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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 then every 3 months during the first year, and annually thereafter. Combination products also recommend bilirubin monitoring prior to initiating therapy then every 3 months during the first year, and annually thereafter. Ivacaftor monotherapy should be interrupted in patients with ALT or AST values greater than 5 times the upper limit of normal (ULN). Combination product dosing should be interrupted in patients with ALT or AST values of greater than 5 times the ULN or ALT or AST values greater than 3 times the ULN with bilirubin greater than 2 times the ULN . Following the resolution of transaminase elevations, consider the benefits and risks of resuming ivacaftor. The use of ivacaftor in patients one month to less than six months of age with hepatic impairment is not recommended. For ivacaftor, lumacaftor/ivacaftor, tezacaftor/ivacaftor, and elexacaftor/tezacaftor/ivacaftor, studies have not been conducted in patients with severe hepatic impairment (Child-Pugh Class C), but the exposure is expected to be higher than in patients with moderate hepatic impairment. Therefore, use with caution is recommended1-5. 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)1,2
Child-Pugh ClassRecommendation
ANo dosage adjustment
B150 mg once daily
C150 mg once daily or less frequently (not studied)
Table 11. Ivacaftor Dosing in Hepatic Impairment (Pediatric Patients 6 Months to less than 6 Years)1,2
Child-Pugh ClassRecommendation
A
  • No dosage adjustment
B
  • greater than or equal to 14 kg: 75 mg granule packet once daily
  • 7 kg to less than 14 kg: 50 mg granule packet once daily
  • 5 kg to less than 7 kg: 25 mg granule packet once daily
C
  • greater than or equal to14 kg: 75 mg granule packet once daily or less frequently (not studied)
  • 7 kg to less than 14 kg: 50 mg granule packet once daily or less frequently (not studied)
  • 5 kg 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
Child-Pugh ClassRecommendation
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 1 to 5 Years)1,3
Child-Pugh ClassRecommendation
A
  • No dosage adjustment
B
  • 2-5 years (greater than or equal to 14 kg): lumacaftor 150 mg/ivacaftor 188 mg as oral granules in the morning and lumacaftor 150 mg/ivacaftor 188 mg as oral granules in the evening every other day
  • 2-5 years (less than 14 kg): lumacaftor 100 mg/ivacaftor 125 mg as oral granules in the morning and lumacaftor 100 mg/ivacaftor 125 mg as oral granules in the evening every other day
  • 1-2 years: (greater than or equal to 14 kg): lumacaftor 150 mg/ivacaftor 188 mg as oral granules in the morning and lumacaftor 150 mg/ivacaftor 188 mg as oral granules in the evening every other day
  • 1-2 years: (9 to less than 14 kg): lumacaftor 100 mg/ivacaftor 125 mg as oral granules in the morning and lumacaftor 100 mg/ivacaftor 125 mg as oral granules in the evening every other day
  • 1-2 years (7 to less than 9 kg): lumacaftor 75 mg/ivacaftor 94 mg as oral granules in the morning and lumacaftor 75 mg/ivacaftor 94 mg as oral granules in the evening every other day
C
  • 2-5 years of age (greater than or equal to 14 kg): lumacaftor 150 mg/ivacaftor 188 mg as oral granules in the morning (or less frequently). The evening dose should NOT be given
  • 2-5 years of age (less than 14 kg): lumacaftor 100 mg/ivacaftor 125 mg as oral granules in the morning (or less frequently). The evening dose should NOT be given
  • 1-2 years of age (greater than or equal to 14 kg): lumacaftor 150 mg/ivacaftor 188 mg as oral granules in the morning (or less frequently). The evening dose should NOT be given
  • 1-2 years of age (9 to less than 14 kg): lumacaftor 100 mg/ivacaftor 125 mg as oral granules in the morning (or less frequently). The evening dose should NOT be given
  • 1-2 years of age (7 to less than 9 kg): lumacaftor 75 mg/ivacaftor 94 mg as oral granules in the morning (or less frequently). The evening dose should NOT be given

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 to30 kg) and Children/Adolescents greater than or equal to12 Years]1,4
Child-Pugh ClassRecommendation
A
  • No dosage adjustment
B
  • Tezacaftor 100 mg/ivacaftor 150 mg once daily in morning; the evening ivacaftor 150 mg dose should not be given
C
  • Tezacaftor 100 mg/ivacaftor 150 mg 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)1,4
Child-Pugh ClassRecommendation
A
  • No dosage adjustment
B
  • Tezacaftor 50 mg/ivacaftor 75 mg once daily in morning; the evening ivacaftor 75 mg dose should not be given
C
  • Tezacaftor 50 mg/ivacaftor 75 mg 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 to12 years with hepatic impairment, and Tables 17 and 18 summarize dosing recommendations for pediatric patients two years and older with hepatic impairment.

Table 16. Elexacaftor/Tezacaftor/Ivacaftor Dosing in Hepatic Impairment (Adults, Pediatric Patients greater than or equal to12 Years)1,5
Child-Pugh ClassRecommendation
ANo 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
CNot recommended for use
Table 17. Elexacaftor/Tezacaftor/Ivacaftor Dosing in Hepatic Impairment (Pediatric Patients 6-11 Years)1,5
Child-Pugh ClassRecommendation
ANo dosage adjustment
B
  • Greater than or equal to 30 kg:
    • 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
  • Less than 30 kg:
    • 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
CNot recommended for use
Table 18. Elexacaftor/Tezacaftor/Ivacaftor Dosing in Hepatic Impairment (Pediatric Patients 2 to less than 6 Years)1,5
Child-Pugh ClassRecommendation
ANo dosage adjustment
B
  • Greater than or equal to 14 kg:
    • Days 1-3: One packet (containing elexacaftor 100 mg/ tezacaftor 50 mg/ ivacaftor 75 mg) oral granules each day with no evening ivacaftor doses
    • Day 4: no dose
    • Day 5-6: One packet (containing elexacaftor 100 mg/ tezacaftor 50 mg/ ivacaftor 75 mg) oral granules each day with no evening ivacaftor doses
    • Day 7: no dose
    • Continue weekly dosing thereafter
  • Less than 14 kg:
    • Days 1-3: One packet (containing elexacaftor 80 mg/ tezacaftor 40 mg/ ivacaftor 60 mg) oral granules each day with no evening ivacaftor doses
    • Day 4: no dose
    • Day 5-6: One packet (containing elexacaftor 80 mg/ tezacaftor 40 mg/ ivacaftor 60 mg) oral granules each day with no evening ivacaftor doses
    • Day 7: no dose
    • Continue weekly dosing thereafter
CNot recommended for use