1.4. Dosing in Hepatic Impairment

It is recommended that ALT and AST values be assessed prior to initiating ivacaftor, lumacaftor/ivacaftor, tezacaftor/ivacaftor, or elexacaftor/tezacaftor/ivacaftor therapy every 3 months during the first year, and annually thereafter. Dosing should be interrupted in patients with ALT or AST values of greater than 5 times the upper limit of normal (ULN). Following the resolution of transaminase elevations, consider the benefits and risks of resuming ivacaftor. The use of ivacaftor in patients four months to less than six months of age with hepatic impairment is not recommended. Tables 10 and 11 summarize ivacaftor dosing recommendations in adults and pediatric patients with hepatic impairment.

Table 10. Ivacaftor Dosing in Hepatic Impairment (Adults, Pediatric Patients greater than or equal to 6 Years)1-4
Child-Pugh Class Recommendation
A No dosage adjustment
B 150 mg once daily
C 150 mg once daily or less frequently (not studied)
Table 11. Ivacaftor Dosing in Hepatic Impairment (Pediatric Patients 6 Months to less than 6 Years)1-4
Child-Pugh Class Recommendation
A No dosage adjustment
B

Greater than or equal to 14 kg: 75 mg granule packet once daily

7 to less than 14 kg: 50 mg granule packet once daily

5 to less than 7 kg: 25 mg granule packet once daily
C

Greater than or equal to 14 kg: 75 mg granule packet once daily or less frequently (not studied)

7 to less than 14 kg: 50 mg granule packet once daily or less frequently (not studied)

5 to less than 7 kg: 25 mg granule packet once daily or less frequently (not studied)

Tables 12 and 13 summarize lumacaftor/ivacaftor dosing recommendations in adult and pediatric patients with hepatic impairment.

Table 12. Lumacaftor/Ivacaftor Dosing in Hepatic Impairment (Adults, Pediatric Patients greater than or equal to 6 Years)1-3, 6
Child-Pugh Class Recommendation
A No dosage adjustment
B

greater than or equal to 6-11 years: Lumacaftor 200 mg/ivacaftor 250 mg in morning, and lumacaftor 100 mg/ivacaftor 125 mg in evening

12 to less than 18 years: Lumacaftor 400 mg/ivacaftor 250 mg in morning, and lumacaftor 200 mg/ivacaftor 125 mg in evening
C

greater than or equal to 6-11 years: Maximum dose of lumacaftor 100 mg/ivacaftor 125 mg every 12 hours (or less frequently); use with caution

12 to less than 18 years: Maximum dose of lumacaftor 200 mg/ivacaftor 125 mg every 12 hours (or less frequently); use with caution
Table 13. Lumacaftor/Ivacaftor Dosing in Hepatic Impairment (Pediatric Patients 2 to 5 Years)1-3, 6
Child-Pugh Class Recommendation
A No dosage adjustment
B Lumacaftor 150 mg/ivacaftor 188 mg (greater than or equal to 14 kg) or lumacaftor 100 mg/ivacaftor 125 mg (less than 14 kg) as oral granules in morning, and lumacaftor 150 mg/ivacaftor 188 mg (greater than or equal to 14 kg) or lumacaftor 100 mg/ivacaftor 125 mg (less than 14 kg) as oral granules in the evening every other day
C Lumacaftor 150 mg/ivacaftor 188 mg (greater than or equal to 14 kg) or lumacaftor 100 mg/ivacaftor 125 mg (less than 14 kg) as oral granules in morning (or less frequently); no dose should be given in evening (use with caution) 

Tables 14 and 15 summarize tezacaftor/ivacaftor dosing recommendations in adults and pediatric patients 6 years and older with hepatic impairment.

Table 14. Tezacaftor/Ivacaftor Dosing in Hepatic Impairment [Adults, Pediatric Patients 6 to 11 Years (greater than or equal to 30 kg) and Children/Adolescents greater than or equal to 12 Years]1-3, 7
Child-Pugh Class Recommendation
A No dosage adjustment
B Tezacaftor/ivacaftor 100 mg/150 once daily in morning; the evening ivacaftor 150 mg dose should not be given
C Tezacaftor/ivacaftor 100 mg/150 once daily in morning (or less frequently); the evening ivacaftor 150 mg dose should not be given; use with caution – not studied in severe hepatic impairment)
Table 15. Tezacaftor/Ivacaftor Dosing in Hepatic Impairment (Pediatric Patients 6 to 11 Years (less than 30 kg)1-3, 7
Child-Pugh Class Recommendation
A No dosage adjustment
B Tezacaftor/ivacaftor 50 mg/75 once daily in morning; the evening ivacaftor 75 mg dose should not be given
C Tezacaftor/ivacaftor 50 mg/75 once daily in morning (or less frequently); the evening ivacaftor 75 mg dose should not be given; use with caution – not studied in severe hepatic impairment)

Table 16 summarizes elexacaftor/tezacaftor/ivacaftor dosing recommendations in adults and pediatric patients greater than or equal to 12 years with hepatic impairment, and Table 17 summarizes dosing recommendations for patients 6-11 years with hepatic impairment.

Table 16. Elexacaftor/Tezacaftor/Ivacaftor Dosing in Hepatic Impairment (Adults, Pediatric Patients greater than or equal to 12 Years)1-3,10
Child-Pugh Class Recommendation
A No dosage adjustment
B
  • Day 1:
    • 2 tablets (elexacaftor 100 mg/ tezacaftor 50 mg/ ivacaftor 75 mg) in morning, with no evening ivacaftor 150 mg dose 
  • Day 2:
    • 1 tablet (elexacaftor 100 mg/ tezacaftor 50 mg/ ivacaftor 75 mg) in morning, with no evening ivacaftor 150 mg dose 
  • Continue alternating day 1 and day 2 dosing thereafter
C Not recommended for use
Table 17. Elexacaftor/Tezacaftor/Ivacaftor Dosing in Hepatic Impairment (Pediatric Patients 6-11 Years, greater than or equal to 30 kg)1-3, 10
Child-Pugh Class Recommendation
A No dosage adjustment
B
  • Day 1:
    • 2 tablets (elexacaftor 100 mg/ tezacaftor 50 mg/ ivacaftor 75 mg) in morning, with no evening ivacaftor 150 mg dose
  • Day 2:
    •  tablet (elexacaftor 100 mg/ tezacaftor 50 mg/ ivacaftor 75 mg) in morning, with no evening ivacaftor 150 mg dose
  • Continue alternating day 1 and day 2 dosing thereafter
C Not recommended for use
Table 18. Elexacaftor/Tezacaftor/Ivacaftor Dosing in Hepatic Impairment (Pediatric Patients 6-11 Years, less than 30 kg)1-3, 10
Child-Pugh Class Recommendation
A No dosage adjustment
B
  • Day 1:
    • 2 tablets (elexacaftor 50 mg/ tezacaftor 25 mg/ ivacaftor 37.5 mg) in morning, with no evening ivacaftor 75 mg dose
  • Day 2:
    • 1 tablet (elexacaftor 50 mg/ tezacaftor 25 mg/ ivacaftor 37.5 mg) in morning, with no evening ivacaftor 75 mg dose
  • Continue alternating day 1 and day 2 dosing thereafter
C Not recommended for use