Dosing & AE management

Twice daily oral VARGATEF® has a well-defined and simple dosing regimen1​


Dosing adjustments for diarrhoea, vomiting and other non-haematological adverse reactions1

Diarrhoea

CTCAE adverse events

Dose adjustment

  • Diarrhoea ≥ grade 2 for more than 7 consecutive day despite anti-diarrhoeal treatment

OR
 

  • Diarrhoea ≥ grade 3 despite anti-diarrhoeal treatment
  • Interrupt treatment and allow recovery to grade 1 or baseline
  • Then, reduce dose from 200 mg twice daily to 150 mg twice daily
  • If a 2nd dose reduction is considered necessary, reduce dose from 150 mg twice daily to 100 mg twice daily

CTCAE adverse events

  • Diarrhoea ≥ grade 2 for more than 7 consecutive day despite anti-diarrhoeal treatment

OR
 

  • Diarrhoea ≥ grade 3 despite anti-diarrhoeal treatment

Dose adjustment

  • Interrupt treatment and allow recovery to grade 1 or baseline
  • Then, reduce dose from 200 mg twice daily to 150 mg twice daily
  • If a 2nd dose reduction is considered necessary, reduce dose from 150 mg twice daily to 100 mg twice daily

Nausea/vomiting

CTCAE adverse events

Dose adjustment

  • Vomiting ≥ grade 2

AND/OR
 

  • Nausea ≥ grade 3 despite anti-emetic treatment
  • Interrupt treatment and allow recovery to grade 1 or baseline
  • Then, reduce dose from 200 mg twice daily to 150 mg twice daily
  • If a 2nd dose reduction is considered necessary, reduce dose from 150 mg twice daily to 100 mg twice daily

CTCAE adverse events

  • Vomiting ≥ grade 2

AND/OR
 

  • Nausea ≥ grade 3 despite anti-emetic treatment

Dose adjustment

  • Interrupt treatment and allow recovery to grade 1 or baseline
  • Then, reduce dose from 200 mg twice daily to 150 mg twice daily
  • If a 2nd dose reduction is considered necessary, reduce dose from 150 mg twice daily to 100 mg twice daily

Elevated liver enzymes

AST/ALT and bilirubin elevations

Dose adjustment

  • Elevation of AST and/or ALT values to > 2.5 x ULN in conjunction with total bilirubin elevation to ≥ 1.5 x ULN

OR
 

  • Elevation of AST and/or ALT values to > 5 x ULN
  • Interrupt treatment and allow recovery of transaminase values to ≤ 2.5 x ULN in conjunction with bilirubin to normal
  • Then reduce dose from 200 mg twice daily to 150 mg twice daily
  • If a 2nd dose reduction is considered necessary, reduce dose from 150 mg twice daily to 100 mg twice daily
  • Elevation of AST and/or ALT values to > 3 x ULN in conjunction with an increase of total bilirubin to ≥ 2 x ULN and ALKP < 2 x ULN
  • Unless there is an alternative cause established, VARGATEF ® should be permanently discontinued

AST/ALT and bilirubin elevations

  • Elevation of AST and/or ALT values to > 2.5 x ULN in conjunction with total bilirubin elevation to ≥ 1.5 x ULN

OR
 

  • Elevation of AST and/or ALT values to > 5 x ULN
  • Elevation of AST and/or ALT values to > 3 x ULN in conjunction with an increase of total bilirubin to ≥ 2 x ULN and ALKP < 2 x ULN

Dose adjustment

  • Interrupt treatment and allow recovery of transaminase values to ≤ 2.5 x ULN in conjunction with bilirubin to normal
  • Then reduce dose from 200 mg twice daily to 150 mg twice daily
  • If a 2nd dose reduction is considered necessary, reduce dose from 150 mg twice daily to 100 mg twice daily
  • Unless there is an alternative cause established, VARGATEF ® should be permanently discontinued

Dose Reduction Algorithms

CTCAE adverse events

Dose adjustment

  • Other non-haematological or haematologic adverse reactions of ≥ grade 3
  • Interrupt treatment and allow recovery to grade 1 or baseline, then reduce dose from 200 mg twice daily to 150 mg twice daily
  • If a 2nd dose reduction is considered necessary, reduce dose from 150 mg twice daily to 100 mg twice daily

CTCAE adverse events

  • Other non-haematological or haematologic adverse reactions of ≥ grade 3

Dose adjustment

  • Interrupt treatment and allow recovery to grade 1 or baseline, then reduce dose from 200 mg twice daily to 150 mg twice daily
  • If a 2nd dose reduction is considered necessary, reduce dose from 150 mg twice daily to 100 mg twice daily

Summary of dose reduction schedule

Dose adjustments / interruption available for VARGATEF® in case of adverse events:1​

Dose Reduction Schedule: Morning and Evening
Vargatef® (nintedanib) 100mg and 150mg cases

For full dose adjustment / interruption recommendations, see VARGATEF® SmPC



References

1
GIOTRIF® (afatinib), Summary of Product Characteristics, 2018.
2
Yang JC, et al. Ann Oncol 2016;27(11):2103–2110.
3
Halmos B, et al. Lung Cancer 2018;127:103–111.