About OFEV (Nintedanib)
Clinical trial population
Q. What was the range of FVC and DLCO among patients included in the 3 clinical trials?
A. The study populations included a range of patients with IPF with FVC ≥50% predicted value (no upper limit) and DLCO 30%-79% of predicted value. Specifically, 26% of the patient population had >90% FVC predicted at baseline.1,2
Q. Were patients required to have a surgical lung biopsy confirming the IPF diagnosis for enrollment into OFEV clinical trials?
A. No, surgical lung biopsy was not required. If surgical lung biopsy was not available, HRCT pattern had to be consistent with a diagnosis of IPF. Patients with definite UIP and possible UIP on HRCT were enrolled.1,3-5
Q. What percentage of patients had emphysema on HRCT in clinical trials with OFEV?
A. The percentage of patients with IPF who had emphysema on HRCT in the TOMORROW, INPULSIS®-1, and INPULSIS®-2 trials were as follows: 27.1% in the OFEV arm vs 22.4% in the placebo arm, 38.2% in the OFEV arm vs 38.2% in the placebo arm, and 41.3% in the OFEV arm vs 40.2% in the placebo arm, respectively. Approximately 40% of patients had concomitant emphysema in the pooled INPULSIS® population (OFEV and placebo arms) compared to 60% without concomitant emphysema.6
Q. Were patients with PAH excluded from clinical trials with OFEV?
A. No, patients with PAH were not excluded from clinical trials.1,3,4
Q. Does OFEV slow IPF progression?
A. Yes. The totality of the evidence demonstrates that OFEV slows IPF progression.1,7-10 OFEV demonstrated reproducible reductions in the annual rate of FVC decline in 3 clinical trials and reduced the risk of first acute IPF exacerbation over 52 weeks compared with placebo in 2 out of 3 clinical trials.1
Q. Did the effect of OFEV differ in patients with lower or higher percent-predicted FVC at baseline?
A. The effect of OFEV was evaluated in a prespecified subgroup analysis in patients with <70% and >70% FVC predicted at baseline as well as in a post hoc analysis in patients with <90% and >90% FVC predicted at baseline. In both analyses, there was a consistent treatment effect in the two groups.2,6
Q. How were acute IPF exacerbations adjudicated in the INPULSIS® trials?
A. Acute IPF exacerbations were adjudicated using the following criteria1,3:
- Unexplained worsening or development of dyspnea within 30 days
- New diffuse pulmonary infiltrates on chest X-ray and/or HRCT
- Parenchymal abnormalities with no pneumothorax or pleural effusion (new ground-glass opacities)
- Exclusion of alternative causes of the acute worsening (including infection, left heart failure, pulmonary embolism, etc)
Safety and dosing
Q. How should GI adverse reactions be managed?
A. Below is a top-level overview of an approach to managing GI adverse reactions for patients receiving OFEV.
- Advise your patients before initiating OFEV. They should know about the possibility of experiencing GI adverse reactions and when to notify you if symptoms occur1
- Initiate symptomatic treatment at the first signs of symptoms1
- Dose modification, including discontinuation, may be required if GI adverse reactions are persistent or severe, despite symptomatic treatment1
Q. How often should liver enzymes be monitored?
A. Liver function tests, including ALT, AST, and bilirubin, should be conducted in all patients prior to initiation of treatment with OFEV, at regular intervals during the first 3 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.1
Q. How should liver enzyme elevations be managed?
A. For ALT or AST elevations greater than 3x to less than 5x ULN without signs of liver damage, interrupt treatment or reduce OFEV to 100 mg twice daily. Once liver enzymes have returned to baseline values, OFEV may be reintroduced at the reduced dosage (100 mg twice daily). OFEV may subsequently be increased to the full dosage (150 mg twice daily). For ALT or AST greater than 3x ULN with signs or symptoms of liver injury and for ALT or AST elevations greater than 5x ULN, discontinue OFEV.1
Q. Can OFEV be used in patients who are taking anticoagulants?
A. 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. Monitor patients on full anticoagulation therapy closely for bleeding and adjust anticoagulation treatment as necessary.1
Q. Should OFEV be used in patients with cardiovascular risk?
A. 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.1
Q. Can I use OFEV in patients with advanced liver disease?
A. No. Treatment with OFEV is not recommended in patients with moderate (Child Pugh B) or severe (Child Pugh C) 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.1
Q. Are there any contraindications for OFEV?
A. No, there are no contraindications for OFEV.1
Q. What is the recommended dosage for OFEV?
A. OFEV offers dosing simplicity with 1 capsule, twice daily, which can be integrated into a patient’s morning and evening routine.1
The recommended dosage of OFEV is 150 mg twice daily administered approximately 12 hours apart, with food, and should be swallowed with a glass of water. For patients with mild hepatic impairment (Child Pugh A), the recommended dosage is 100 mg twice daily with food.1
Q. Is OFEV still effective at the reduced dose (100 mg twice daily) when managing adverse events?
A. Yes. Dose reduction or temporary interruption of treatment with OFEV allows for the management of adverse reactions while supporting continued clinical benefit. If patient does not tolerate dose reduction, discontinue treatment with OFEV.1,4,6 In a prespecified analysis of the primary endpoint of the INPULSIS® trials, there was a consistent treatment effect on the reduction of the annual rate of FVC decline between patients on >90% of the maximum dose and <90% of the maximum dose (as measured by dose intensity). Dose intensity is defined as the amount of drug administered over the study divided by the amount of drug that would have been received had the 150-mg twice-daily dose been administered throughout the 52-week study or until discontinuation in patients who discontinued prematurely.6
Access and resources
Q. How are prescriptions for OFEV filled?
A. OFEV prescriptions are filled through our participating specialty pharmacies. Just complete the OFEV Prescription Form and fax it to one of the specialty pharmacies in our distribution network listed on the Prescription Form. The specialty pharmacy will begin benefit investigation and communicate with both you and your patient.
Q. How are prior authorizations handled if they are required?
A. If the prescription requires a prior authorization or an appeal, the specialty pharmacy will notify you to discuss the steps necessary to complete the claim. Common prior authorizations for OFEV coverage are confirmed diagnosis and additional lab/test results.
If this process is delayed for ≥7 days due to investigation, prior authorization, or appeal, the patient may be eligible for the OFEV Bridge Program. This service provides a 15-day supply of OFEV and up to 3 additional 15-day refills to the patient at no cost.
Q. Is financial assistance available for patients who are prescribed OFEV?
A. Patients have different financial assistance options available to them, depending on their insurance coverage and financial situation.
Q. What happens if a prescription is sent to the wrong specialty pharmacy?
A. If this happens, the specialty pharmacy will refer the prescription to a different specialty pharmacy that is part of the patient’s prescription coverage network.
Q. If a patient starts on 150 mg of OFEV capsules and requires a dose modification to 100 mg, will there be a gap in coverage?
A. The OFEV Bridge Program can provide complimentary 15-day or 30-day supplies of OFEV for patients who have had their dose of OFEV changed more than once within the same month and whose plan will not cover the cost of the second prescription.
Q. What resources are available for patients?
A. The OPEN DOORS® Patient Support Program provides a comprehensive suite of services designed with your patients’ needs in mind. Through education, support, and access they encourage an informed and proactive approach in patients and their caregivers. Through OPEN DOORS®, patients can have access to nurse support, social services, Clinical Educators, and our Patient Mentor Program.
Q. How can I initiate an educational program with an OFEV Clinical Educator for my patients or for my practice?
A. OFEV Clinical Educators are highly trained specialists who offer education to clinical staff and patients alike. Programs with OFEV Clinical Educators can be initiated by calling OPEN DOORS® Patient Support Program at 1-866-OPENDOOR (673-6366) or by contacting your local OFEV Sales Representative.
ALT, alanine aminotransferase; AST, aspartate aminotransferase; DLCO, diffusing capacity for carbon monoxide; FVC, forced vital capacity; GI, gastrointestinal; HRCT, high-resolution computed tomography; IPF, idiopathic pulmonary fibrosis; PAH, pulmonary arterial hypertension; UIP, usual interstitial pneumonia; ULN, upper limit of normal.
IMPORTANT SAFETY INFORMATION AND INDICATIONS
WARNINGS AND PRECAUTIONS
Hepatic Impairment: OFEV is not recommended in patients with moderate (Child Pugh B) or severe (Child Pugh C) hepatic impairment. Patients with mild hepatic impairment (Child Pugh A) can be treated with a reduced dosage (100 mg twice daily). Consider treatment interruption or discontinuation for management of adverse reactions.
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 post-marketing period, non-serious and serious cases of DILI were reported. Cases of severe liver injury with fatal outcome have been reported in the post-marketing period. The majority of hepatic events occur within the first three months of treatment. OFEV was associated with elevations of liver enzymes (ALT, AST, ALKP, and GGT) and bilirubin. Liver enzyme and bilirubin increases were reversible with dose modification or interruption in the majority of cases.
- In IPF studies, 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, a maximum ALT and/or AST greater than or equal to 3 times ULN was observed in 4.9% of patients treated with OFEV.
- Patients with low body weight (less than 65 kg), patients who are Asian, and female patients may have a higher risk of elevations in liver enzymes. Nintedanib exposure increased with patient age, which may result in increased liver enzymes.
- Conduct liver function tests prior to initiation of treatment, at regular intervals during the first three months of treatment, and periodically thereafter or as clinically indicated. Measure liver function 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, interruption, or discontinuation may be necessary for liver enzyme elevations.
- In IPF studies, diarrhea was the most frequent gastrointestinal event reported in 62% versus 18% of patients treated with OFEV and placebo, respectively. Events were primarily mild to moderate in intensity and occurred within the first 3 months. Diarrhea led to permanent dose reduction in 11% and discontinuation in 5% of OFEV patients versus 0 and less than 1% in placebo patients, respectively.
- In the SSc-ILD study, diarrhea was the most frequent gastrointestinal event reported in 76% versus 32% of patients treated with OFEV and placebo, respectively. Events were primarily mild to moderate in intensity and occurred within the first 3 months. Diarrhea led to permanent dose reduction in 22% and discontinuation in 7% of OFEV patients versus 1% and 0.3% in placebo patients, respectively.
- Dosage modifications or treatment interruptions may be necessary in patients with 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, discontinue treatment.
Nausea and Vomiting
- In IPF studies, nausea was reported in 24% versus 7% and vomiting was reported in 12% versus 3% of patients treated with OFEV and placebo, respectively. Events were primarily of mild to moderate intensity. Nausea and vomiting led to discontinuation of OFEV in 2% and 1% of patients, respectively.
- In the SSc-ILD study, nausea was reported in 32% versus 14% and vomiting was reported in 25% versus 10% of patients treated with OFEV and placebo, respectively. Events were primarily of mild to moderate intensity. Nausea and vomiting led to discontinuation of OFEV in 2% and 1% of patients, respectively.
- If nausea or vomiting persists despite appropriate supportive care including anti-emetic therapy, consider dose reduction or treatment interruption. OFEV treatment may be resumed at full dosage or at reduced dosage, which subsequently may be increased to full dosage. If severe nausea or vomiting does not resolve, discontinue treatment.
Embryofetal Toxicity: OFEV can cause fetal harm when administered to a pregnant woman and patients should be advised of the potential risk to a fetus. Women should be advised to avoid becoming pregnant while receiving OFEV and to use highly effective contraception during treatment and at least 3 months after the last dose of OFEV. As the impact of nintedanib on the effectiveness of hormonal contraception is unknown, advise women using hormonal contraceptives to add a barrier method. Verify pregnancy status prior to starting OFEV and during treatment as appropriate.
Arterial Thromboembolic Events:
- In IPF studies, arterial thromboembolic events were reported in 2.5% of OFEV and 0.8% of placebo patients, respectively. Myocardial infarction was the most common arterial thromboembolic event, occurring in 1.5% of OFEV and 0.4% of placebo patients.
- In the SSc-ILD study, arterial thromboembolic events were reported in 0.7% of patients in both the OFEV-treated and placebo-treated patients. 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
- OFEV may increase the risk of bleeding.
- In IPF studies, bleeding events were reported in 10% of OFEV versus 7% of placebo patients. In the post-marketing period, non-serious and serious bleeding events, some of which were fatal, have been observed.
- In the SSc-ILD study, bleeding events were reported in 11% of OFEV versus 8% of placebo patients.
- Use OFEV in patients with known risk of bleeding only if the anticipated benefit outweighs the potential risk.
- OFEV may increase the risk of gastrointestinal perforation.
- In IPF studies, gastrointestinal perforation was reported in 0.3% of OFEV versus in 0% of placebo patients.
- In the SSc-ILD study, no cases of gastrointestinal perforation were reported in either OFEV or 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, have a previous history of diverticular disease, or who are 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.
- Adverse reactions reported in greater than or equal to 5% of OFEV patients, and more than placebo, included diarrhea, nausea, vomiting, skin ulcer, abdominal pain, liver enzyme elevation, weight decreased, fatigue, decreased appetite, headache, pyrexia, back pain, dizziness and hypertension.
- In IPF studies, 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 OFEV patients versus 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 versus 1.8% in placebo patients.
- In the SSc-ILD study, the most frequent serious adverse events reported in patients treated with OFEV, more than placebo, were interstitial lung disease (2.4% vs. 1.7%) and pneumonia (2.8% vs. 0.3%). 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.
- P-glycoprotein (P-gp) and CYP3A4 Inhibitors and Inducers: Coadministration with oral doses of a P-gp and CYP3A4 inhibitor, ketoconazole, increased exposure to nintedanib by 60%. Concomitant use of potent P-gp and CYP3A4 inhibitors (e.g., erythromycin) with OFEV may increase exposure to nintedanib. 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. 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.
- Anticoagulants: Nintedanib may increase the risk of bleeding. Monitor patients on full anticoagulation therapy closely for bleeding and adjust anticoagulation treatment as necessary.
USE IN SPECIFIC POPULATIONS
- Nursing Mothers: Because of the potential for serious adverse reactions in nursing infants from OFEV, advise women that breastfeeding is not recommended during treatment.
- Reproductive Potential: OFEV may reduce fertility in females of reproductive potential.
- Smokers: Smoking was associated with decreased exposure to OFEV, which may affect the efficacy of OFEV. Encourage patients to stop smoking prior to and during treatment.
OFEV is indicated for the treatment of idiopathic pulmonary fibrosis (IPF).
OFEV is indicated to slow the rate of decline in pulmonary function in patients with systemic sclerosis-associated interstitial lung disease (SSc-ILD).
- OFEV® (nintedanib) Prescribing Information. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc; 2019.
- Kolb M et al. Thorax. 2017;72(4):340-346.
- Richeldi L et al; for the INPULSIS Trial Investigators. N Engl J Med. 2014;370(22):2071-2082.
- Richeldi L et al. N Engl J Med. 2011;365(12):1079-1087.
- Raghu G et al; on behalf of the ATS/ERS/JRS/ALAT Committee on Idiopathic Pulmonary Fibrosis. Am J Respir Crit Care Med. 2011;183(6):788-824.
- Data on file. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc.
- Zappala CJ et al. Eur Respir J. 2010;35(4):830-836.
- Schmidt SL et al. Chest. 2014;145(3):579-585.
- du Bois RM et al. Am J Respir Crit Care Med. 2011;184(12):1382-1389.
- Song JW et al. Eur Respir J. 2011;37(2):356-363.