OFEV(NINTEDANIB ESYLATE)CAPSULE ORAL-为特发性肺间质纤维化的治疗新药
OFEV is a kinase inhibitor indicated for the treatment of idiopathic pulmonary fibrosis (IPF). (1) DOSAGE AND ADMINISTRATION Recommended dosage: 150 mg twice daily approximately 12 hours apart taken with food. (2.2) Recommended dosage in patients with mild hepatic impairment (Child Pugh A): 100 mg twice daily approximately 12 hours apart taken with food. (2.2, 8.6) Consider temporary dose reduction to 100 mg, treatment interruption, or discontinuation for management of adverse reactions. (2.3, 5.2, 5.3, 6) Prior to treatment, conduct liver function tests and a pregnancy test. (2.1, 5.2, 5.4) DOSAGE FORMS AND STRENGTHS Capsules: 150 mg and 100 mg (3) CONTRAINDICATIONS None WARNINGS AND PRECAUTIONS Hepatic impairment: OFEV is not recommended for use in patients with moderate or severe hepatic impairment. In patients with mild hepatic impairment (Child Pugh A), the recommended dosage is 100 mg twice daily approximately 12 hours apart taken with food. Consider treatment interruption, or discontinuation for management of adverse reactions in these patients. (2.2, 2.3, 5.1, 8.6, 12.3) Elevated liver enzymes: ALT, AST, and bilirubin elevations have occurred with OFEV. Monitor ALT, AST, and bilirubin before and during treatment. Temporary dosage reductions or discontinuations may be required. (2.1, 2.3, 5.2) Gastrointestinal disorders: Diarrhea, nausea, and vomiting have occurred with OFEV. Treat patients at first signs with adequate hydration and antidiarrheal medicine (e.g., loperamide) or anti-emetics. Discontinue OFEV if severe diarrhea, nausea, or vomiting persists despite symptomatic treatment. (5.3) Embryo-Fetal toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception. (5.4, 8.1, 8.3) Arterial thromboembolic events have been reported. Use caution when treating patients at higher cardiovascular risk including known coronary artery disease. (5.5) Bleeding events have been reported. Use OFEV in patients with known bleeding risk only if anticipated benefit outweighs the potential risk. (5.6) Gastrointestinal perforation has been reported. Use OFEV with caution when treating patients with recent abdominal surgery. Discontinue 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. (5.7) ADVERSE REACTIONS Most common adverse reactions (≥5%) are: diarrhea, nausea, abdominal pain, vomiting, liver enzyme elevation, decreased appetite, headache, weight decreased, hypertension. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Boehringer Ingelheim Pharmaceuticals, Inc. at (800) 542-6257 or (800) 459-9906 TTY or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. DRUG INTERACTIONS Coadministration of P-gp and CYP3A4 inhibitors may increase nintedanib exposure. Monitor patients closely for tolerability of OFEV. (7.1) USE IN SPECIFIC POPULATIONS Lactation: Breastfeeding is not recommended. (8.2) Renal impairment: The safety and efficacy of OFEV have not been studied in patients with severe renal impairment and end-stage renal disease. (8.7, 12.3) Smokers: Decreased exposure has been noted in smokers which may alter the efficacy profile of OFEV. (8.8) See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling. Revised: 2/2016 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE OFEV is indicated for the treatment of idiopathic pulmonary fibrosis (IPF). 2 DOSAGE AND ADMINISTRATION 2.1 Testing Prior to OFEV Administration Conduct liver function tests and a pregnancy test 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 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. In patients with mild hepatic impairment (Child Pugh A), the recommended dosage of OFEV is 100 mg twice daily approximately 12 hours apart taken with food. 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 (5.2, 5.3, 5.5, 5.7) 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 (5.2) 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. In patients with mild hepatic impairment (Child Pugh A), consider treatment interruption, or discontinuation for management of adverse reactions. 3 DOSAGE FORMS AND STRENGTHS 150 mg capsules: brown, opaque, oblong, soft capsules imprinted in black with the Boehringer Ingelheim company symbol and "150". 100 mg capsules: peach, opaque, oblong, soft capsules imprinted in black with the Boehringer Ingelheim company symbol and "100". 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 (2.2)]. 5.2 Elevated Liver Enzymes 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)]. 5.3 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. 5.4 Embryo-Fetal Toxicity Based on findings from animal studies and its mechanism of action, OFEV can cause fetal harm when administered to a pregnant woman. Nintedanib caused embryo-fetal deaths and structural abnormalities in rats and rabbits when administered during organogenesis at less than (rats) and approximately 5 times (rabbits) the maximum recommended human dose (MRHD) in adults. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to avoid becoming pregnant while receiving treatment with OFEV and to use effective contraception during treatment and at least 3 months after the last dose of OFEV. Verify pregnancy status prior to treatment with OFEV [see Use in Specific Populations (8.1, 8.3) and Clinical Pharmacology (12.1)]. 5.5 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. 5.6 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. 5.7 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 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling: Liver Enzyme and Bilirubin Elevations [see Warnings and Precautions (5.2)] Gastrointestinal Disorders [see Warnings and Precautions (5.3)] Embryo-Fetal Toxicity [see Warnings and Precautions (5.4)] Arterial Thromboembolic Events [see Warnings and Precautions (5.5)] Risk of Bleeding [see Warnings and Precautions (5.6)] Gastrointestinal Perforation [see Warnings and Precautions (5.7)] 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 evaluated 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. Table 1 Adverse Reactions Occurring in ≥5% of OFEV-treated Patients and More Commonly Than Placebo in Studies 1, 2, and 3
b Includes gamma-glutamyltransferase increased, hepatic enzyme increased, alanine aminotransferase increased, aspartate aminotransferase increased, hepatic function abnormal, liver function test abnormal, transaminase increased, blood alkaline phosphatase-increased, alanine aminotransferase abnormal, aspartate aminotransferase abnormal, and gamma-glutamyltransferase abnormal. c Includes hypertension, blood pressure increased, hypertensive crisis, and hypertensive cardiomyopathy. In addition, hypothyroidism was reported in patients treated with OFEV, more than placebo (1.1% vs. 0.6%). 7 DRUG INTERACTIONS 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 (5.6)]. 8 USE IN SPECIFIC POPULATIONS 8.1 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). 8.2 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. 8.3 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), 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 [see Dosage and Administration (2.1), Warnings and Precautions (5.4) and Use in Specific Populations (8.1)]. Contraception Advise females of reproductive potential to avoid becoming pregnant while receiving treatment with OFEV. Advise females of reproductive potential to use effective contraception during treatment, and for at least 3 months after taking the last dose of OFEV. Infertility Based on animal data, OFEV may reduce fertility in females of reproductive potential [see Nonclinical Toxicology (13.1)]. 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%). 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 (2.2)]. Monitor for adverse reactions and consider treatment interruption, or discontinuation for management of adverse reactions in these patients [see Dosage and Administration (2.3)]. 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. 10 OVERDOSAGE In the trials, one patient was inadvertently exposed to a dose of 600 mg daily for a total of 21 days. A non-serious adverse event (nasopharyngitis) occurred and resolved during the period of incorrect dosing, with no onset of other reported events. Overdose was also reported in two patients in oncology studies who were exposed to a maximum of 600 mg twice daily for up to 8 days. Adverse events reported were consistent with the existing safety profile of OFEV. Both patients recovered. In case of overdose, interrupt treatment and initiate general supportive measures as appropriate. 11 DESCRIPTION OFEV capsules contain nintedanib, a kinase inhibitor [see Mechanism of Action (12.1)]. Nintedanib is presented as the ethanesulfonate salt (esylate), with the chemical name 1H-Indole-6-carboxylic acid, 2,3-dihydro-3-[[[4-[methyl[(4-methyl-1-piperazinyl)acetyl]amino]phenyl]amino]phenylmethylene]-2-oxo-,methyl ester, (3Z)-, ethanesulfonate (1:1). Its structural formula is:
bEstimated based on a random coefficient regression model Figure 1 displays the change from baseline over time in both treatment groups for Study 2. When the mean observed FVC change from baseline was plotted over time, the curves diverged at all timepoints through Week 52. Similar plots were seen for Studies 1 and 3. Figure 1 Mean (SEM) Observed FVC Change from Baseline (mL) Over Time in Study 2 bid = twice daily *Missing data for change from baseline at Week 52 in percent predicted FVC (due to death, lost to follow-up or censoring before 52 weeks) was imputed using the worst decline from baseline at Week 52 observed among all patients with available data, regardless of treatment.
德国上市包装
|