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OFEV®

Side effects and safety

Adverse events profile

OFEV® has demonstrated a manageable safety and tolerability profile, with 5 years of post-approval clinical evidence in patients with idiopathic pulmonary fibrosis (IPF).1

Additional safety information

OFEV® has an established safety profile with additional safety data on liver enzyme, cardiac events and bleeding events.2-4

Adverse event management

Gastrointestinal (GI)-related adverse events (AEs) can be effectively managed in most patients with dose modification and
symptomatic treatment.2

Adverse events profile

OFEV® has demonstrated a manageable safety and tolerability profile, with 5 years of post-approval clinical evidence in patients with idiopathic pulmonary fibrosis (IPF)1

profile

The most common adverse events (AEs) were gastrointestinal (GI)-related and could be effectively managed2,5

  • Serious AEs were comparable across treatment groups5
  • OFEV® has NOT been associated with photosensitivity3

Real-world data

In a postmarketing surveillance study:3,6†

 

 

The rate of diarrhea reported in postmarketing surveillance was lower than the rate reported in the INPULSIS® trials and similar to epidemiological data from the general population6

 

 

data

 

Known risk factors for cardiac events were reported in 42.3% of cases6

 

data1

 

The rate of bleeding events‡ reported in postmarketing surveillance was similar to the rate in the INPULSIS® trials, but higher than in epidemiological data from patients with IPF6

 

data2
data3

 

Claims-based rates (from epidemiological data) for nonserious bleeding events (e.g. epistaxis) are not accurate as only events that are severe enough for the patient to seek medical attention at a healthcare facility are captured6

Long-term exposure

The safety profile of OFEV® observed in the INPULSIS® trials was sustained in the INPULSIS®-ON trial1§

  • Continued treatment with OFEV® for up to 68 months had a manageable safety and tolerability profile1¶
  • There were no new safety signals identified1
  • The safety profile of OFEV® was shown to be consistent with the INPULSIS® trials1§

Additional safety information

Liver enzyme elevations

Incidence

  • Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) elevations ≥3x upper limit of normal (ULN) occurred in approximately 5% of patients and bilirubin elevations ≥1.5x ULN occurred in approximately 2% of patients3
  • All transaminase elevations were reversible upon dose reduction or interruption2

Monitoring2

  • Conduct liver function tests (hepatic transaminase and bilirubin levels) before treatment initiation, during the first month of treatment, at regular intervals during the subsequent 2 months and periodically thereafter (e.g. at each patient visit or as clinically indicated)
  • For AST or ALT elevations ≥3x ULN, dose reduction or interruption of therapy with OFEV® and close monitoring of the patient are recommended
  • Once levels return to baseline values, treatment with OFEV® may be resumed at the full dose (150 mg twice daily) or a reduced dose (100 mg twice daily), which subsequently may be increased to the full dose
  • If the liver test elevations are associated with clinical signs or symptoms of liver injury (e.g. jaundice), then permanently discontinue therapy with OFEV®

Hepatic function2

  • The safety and efficacy of OFEV® have not been studied in patients with moderate or severe hepatic impairment (Child-Pugh B or C). OFEV® is not recommended in these patients
  • Patients with mild hepatic impairment (Child-Pugh A) should be treated with a reduced dose (100 mg twice daily) of OFEV®

Pregnancy2

  • OFEV® may cause fetal harm in humans. Advise women of childbearing potential to avoid becoming pregnant while receiving treatment with OFEV® and to use highly effective contraception methods during and at least 3 months after the last dose of OFEV®. Advise women using hormonal contraceptives to add a barrier method
  • Prior to initiating treatment, conduct a pregnancy test in females of childbearing potential
data4

Cardiac events

  • The incidence of serious and nonserious cardiac adverse events (AEs), including ischemic heart disease and cardiac disorders, was balanced between the treatment arms3,4

The incidence rate of myocardial infarction observed for the OFEV®-treated patients remains substantially below the incidence for myocardial infarction in a representative idiopathic pulmonary fibrosis (IPF) population4,7

The incidence rate of major adverse cardiovascular events (MACE) was similar between both treatment arms in high- and low-cardiovascular (CV) risk patients in a post hoc analysis of pooled INPULSIS®-1 and -2 and TOMORROW data8‡‡

Bleeding events

  • Due to the mechanism of action, OFEV® may be associated with an increased risk of bleeding2

Nonserious epistaxis and contusion were the most frequently reported bleeding events2,4

Serious bleeding events occurred with a low and similar frequency in both groups2,4

data5

Note

Patients at known risk for bleeding (including those with inherited predisposition to bleeding or patients receiving a full dose of anticoagulative treatment) were not included in the INPULSIS® trials.2  These patients should only be treated with OFEV® if the anticipated benefit outweighs the potential risk.2

Adverse event management

Gastrointestinal (GI)-related adverse events (AEs) can be effectively managed in most idiopathic pulmonary fibrosis (IPF) patients with dose modification and symptomatic treatment2

Management of GI side effects should begin as early as possible after onset of symptoms2

Supportive medications2

  • Antidiarrheals, such as loperamide
  • Antiemetic therapy, such as a dopamine receptor antagonist or an H1 antihistaminic

Dose adjustment2

  • Temporary treatment interruption or dose reduction (100 mg twice daily) should be considered if symptomatic treatment is ineffective¶¶
  • If a patient does not tolerate 100 mg twice daily, treatment with OFEV® should be discontinued

Dietary changes

  • Adequate hydration at first sign of diarrhea2
  • Avoidance of certain foods/drinks, such as high-fiber foods, dairy products, coffee, tea, and alcohol9
  • Diet of bland, low-fiber foods, such as white bread, bananas, eggs, cooked potatoes without the skin, and fish, chicken, or turkey without the skin9

Footnotes:

  • *
    The most common AEs were defined as those with an incidence of >10% in either study group.5
  • † 
    The postmarketing surveillance study was based on data collected between the drug’s launch in the United States on 15 October 2014 and a data snapshot on 31 October 2015. Adverse events were coded according to preferred terms in the MedDRA version 18.1. Data have been proactively communicated between specialty pharmacies and patients since the launch of OFEV®.6
  • ‡
    Bleeding was based on the SMQ “hemorrhage terms (excluding laboratory terms).”6
  • §
    Per protocol, the off-treatment period between INPULSIS®-1 and -2 and INPULSIS®-ON could be between 4 and 12 weeks.1
  • ¶ 
    Median total exposure for those treated with OFEV® in both the INPULSIS® trials and the INPULSIS®-ON trial extension was 44.7 months and the maximum total exposure was 68.3 months.1
  • || 
    Rates of major adverse cardiovascular events, myocardial infarction, and bleeding in patients were similar to those observed in patients who received placebo during the INPULSIS® trials, suggesting there is no increased risk of these events with long-term use of OFEV®.1
  • **
    System organ class “cardiac disorder.,,8
  • ††
    SMQ “ischemic heart disease” (includes myocardial infarction).8
  • ‡‡ 
    The category of MACE comprised the following: AEs leading to death from cardiac disorders and vascular disorders; fatal and nonfatal events in the subordinate SMQ “myocardial infarction”; stroke based on selected preferred terms from the subordinate SMQs “hemorrhagic cerebrovascular conditions” and “ischemic cerebrovascular conditions”; and the preferred terms sudden death, cardiac death, and sudden cardiac death.8
  • §§ 
    High CV risk was defined as patients who had a history of atherosclerotic CV disease and/or ≥1 CV risk factor at baseline (e.g. smoking history, high blood pressure, or high cholesterol).8
  • ¶¶
    In addition to symptomatic treatment if applicable, the management of adverse reactions to OFEV® could include dose reduction and temporary interruption until the specific adverse reaction has resolved to levels that allow continuation of therapy. OFEV® treatment may be resumed at the full dose (150 mg twice daily) or a reduced dose (100 mg twice daily). If a patient does not tolerate 100 mg twice daily, treatment with OFEV® should be discontinued. In case of interruptions due to AST or ALT elevations >3x ULN, once transaminases have returned to baseline values, treatment with OFEV® may be reintroduced at a reduced dose (100 mg twice daily), which subsequently may be increased to the full dose (150 mg twice daily).2
  • AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CV, cardiovascular; GI, gastrointestinal; IPF, idiopathic pulmonary fibrosis; MACE, major adverse cardiovascular events; MedDRA, Medical Dictionary for Regulatory Activities; SMQ, standardized Medical Dictionary for Regulatory Activities Queries;
  • ULN, upper limit of normal. 

References

  1. Crestani B, et al. Long-term safety and tolerability of nintedanib in patients with idiopathic pulmonary fibrosis: results from the open-label extension study,
    INPULSIS- ON. Lancet Respir Med. 2019;7(1):60-68. Doi:10.1016/S2213-2600(18)30339-4.

  2. OFEV® summary of product characteristics. Boehringer lngelheim International GmbH. July 2020.

  3. Richeldi L, et al; for the INPULSIS® Trial Investigators. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N Engl J Med. 2014;380(22):2071-2082.

  4. Corte T, et al. Safety, tolerability and appropriate use of nintedanib in idiopathic pulmonary fibrosis. Respir Res. 2015;16:116. doi:10.1186/s12931-015-0276-5.

  5. Richeldi L, et al. Nintedanib in patients with idiopathic pulmonary fibrosis: combined evidence from the TOMORROW and INPULSIS® trials. Respir Med. 2016;113:74-79.
    doi:10.1016/j.rmed.2016.02.001.

  6. Noth I, et al. Safety and tolerability of nintedanib in patients with idiopathic pulmonary fibrosis (IPF): one-year data from post-marketing surveillance in the United
    States. Abstract presented at: American Thoracic Society 2016 International Conference; May 13-18, 2016; San Francisco, CA.

  7. Collard HR, et al. Burden of illness in idiopathic pulmonary fibrosis. J Med Econ. 2012;15(5):829-835. doi:10.3111/13696998.2012.680553.

  8. Noth I, et al. CV safety of nintedanib in subgroups by CV risk at baseline in the TOMORROW and INPULSIS® trials. Eur Respir J. 2019; In press.
    doi:10.1183/13993003.01797-2018.

  9. Cancer Network. Diarrhea in cancer patients. (Accessed August 2020). Available at: https://www.cancernetwork.com/view/diarrhea-cancer-patients

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