

Vascular Disorders: Non-serious and serious bleeding events, some of which were fatal

06/18/2024 (SUPPL-27)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.4 Pediatric Use

Newly added information:

The safety and effectiveness of OFEV have not been established in pediatric patients for the treatment of fibrosing interstitial lung diseases. Effectiveness was not demonstrated in a randomized, double-blind, placebo- controlled study conducted in 26 OFEV-treated pediatric patients aged 6 to 17 years with fibrosing interstitial lung diseases, who were treated with OFEV based on weight.

Animal Toxicity Data

In repeat-dose toxicology studies, young animals (mice, rats, and monkeys) dosed with nintedanib showed changes in the bone and fast-growing teeth. Bone changes include thickening of the growth plate in all species. These changes were fully or at least partially reversible in rats and monkeys; reversibility in mice has not been studied.

Tooth changes include broken incisors and discoloration in rodents. These changes were irreversible after discontinuation of nintedanib treatment.

01/13/2022 (SUPPL-16)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.4 Embryo-Fetal Toxicity

Additions and/or revisions underlined:

… Advise females of reproductive potential to avoid becoming pregnant while receiving treatment with OFEV and to use highly effective contraception at initiation of, during treatment, and at least 3 months after the last dose of OFEV. Nintedanib does not change the exposure to oral contraceptive containing ethinyl estradiol and levonorgestrel in patients with SSc-ILD. However, the efficacy of oral hormonal contraceptives may be compromised by vomiting and/or diarrhea or other conditions where the drug absorption may be reduced.

Advise women taking oral hormonal contraceptives experiencing these conditions to use alternative highly effective contraception. Verify pregnancy status prior to treatment with OFEV and during treatment as appropriate [see Use in Specific Populations (8.1, 8.3) and Clinical Pharmacology (12.1, 12.3)].

5.5 Arterial Thromboembolic Events

Additions and/or revisions underlined:

… Myocardial infarction was the most common adverse reaction under arterial thromboembolic events, occurring in 1.5% of OFEV-treated patients compared to less than 1% of placebo- treated patients. In the chronic fibrosing ILDs with a progressive phenotype study (Study 5), arterial thromboembolic events were reported in less than 1% of patients in both treatment arms. Myocardial infarction was observed in less than 1% of patients in both treatment arms. In the SSc-ILD study (Study 4), arterial thromboembolic events were reported …

5.6 Risk of Bleeding

Additions and/or revisions underlined:

… In IPF studies (Study 1, Study 2, and Study 3), bleeding events were reported in 10% of patients treated with OFEV and in 7% of patients treated with placebo. In the chronic fibrosing ILDs with a progressive phenotype study (Study 5), bleeding events were reported in 11% of patients treated with OFEV and in 13% of patients treated with placebo. In the SSc-ILD study (Study 4), bleeding events were reported in 11% of patients treated with OFEV and in 8% of patients treated with placebo. In clinical trials, epistaxis was the most frequent bleeding event reported.

5.7 Gastrointestinal Perforation

Additions and/or revisions underlined:

In IPF studies (Study 1, Study 2, and Study 3), gastrointestinal perforation was reported in less than 1% of patients treated with OFEV, compared to 0 cases in the placebo-treated patients. In the chronic fibrosing ILDs with a progressive phenotype study (Study 5), gastrointestinal perforation was not reported in any patients in any treatment arm. In the SSc-ILD study (Study 4), no cases of gastrointestinal perforation were reported in patients treated with OFEV or in placebo-treated patients.

Newly added subsection:

5.8 Nephrotic Range Proteinuria

Cases of proteinuria within the nephrotic range have been reported in the postmarketing period. Histological findings, when available, were consistent with glomerular microangiopathy with or without renal thrombi. Improvement in proteinuria has been observed after OFEV was discontinued; however, in some cases, residual proteinuria persisted. Consider treatment interruption in patients who develop new or worsening proteinuria.

6 Adverse Reactions

Additions and/or revisions underlined:

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

Newly added information:

Nephrotic Range Proteinuria [see Warnings and Precautions (5.8)]

6.1 Clinical Trials Experience

Additions and/or revisions underlined:

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.

Table 1 Adverse Reactions Occurring in greater than or equal to 5% of OFEV-treated Patients with Idiopathic Pulmonary Fibrosis and More Commonly Than Placebo in Study 1, Study 2, and Study 3 (Table data has remained the same)

In addition, hypothyroidism was reported in patients treated with OFEV, more than placebo (1.1% vs. 0.6%). Alopecia was also reported in more patients treated with OFEV than placebo (0.8% vs. 0.4%).

Combination with Pirfenidone

Newly added information:

Chronic Fibrosing Interstitial Lung Diseases with a Progressive Phenotype

OFEV was studied in a phase 3, double-blind, placebo-controlled trial (Study 5) in which 663 patients with chronic fibrosing ILDs with a progressive phenotype were randomized to receive OFEV 150 mg twice daily (n=332) or placebo (n=331) for at least 52 weeks. At 52 weeks, the median duration of exposure was 12 months for patients in both treatment arms. Subjects ranged in age from 27 to 87 years (median age of 67 years). The majority of patients were Caucasian (74%) or Asian (25%). Most patients were male (54%).

The most frequent serious adverse event reported in patients treated with OFEV, more than placebo, was pneumonia (4% vs. 3%). Adverse events leading to death were reported in 3% of patients treated with OFEV and in 5% of patients treated with placebo. No pattern was identified in the adverse events leading to death.

Adverse reactions leading to permanent dose reductions were reported in 33% of OFEV-treated patients and 4% of placebo-treated patients. The most frequent adverse reaction that led to permanent dose reduction in the patients treated with OFEV was diarrhea (16%).

Adverse reactions leading to discontinuation were reported in 20% of OFEV-treated patients and 10% of placebo-treated patients. The most frequent adverse reaction that led to discontinuation in OFEV-treated patients was diarrhea (6%).

The safety profile in patients with chronic fibrosing ILDs with a progressive phenotype treated with OFEV was consistent with that observed in IPF patients. In addition, the following adverse events were reported in OFEV more than placebo in chronic progressive fibrosing ILD: nasopharyngitis (13% vs. 12%), upper respiratory tract infection (7% vs 6%), urinary tract infection (6% vs. 4%), fatigue (10% vs. 6%), and back pain (6% vs. 5%).

Additions and/or revisions underlined:

Table 2 Adverse Reactions Occurring in greater than or equal to 5% of OFEV-treated Patients with Systemic Sclerosis-Associated Interstitial Lung Disease and More Commonly Than Placebo in Study 4 (Table data has remained the same)

In addition, alopecia was reported in patients treated with OFEV, more than placebo (1.4% vs. 1.0%).

6.2 Postmarketing Experience

Additions and/or revisions underlined:

The following adverse reactions have been identified during postapproval use of OFEV: drug-induced liver injury [see Warnings and Precautions (5.2)], non-serious and serious bleeding events, some of which were fatal [see Warnings and Precautions (5.6)], proteinuria [see Warnings and Precautions (5.8)], pancreatitis, thrombocytopenia, rash, pruritus.

8 Use in Specific Populations

8.3 Females and Males of Reproductive Potential

Contraception

Additions and/or revisions underlined:

OFEV can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to avoid becoming pregnant while receiving treatment with OFEV. Advise females of reproductive potential to use highly effective contraception at initiation of, during treatment, and for at least 3 months after taking the last dose of OFEV. Nintedanib does not change the exposure to oral contraceptive containing ethinyl estradiol and levonorgestrel in patients with SSc-ILD. However, the efficacy of oral hormonal contraceptives may be compromised by vomiting and/or diarrhea or other conditions where the drug absorption may be reduced.

Advise women taking oral hormonal contraceptives experiencing these conditions to use alternative highly effective contraception.

8.5 Geriatric Use

Additions and/or revisions underlined:

Of the total number of subjects in phase 2 and 3 clinical studies of OFEV in IPF (Study 1, Study 2, and Study 3), 61% were 65 and over, while 16% were 75 and over. In the chronic fibrosing ILDs with a progressive phenotype clinical study (Study 5), 61% were 65 and over, while 19% were 75 and older. In SSc-ILD (Study 4), 21.4% were 65 and over, while 1.9% were 75 and older.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT COUNSELING INFORMATION

Embryo-Fetal Toxicity

Additions and/or revisions underlined:

… Advise females of reproductive potential to use highly effective contraception at initiation of, during treatment, and for at least 3 months after taking the last dose of OFEV. Advise women taking oral hormonal contraceptives who experience vomiting and/or diarrhea or other conditions where the drug absorption may be reduced to contact their doctor to discuss alternative highly effective contraception. Advise female patients to notify their doctor if they become pregnant or suspect they are …

Newly added information:

Nephrotic Range Proteinuria

Nephrotic range proteinuria has been reported. Advise patients to report signs and symptoms of proteinuria (e.g., fluid retention, foamy urine) [see Warnings and Precautions (5.8)].

Administration

Additions and/or revisions underlined:

Instruct patients to take OFEV with food, to swallow OFEV capsules whole with liquid, and not to chew the capsules due to the bitter taste. Advise patients or caregivers not to open or crush OFEV capsules and to wash hands immediately and thoroughly if contact with the content of the capsule occurs. Advise patients to not make up for a missed dose [see Dosage and Administration (2.2)].

PATIENT INFORMATION

Additions and/or revisions underlined:

How should I take OFEV?

Do not chew, crush, or open OFEV capsules. If you or your caregiver accidently comes in contact with the content of the capsule, wash hands well right away.

What are the possible side effects of OFEV?

OFEV may cause serious side effects, including:

increased protein in your urine (proteinuria). OFEV may increase your chances of having protein in your urine. Tell your doctor if you have any signs and symptoms of protein in the urine such as foamy urine, swelling, including in your hands, arms, legs, or feet, or sudden weight gain.

10/28/2020 (SUPPL-14)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.4 Embryo-Fetal Toxicity

(Additions and/or revisions underlined)

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 highly effective contraception at initiation of, during treatment, and at least 3 months after the last dose of OFEV. Nintedanib does not change the exposure to oral contraceptive containing ethinylestradiol and levonorgestrel in patients with SSc-ILD. However, the efficacy of oral hormonal contraceptives may be compromised by vomiting and/or diarrhea or other conditions where the drug absorption may be reduced.

8 Use in Specific Populations

8.3 Females and Males of Reproductive Potential

(Additions and/or revisions underlined)

Based on findings from animal studies and its mechanism of action, OFEV can cause fetal harm when administered to a pregnant woman and may reduce fertility in females of reproductive potential [see Use in Specific Populations (8.1), Clinical Pharmacology (12.1, 12.3), and Nonclinical Toxicology (13.1)]. Counsel patients on pregnancy prevention and planning.

Pregnancy Testing

Verify the pregnancy status of females of reproductive potential prior to treatment with OFEV and during treatment as appropriate [see Dosage and Administration (2.1), Warnings and Precautions (5.4), and Use in Specific Populations (8.1)].

Contraception

OFEV can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to avoid becoming pregnant while receiving treatment with OFEV. Advise females of reproductive potential to use highly effective contraception at initiation of, during treatment, and for at least 3 months after taking the last dose of OFEV. Nintedanib does not change the exposure to oral contraceptive containing ethinylestradiol and levonorgestrel in patients with SSc-ILD. However, the efficacy of oral hormonal contraceptives may be compromised by vomiting and/or diarrhea or other conditions where the drug absorption may be reduced.

Advise women taking oral hormonal contraceptives experiencing these conditions to use alternative highly effective contraception.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions underlined)

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 highly effective contraception at initiation of, during treatment, and for at least 3 months after taking the last dose of OFEV. Advise women taking oral hormonal contraceptives who experience vomiting and/or diarrhea or other conditions where the drug absorption may be reduced to contact their doctor to discuss alternative highly effective contraception. Advise female patients to notify their doctor if they become pregnant or suspect they are pregnant during therapy with OFEV [see Warnings and Precautions (5.4) and Use in Specific Populations (8.1, 8.3)].

Administration

Instruct patients to take OFEV with food, to swallow OFEV capsules whole with liquid, and not to chew or crush the capsules due to the bitter taste. Advise patients to not make up for a missed dose [see Dosage and Administration (2.2)].

03/09/2020 (SUPPL-13)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2 Elevated Liver Enzymes and Drug-Induced Liver Injury

In all cases where it states ‘IPF Studies (1, 2, and 3), ‘Study has been added prior to each numeral. Additions and/or revisions underlined:

… 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)] …

5.3 Gastrointestinal Disorders

Diarrhea

Additions and/or revisions underlined:

… 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 …

Nausea and Vomiting

In IPF studies … 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.

5.5 Arterial Thromboembolic Events

Additions and/or revisions underlined:

In IPF studies … arterial thromboembolic events were reported in 2.5% of patients treated with OFEV and less than 1% 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 less than 1% of placebo- treated patients. In the chronic fibrosing ILDs with a progressive phenotype study (Study 5), arterial thromboembolic events were reported in less than 1% of patients in both treatment arms. Myocardial infarction was observed in less than 1% of patients in both treatment arms. In the SSc-ILD study (Study 4), arterial thromboembolic events were reported in 0.7% of patients in both treatment arms …

5.6 Risk of Bleeding

Additions and/or revisions underlined:

… In IPF studies … bleeding events were reported in 10% of patients treated with OFEV and in 7% of patients treated with placebo. In the chronic fibrosing ILDs with a progressive phenotype study (Study 5), bleeding events were reported in 11% of patients treated with OFEV and in 13% of patients treated with placebo. In the SSc-ILD study (Study 4), bleeding events were reported in 11% of patients treated with OFEV and in 8% of patients treated with placebo. In clinical trials, epistaxis was the most frequent bleeding event reported …

5.7 Gastrointestinal Perforation

Additions and/or revisions underlined:

… In IPF studies … gastrointestinal perforation was reported in less than 1% of patients treated with OFEV, compared to 0 cases in the placebo-treated patients. In the chronic fibrosing ILDs with a progressive phenotype study (Study 5), gastrointestinal perforation was not reported in any patients in any treatment arm. In the SSc-ILD study (Study 4), no cases of gastrointestinal perforation were reported in patients treated with OFEV or in placebo-treated patients.

6 Adverse Reactions

6.1 Clinical Trials Experience

Additions and/or revisions underlined:

… 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.

Following Table 1:

In addition, hypothyroidism was reported in patients treated with OFEV, more than placebo (1.1% vs. 0.6%). Alopecia was also reported in more patients treated with OFEV than placebo (0.8% vs. 0.4%).

Newly added indication information:

Chronic Fibrosing Interstitial Lung Diseases with a Progressive Phenotype

Following Table 2, additions and/or revisions underlined:
In addition, alopecia was reported in patients treated with OFEV, more than placebo (1.4% vs. 1.0%).

8 Use in Specific Populations

8.5 Geriatric Use

Additions and/or revisions underlined:

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

PATIENT INFORMATION

Additions and/or revisions underlined:
What is OFEV?

OFEV is a prescription medicine used:
- to treat people with a chronic (long lasting) interstitial lung disease in which lung fibrosis continues to worsen (progress).

09/06/2019 (SUPPL-12)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2 Elevated Liver Enzymes and Drug-Induced Liver Injury

(Additions and/or revisions are underlined)

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 (Studies 1, 2, and 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 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. 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.

5.3 Gastrointestinal Disorders

(Additions and/or revisions are underlined)

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 (Studies 1, 2, and 3), diarrhea was reported in 62% versus 18% of patients treated with OFEV and placebo, respectively. 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 SSc-ILD study (Study 4), diarrhea was reported in 76% versus 32% of patients treated with OFEV and placebo, respectively.

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 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 treatment interruption if diarrhea continues. 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 (Studies 1, 2, and 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 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. In most patients, these events were of mild to moderate intensity. In IPF studies (Studies 1, 2, and 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 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.

5.4 Embryo-Fetal Toxicity

(Additions and/or revisions are underlined)

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 highly effective contraception during treatment and at least 3 months after the last dose of OFEV. It is currently unknown whether nintedanib may reduce the effectiveness of hormonal contraceptives, therefore advise women using hormonal contraceptives to add a barrier method. Verify pregnancy status prior to treatment with OFEV and during treatment as appropriate.

5.5 Arterial Thromboembolic Events

(Additions and/or revisions are underlined)

Arterial thromboembolic events have been reported in patients taking OFEV. In IPF studies (Studies 1, 2, and 3), 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. In the SSc- ILD study (Study 4), arterial thromboembolic events were reported in 0.7% of patients in both treatment arms. There were 0 cases of myocardial infarction in OFEV-treated patients compared to 0.7% of placebo-treated patients.

5.6 Risk of Bleeding

(Additions and/or revisions are underlined)

Based on the mechanism of action (VEGFR inhibition), OFEV may increase the risk of bleeding. In IPF studies (Studies 1, 2, and 3), bleeding events were reported in 10% of patients treated with OFEV and in 7% of patients treated with placebo. In the SSc-ILD study (Study 4), bleeding events were reported in 11% of patients treated with OFEV and in 8% 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.

5.7 Gastrointestinal Perforation

(Additions and/or revisions are underlined)

Based on the mechanism of action, OFEV may increase the risk of gastrointestinal perforation. In IPF studies (Studies 1, 2, and 3), gastrointestinal perforation was reported in 0.3% of patients treated with OFEV, compared to 0 cases in the placebo-treated patients. In the SSc-ILD study (Study 4), no cases of gastrointestinal perforation were reported in patients treated with OFEV or in 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.

6 Adverse Reactions

6.1 Clinical Trials Experience

(Additions and/or revisions are underlined)

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 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 (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%).

Systemic Sclerosis-Associated Interstitial Lung Disease

OFEV was studied in a phase 3, randomized, double-blind, placebo-controlled trial (Study 4) in which 576 patients with SSc-ILD received OFEV 150 mg twice daily (n=288) or placebo (n=288). Patients were to receive treatment for at least 52 weeks; individual patients were treated for up to 100 weeks. The median duration of exposure was 15 months for patients treated with OFEV and 16 months for patients treated with placebo. Subjects ranged in age from 20 to 79 years (median age of 55 years). Most patients were female (75%). Patients were mostly Caucasian (67%), Asian (25%), or Black (6%). At baseline, 49% of patients were on stable therapy with mycophenolate.

The most frequent serious adverse events reported in patients treated with OFEV, more than placebo, were interstitial lung disease (2.4% nintedanib vs. 1.7% placebo) and pneumonia (2.8% nintedanib vs. 0.3% placebo). Within 52 weeks, 5 patients treated with OFEV (1.7%) and 4 patients treated with placebo (1.4%) died. There was no pattern among adverse events leading to death in either treatment arm.

Adverse reactions leading to permanent dose reductions were reported in 34% of OFEV-treated patients and 4% of placebo-treated patients. The most frequent adverse reaction that led to permanent dose reduction in the patients treated with OFEV was diarrhea (22%).

Adverse reactions leading to discontinuation were reported in 16% of OFEV-treated patients and 9% of placebo-treated patients. The most frequent adverse reactions that led to discontinuation in OFEV-treated patients were diarrhea (7%), nausea (2%), vomiting (1%), abdominal pain (1%), and interstitial lung disease (1%).

The safety profile in patients treated with OFEV with or without mycophenolate at baseline was comparable.

The most common adverse reactions with an incidence of greater than or equal to 5% in OFEV-treated patients and more commonly than in placebo are listed in Table 2.

7 Drug Interactions

7.4 Bosentan

(Newly Added Subsection)

Coadministration of nintedanib with bosentan did not alter the pharmacokinetics of nintedanib.

8 Use in Specific Populations

8.3 Females and Males of Reproductive Potential

(Additions and/or revisions are underlined)

Pregnancy Testing

Verify the pregnancy status of females of reproductive potential prior to treatment with OFEV and during treatment as appropriate.

Contraception

OFEV can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to avoid becoming pregnant while receiving treatment with OFEV. Advise females of reproductive potential to use highly effective contraception during treatment, and for at least 3 months after taking the last dose of OFEV. It is currently unknown whether nintedanib may reduce the effectiveness of hormonal contraceptives, therefore advise women using hormonal contraceptives to add a barrier method.

Infertility

Based on animal data, OFEV may reduce fertility in females of reproductive potential.

8.5 Geriatric Use

(Additions and/or revisions are underlined)

Of the total number of subjects in phase 2 and 3 clinical studies of OFEV in IPF, 60.8% were 65 and over, while 16.3% were 75 and over. In SSc-ILD, 21.4% were 65 and over, while 1.9% were 75 and older. 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.

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions are underlined)

Embryo-Fetal Toxicity

Patient Information OFEV (OH-fev) (nintedanib) capsules

(Extensive changes; please refer to labeling)

11/09/2018 (SUPPL-10)

Approved Drug Label (PDF)

6 Adverse Reactions

6.1 Clinical Trials Experience

Newly added information to the end of the subsection:

Combination with Pirfenidone

Concomitant treatment with nintedanib and pirfenidone was investigated in an exploratory open-label, randomized (1:1) trial of nintedanib 150 mg twice daily with add-on pirfenidone (titrated to 801 mg three times a day) compared to nintedanib 150 mg twice daily alone in 105 randomized patients for 12 weeks. The primary endpoint was the percentage of patients with gastrointestinal adverse events from baseline to Week 12. Gastrointestinal adverse events were in line with the established safety profile of each component and were experienced in 37 (70%) patients treated with pirfenidone added to nintedanib versus 27 (53%) patients treated with nintedanib alone.

Diarrhea, nausea, vomiting, and abdominal pain (includes upper abdominal pain, abdominal discomfort, and abdominal pain) were the most frequent adverse events reported in 20 (38%) versus 16 (31%), in 22 (42%) versus 6 (12%), in 15 (28%) versus 6 (12%) patients, and in 15 (28%) versus 7 (14%) treated with pirfenidone added to nintedanib versus nintedanib alone, respectively. More subjects reported AST or ALT elevations (greater than or equal to 3x the upper limit of normal) when using pirfenidone in combination with nintedanib (n=3 (6%)) compared to nintedanib alone (n=0).

6.2 Postmarketing Experience

Newly added information:

The following adverse reactions have been identified during postapproval use of OFEV: drug-induced liver injury, non-serious and serious bleeding events, some of which were fatal, pancreatitis, thrombocytopenia, rash, pruritus.

7 Drug Interactions

Newly added subsection:

7.3 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 (12.3)]. Therefore, no dose adjustment is necessary during concomitant administration of nintedanib with pirfenidone.

01/29/2018 (SUPPL-9)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2 Elevated Liver Enzymes and Drug-Induced Liver Injury

(Additions and/or revisions are underlined)

Cases of drug-induced liver injury (DILI) have been observed with OFEV treatment. In the post-marketing 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. 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.

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.

6 Adverse Reactions

6 ADVERSE REACTIONS

(Additions and/or revisions are underlined)

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

Elevated Liver Enzymes and Drug-Induced Liver Injury.

…

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions are underlined)

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)

…

Other

Patient Information

(Additions and/or revisions are underlined)

What are the possible side effects of 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 regularly to check how well your liver function is working during your treatment with OFEV.
…

12/13/2017 (SUPPL-7)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.6 Risk of Bleeding

(additions underlined)

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 post-marketing 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.

5.7 Gastrointestinal Perforation

(additions underlined)

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 post-marketing 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.

6 Adverse Reactions

6.2 Postmarketing Experience

(additions underlined)

The following adverse reactions have been identified during postapproval use of OFEV. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Drug-induced liver injury
Pancreatitis
Thrombocytopenia
Non-serious and serious bleeding events, some of which were fatal, have been observed in the postmarketing period.

08/04/2017 (SUPPL-5)

Approved Drug Label (PDF)

5 Warnings and Precautions

5.2 Elevated Liver Enzymes

Additions and/or revisions underlined

Cases of drug-induced liver injury have been observed with OFEV 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 … The majority (95%) of patients with bilirubin elevations had elevations less than 2 times ULN. 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. Conduct liver function tests (ALT, AST, and bilirubin) prior to treatment with OFEV, then as clinically indicated. Dosage modifications or interruption may be necessary for liver enzyme elevations. If serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment with OFEV, promptly interrupt therapy.

6 Adverse Reactions

6.2 Postmarketing Experience

Addition of the following:

Drug-induced liver injury

02/09/2017 (SUPPL-4)

Approved Drug Label (PDF)

6 Adverse Reactions

6.2 Postmarketing Experience

(new subsection added)

Pancreatitis
Thrombocytopenia

Non-serious and serious bleeding events have been observed in the postmarketing period in line with clinical trial experience.