Ofev
(nintedanib)Dosage & Administration
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Ofev Prescribing Information
Idiopathic Pulmonary Fibrosis
OFEV is indicated for the treatment of adults with idiopathic pulmonary fibrosis (IPF).
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)].
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).
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)].
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.
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)].
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.
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".
Pregnancy
Risk Summary
Based on findings from animal studies and its mechanism of action [see Clinical Pharmacology (12.1)], OFEV can cause fetal harm when administered to a pregnant woman. There are no data on the use of OFEV during pregnancy. In animal studies of pregnant rats and rabbits treated during organogenesis, nintedanib caused embryo-fetal deaths and structural abnormalities at less than (rats) and approximately 5 times (rabbits) the maximum recommended human dose [see Data]. Advise pregnant women of the potential risk to a fetus.
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects is 2% to 4% and miscarriage in clinically recognized pregnancies is 15% to 20%.
Data
Animal Data
In animal reproduction toxicity studies, nintedanib caused embryo-fetal deaths and structural abnormalities 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).
Lactation
Risk Summary
There is no information on the presence of nintedanib in human milk, the effects on the breast-fed infant or the effects on milk production. Nintedanib and/or its metabolites are present in the milk of lactating rats [see Data]. Because of the potential for serious adverse reactions in nursing infants from OFEV, advise women that breastfeeding is not recommended during treatment with OFEV.
Data
Milk and plasma of lactating rats have similar concentrations of nintedanib and its metabolites.
Females and Males of Reproductive Potential
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.
Infertility
Based on animal data, OFEV may reduce fertility in females of reproductive potential [see Nonclinical Toxicology (13.1)].
Pediatric Use
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.
Geriatric Use
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. 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.
Hepatic Impairment
Nintedanib is predominantly eliminated via biliary/fecal excretion (greater than 90%). In a PK study performed in patients with hepatic impairment (Child Pugh A, Child Pugh B), exposure to nintedanib was increased [see Clinical Pharmacology (12.3)]. In patients with mild hepatic impairment (Child Pugh A), the recommended dosage of OFEV is 100 mg twice daily [see Dosage and Administration (2.3)]. Monitor for adverse reactions and consider treatment interruption, or discontinuation for management of adverse reactions in these patients [see Dosage and Administration (2.4)]. 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)].
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 (less than 30 mL/min CrCl) and end-stage renal disease.
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.
None
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)].
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)].
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.
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 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. 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)].
Arterial Thromboembolic Events
Arterial thromboembolic events have been reported in patients taking OFEV. In IPF studies (Study 1, Study 2, and Study 3), 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. There were 0 cases of myocardial infarction in OFEV-treated patients compared to 0.7% 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 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.
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 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.
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.
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.