Interim results from INPULSIS®-ON supports the safety and tolerability demonstrated in the INPULSIS® trials
INPULSIS®-ON is an ongoing, open-label extension trial
- A single-arm, open-label extension trial of the INPULSIS® trials (INPULSIS®-1 and INPULSIS®-2) designed to assess the long-term safety of OFEV (nintedanib) in patients with IPF
- 734 patients who completed the 52-week INPULSIS® trials and follow-up visit enrolled in the extension trial—this included 430 patients who continued treatment on OFEV and 304 patients who were previously taking placebo1
- The first patient was enrolled in INPULSIS®-ON in July 2012. Interim analyses were set to occur every 48 weeks once the last patient to enroll in the trial had reached 48 weeks on treatment1,2
- At the time of the 96-week interim analysis in October 2015, the mean (SD) total exposure for patients treated with OFEV during INPULSIS® and INPULSIS®-ON was 35.7 (10.5) months, with a maximum exposure of 51.1 months1
- The mean (SD) exposure in INPULSIS®-ON for patients initiating OFEV was 21.8 (11.5) months and 23.7 (10.5) months for patients continuing OFEV
91% of eligible patients who completed INPULSIS® enrolled in INPULSIS®-ON2*
- Based on the open-label design, a potential for bias exists in the group of patients who completed the INPULSIS® trials and continued treatment in INPULSIS®-ON
- Due to the lack of a placebo group, statistical comparisons cannot be made
- All analyses were descriptive in nature
ADVERSE EVENTS OBSERVED WERE CONSISTENT BETWEEN INPULSIS® AND INPULSIS®-ON1†
Adverse events reported in ≥5% of patients in any treatment group in INPULSIS® or INPULSIS®-ON
THE MEAN CHANGE IN FVC OBSERVED IN THE INPULSIS® AND INPULSIS®-ON TRIALS1
CI, confidence interval; FVC, forced vital capacity; SD, standard deviation.
*A total of 807 patients completed the planned observation time for INPULSIS® and were eligible for enrollment in INPULSIS®-ON. Of the 807 eligible patients, 734 opted to enroll in INPULSIS®-ON.1,3
†Safety analysis included the treated set from the 52-week INPULSIS® trials and all data collected in INPULSIS®-ON between July 2012 and October 2015, for a total OFEV exposure of 4 years and 3 months.1,2
‡The most frequent adverse events leading to treatment discontinuation in INPULSIS® were diarrhea (4.4%), progression of IPF (2.0%), nausea (2.0%), and decreased appetite (1.4%). Similar frequent adverse events leading to discontinuation were also seen in INPULSIS®-ON.1
§Only patients who completed INPULSIS® and the follow-up visit were eligible to enroll in INPULSIS®-ON.1
¶Adjusted mean difference vs placebo at week 52 based on mixed model for repeated measures.3
INFORMATION AND INDICATION
WARNINGS AND PRECAUTIONS
- OFEV (nintedanib) 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 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. 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. 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 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.
- 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 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.
- 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
- 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.
- 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 effective contraception during treatment and at least 3 months after the last dose of OFEV. Verify pregnancy status prior to starting OFEV.
Arterial Thromboembolic Events: 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. 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. Bleeding events were reported in 10% of OFEV versus 7% of placebo patients. Use OFEV in patients with known risk of bleeding only if the anticipated benefit outweighs the potential risk. In the post-marketing period, non-serious and serious bleeding events, some of which were fatal, have been observed.
Gastrointestinal Perforation: OFEV may increase the risk of gastrointestinal perforation. Gastrointestinal perforation was reported in 0.3% of OFEV versus in 0% placebo 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.
- Adverse reactions reported in greater than or equal to 5% of OFEV patients included diarrhea, nausea, abdominal pain, liver enzyme elevation, vomiting, decreased appetite, weight decreased, headache, and hypertension.
- The most frequent serious adverse reactions reported in OFEV patients were bronchitis and myocardial infarction. 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.
- 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 (nintedanib) is indicated for the treatment of idiopathic pulmonary fibrosis (IPF).
- Data on file. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc.
- Wuyts WA et al. Lung. 2016;194:739-743.
- Richeldi L et al; for the INPULSIS Trial Investigators. N Engl J Med. 2014;370(22):2071-2082.