Safety

Adverse events profile

The most common adverse events (AEs) were mild to moderate, gastrointestinal (GI)-related, and effectively managed in most patients with systemic sclerosis-associated interstitial lung disease (SSc-ILD).1,2 
> Find out more about the safety profile of Cyendiv® in SSc-ILD

Additional safety information

The AEs in patients with SSc-ILD was consistent with the safety and tolerability profile of Cyendiv® in patients with idiopathic pulmonary fibrosis (IPF) and progressive fibrosing interstitial lung diseases (ILDs)1
> Read in detail about the additional safety data for Cyendiv®

Adverse event management

GI-related AEs can be effectively managed in most patients with dose modification and symptomatic treatment.2 
> Find out more about managing AEs in your SSc-ILD patients

Footnotes

AE, adverse event; GI, gastrointestinal; ILD, interstitial lung disease; IPF, idiopathic pulmonary fibrosis; SSc-ILD, systemic sclerosis-associated interstitial lung disease.

Adverse events profile

The most common adverse events (AEs) were mild to moderate, gastrointestinal (GI)-related, and effectively managed in most patients with systemic sclerosis-associated interstitial lung disease (SSc-ILD)1,2
The AEs profile in patients with SSc-ILD seen in SENSCIS® was consistent with the safety and tolerability profile of Cyendiv® in patients with idiopathic pulmonary fibrosis (IPF) and progressive fibrosing interstitial lung disease (ILD)1

Adverse Effects Data

  • No new safety signals were detected in patients with SSc-ILD in the SENSCIS® trial1
  • AEs leading to discontinuation of study drug were reported in 16% of Cyendiv®-treated patients and 9% of placebo-treated patients1
  • There was no between-group difference in net digital ulcer burden1

 

The most common AE was diarrhea but it can be effectively managed1,2

SSc-ILD Disease Information

Adverse Events Data

  • Mycophenolate is commonly used in the treatment of systemic sclerosis (SSc) and is associated with GI side effects and a higher risk of infections5
  • The GI AE profile of Cyendiv® was similar regardless of whether patients were taking mycophenolate at baseline3
The AEs profile of Cyendiv® was similar between subgroups by age, race, weight and corticosteroid use6,7
Footnotes

AE, adverse event; GI, gastrointestinal; ILD, interstitial lung disease; IPF, idiopathic pulmonary fibrosis; MedDRA, Medical Dictionary for Regulatory Activities; SSc, systemic sclerosis; SSc-ILD, systemic sclerosis-associated interstitial lung disease.

* AEs reported over 52 weeks plus 28-day posttreatment period in >5% of patients in either treatment group. Data are n (%) of patients with ≥1 such AE defined based on MedDRA preferred term.1

† AE that was incapacitating or caused an inability to work or perform usual activities.1

‡ AE that resulted in death, was life-threatening, resulted in hospitalization or prolongation of hospitalization, resulted in persistent or clinically significant disability or incapacity, was a congenital anomaly or birth defect, or was deemed to be serious for any other reason.1

§ Data are n (%) of subjects with ≥1 such AE reported over 52 weeks (or until 28 days after last trial drug intake for subjects who discontinued trial drug before week 52). AEs shown are those reported in >5% of subjects in either the Cyendiv® or placebo group by single MedDRA preferred terms in the system organ class “gastrointestinal disorders”, except for abdominal pain, which was based on a MedDRA high-level term (related preferred terms), and weight decrease, which was based on the single MedDRA preferred term “weight decreased”.3

Additional safety information

The safety profile of Cyendiv® is largely consistent among patients with idiopathic pulmonary fibrosis (IPF) and systemic sclerosis-associated interstitial lung disease (SSc-ILD)1
Liver enzyme elevation

Incidence1

  • Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) elevations ≥3x upper limit of normal (ULN) occurred in approximately 5% of patients in the SENSCIS® trial
  • No hepatic injury (based on Hy’s law)* was observed in the SENSCIS® trial

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 Cyendiv® and close monitoring of the patient are recommended
  • Once levels return to baseline values, treatment with Cyendiv® 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 Cyendiv®

Hepatic function2

  • The safety and efficacy of Cyendiv® have not been studied in patients with moderate or severe hepatic impairment (Child-Pugh B or C). Cyendiv® 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 Cyendiv®
Pregnancy2
  • Cyendiv® may cause fetal harm in humans. Advise women of childbearing potential to avoid becoming pregnant while receiving treatment with Cyendiv® and to use highly effective contraception methods during and at least 3 months after the last dose of Cyendiv®. Advise women using hormonal contraceptives to add a barrier method 
  • Prior to initiating treatment, conduct a pregnancy test in females of childbearing potential
Cardiac events2,8
  • Arterial thromboembolic events have been reported. Use caution when treating patients at higher cardiovascular risk, including known coronary artery disease2
  • Major adverse cardiovascular events (MACE) were reported for 4 patients (1.4%) in the Cyendiv® group and 5 patients (1.7%) in the placebo group. In SENSCIS®, events were adjudicated by an independent committee: 1 out of the 4 events in the Cyendiv® group and 3 out of the 5 events in the placebo group were confirmed as MACE by adjudication8
Bleeding events2
  • Serious bleeding events occurred with low frequency in both treatment groups
  • Patients with preidentified bleeding risk (e.g. requiring full-dose therapeutic anticoagulation or high-dose antiplatelet therapy) were excluded from SENSCIS®
  • Use Cyendiv® in patients with known bleeding risk only if anticipated benefit outweighs the potential risk 
Digital ulcer net burden1

There was no significant difference in digital ulcer net burden in patients taking Cyendiv® vs. placebo1

Digital Ulcer Net Burden Data

  • Cyendiv® showed no potential adverse effect on the vascular component of systemic sclerosis (SSc) or on wound healing1
  • There was no difference between the Cyendiv® and placebo groups in change from baseline in digital ulcer net burden at week 521
Footnotes

AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase; IPF, idiopathic pulmonary fibrosis; MACE, major adverse cardiovascular events; SSc, systemic sclerosis; SSc-ILD, systemic sclerosis-associated interstitial lung disease; ULN, upper limit of normal.

*Serum ALT or AST level of >3x ULN and bilirubin level of >2x ULN without an identifiable cause.1

Adverse event management

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

GI Complications are common in patients with systemic sclerosis (SSc)9

  • Around 90% of SSc patients have GI involvement, including disorders of the esophagus, stomach, small intestine and colon9
  •  The proportion of Cyendiv®-treated patients with GI AEs was similar regardless of whether patients had a predisposition to GI events at baseline3
Management of GI side effects should begin as early as possible after onset of symptoms2

1. Supportive medications2  

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

2. 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 Cyendiv® should be discontinued

3. Dietary changes

  • Adequate hydration at first sign of diarrhea2 
  • Avoidance of certain foods/drinks, such as high-fiber foods, dairy products, coffee, tea, and alcohol10
  • Diet of bland, low-fiber foods, such as white bread, bananas, eggs, cooked potatoes without the skin, and fish, chicken, or turkey without the skin10 
Footnotes

AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase; GI, gastrointestinal; SSc, systemic sclerosis; SSc-ILD, systemic sclerosis-associated interstitial lung disease; ULN, upper limit of normal. 

* In addition to symptomatic treatment if applicable, the management of adverse reactions to Cyendiv® could include dose reduction and temporary interruption until the specific adverse reaction has resolved to levels that allow continuation of therapy. Cyendiv® 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 Cyendiv® should be discontinued. In case of interruptions due to AST or ALT elevations >3x ULN, once transaminases have returned to baseline values, treatment with Cyendiv® 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

References

  1. Distler O, et al; the SENSCIS Trial Investigators. Nintedanib for systemic sclerosis-associated lung disease. N Engl J Med. 2019;380(26):2518-2528. doi:10.1056/NEJMoa1903076.
  2. Cyendiv® India pack insert version dated
  3. Maher T, et al; SENSCIS Trial Investigators. Gastrointestinal adverse events in patients with systemic sclerosis-associated interstitial lung disease (SSc-ILD) treated with nintedanib: data from the SENSCIS trial [EULAR abstract FR10301]. Ann Rheum Dis. 2019;78(suppl2):831-832.
  4. Highland K, et al. Efficacy and safety of nintedanib in patients with systemic sclerosis-associated interstitial lung disease by use of mycophenolate at baseline: Subgroup analysis of the SENSCIS trial [abstract]. Arthritis Rheumatol. 2019;71(suppl 10). (Accessed August 2020). Available at:  https://acrabstracts.org/abstract/efficacy-and-safety-of-nintedanib-in-p...
  5. Omair MA, et al. Safety and effectiveness of mycophenolate in systemic sclerosis. A systematic review. PLoS ONE. 2015, doi.org/10.1371/journal.pone.0124205.
  6. Distler O, et al. Safety and tolerability of nintedanib in patients with systemic sclerosis-associated interstitial lung disease (SSc-ILD) in the SENSCIS® trial: Subgroup analysis based on demographic characteristics. Poster presented at the ACR/ARP Annual Meeting, Atlanta, Georgia, 8–13 November 2019.
  7. Vonk MC, et al. Efficacy and safety of nintedanib in patients with systemic sclerosis-associated interstitial lung disease: Subgroup analysis of the SENSCIS® trial by corticosteroid use. Poster presented at the ACR/ARP Annual Meeting, Atlanta, Georgia, 8–13 November 2019.
  8. Boehringer Ingelheim. Presentations for the July 25, 2019 Meeting of the Arthritis Advisory Committee. 2019 (Accessed August 2020). Available at: https://www.fda.gov/advisory-committees/arthritis-advisory-committee/sli...
  9. Kirby DF and Chatterjee S. Evaluation and management of gastrointestinal manifestations in scleroderma. Curr Opin Rheumatol. 2014,26:621–629.
  10. Cancer Network. Diarrhea in cancer patients. (Accessed August 2020). Available at: https://www.cancernetwork.com/view/diarrhea-cancer-patients