1. Dosage

Ivacaftor is categorized as a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator. Cystic fibrosis (CF) occurs because of CFTR genetic mutations causing mucosal obstruction of the distal lung airway and submucosal glands.  Malfunction of the CFTR alters electrolyte homeostasis, which changes cell potentials and can lead to organ damage in CF patients. Patient genotyping shows that approximately 4% of the 30,000 CF patients in America are believed to have a G551D-CFTR mutation. Kalydeco® (Ivacaftor) targets multi-organ chloride channels at the surface of epithelial cells to enhance the opening of the CFTR protein.

Kalydeco® (ivacaftor) is FDA approved for use in patients 4 months or older who have one mutation in the CFTR gene that is responsive to ivacaftor therapy based on clinical and/ or in vitro assay data. If the patient’s genotype is unknown then an FDA-cleared CF mutation test should be used to detect the presence of a CFTR mutation followed by verification with bi-directional sequencing when recommended by the mutation test instructions for use 1,2,4. A list of CF mutations indicated for the treatment of CF in patients 4 months of age and older are provided in the list below.

List of CFTR Gene Mutations that Produce Protein and are Responsive to Kalydeco®

  • 711+3A→G*
  • 2789+5G→A*
  • 3272-26A→G*
  • 3849+10kbC→T*
  • A120T
  • A234D
  • A349V
  • A455E*
  • A1067T
  • D110E
  • D110H
  • D192G
  • D579G*
  • D924N
  • D1152H*
  • D1270N
  • E56K
  • E193K
  • E822K
  • E831X*
  • F311del
  • F311L
  • F508C
  • F508C;S1251N†
  • F1052V
  • F1074L
  • G178E
  • G178R*
  • G194R
  • G314E
  • G551D*
  • G551S*
  • G576A
  • G970D
  • G1069R
  • G1244E*
  • G1249R
  • G1349D*
  • H939R
  • H1375P
  • I148T
  • I175V
  • I807M
  • I1027T
  • I1139V
  • K1060T
  • L206W*
  • L320V
  • L967S
  • L997F
  • L1480P
  • M152V
  • M952I
  • M952T
  • P67L*
  • Q237E
  • Q237H
  • Q359R
  • Q1291R
  • R74W
  • R75Q
  • R117C*
  • R117G
  • R117H*
  • R117L
  • R117P
  • R170H
  • R347H*
  • R347L
  • R352Q*
  • R553Q
  • R668C
  • R792G
  • R933G
  • R1070Q
  • R1070W*
  • R1162L
  • R1283M
  • S549N*
  • S549R*
  • S589N
  • S737F
  • S945L*
  • S977F*
  • S1159F
  • S1159P
  • S1251N*
  • S1255P*
  • T338I
  • T1053I
  • V232D
  • V562I
  • V754M
  • V1293G
  • W1282R
  • Y1014C
  • Y1032C

Legend

  • * Clinical data exists for these mutations.
  • † Complex/compound mutations. Most people with CF have 2 CF mutations, 1 on each copy of the CF gene. However, in rare instances, 1 copy of the CF gene can have more than 1 mutation. This is called a compound, or complex, mutation.

A combination product containing lumacaftor and ivacaftor (Orkambi®) was approved in July 2015 for use in patients 2 years and older who are homozygous for the F508del mutation in the CFTR gene. If the patient’s genotype is unknown, then an FDA-cleared CF mutation test should be used to detect the presence of the F508del mutation on both alleles of the CFTR gene. The F508del mutation is the most common cause of CF, with approximately half of the CF population in the U.S. being homozygous for the mutation. The combined effect of lumacaftor and ivacaftor increases the quantity (lumacaftor) and function (ivacaftor) of the F508del-CFTR ion channel, resulting in improved channel function and clinical benefit. The efficacy and safety of lumacaftor and ivacaftor combination therapy has not been established in patients with cystic fibrosis other than those homozygous for the F508del mutation1-3.

Tezacaftor/ivacaftor (Symdeko®) combination therapy is FDA-approved for CF in patients six years of age and older homozygous for the F508del mutation or who have at least one mutation in the CFTR gene responsive to tezacaftor/ivacaftor. If the patient’s genotype is unknown, then an FDA-cleared CF mutation test should be used to detect the presence of a CFTR mutation followed by verification with bi-directional sequencing when recommended by the mutation test instructions for use. Tezacaftor increases the amount of mature CFTR at the cell surface by expediting cellular processing and trafficking of normal and select mutant forms of CFTR, while ivacaftor enhances channel-opening probability of CFTR proteins at the cell surface. Combined therapy improves CFTR function at the cell surface and increases chloride transport, resulting in clinical benefit1-3, 7. All CFTR protein producing CFTR mutations that are responsive to Symdeko® are listed in the following list8 .

CFTR Mutations that Produce CFTR Protein and Are Responsive to Symdeko®

  • 546insCTA§
  • 711+3A→G*
  • 2789+5G→A*
  • 3272-26A→G*
  • 3849+10kbC→T*
  • A120T§
  • A234D§
  • A349V§
  • A455E*
  • A554E§
  • A1006E§
  • A1067T
  • D110E
  • D110H*
  • D192G§
  • D443Y§
  • D443Y;G576A;R668C‡§
  • D579G*
  • D614G§
  • D836Y§
  • D924N§
  • D979V§
  • D1152H*
  • D1270N
  • E56K
  • E60K§
  • E92K§
  • E116K§
  • E193K
  • E403D§
  • E588V§
  • E822K§
  • E831X
  • F191V§
  • F311del§
  • F311L§
  • F508C§
  • F508C;S1251N‡§
  • F508del†
  • F575Y§
  • F1016S§
  • F1052V
  • F1074L
  • F1099L§
  • G126D§
  • G178E§
  • G178R§
  • G194R§
  • G194V§
  • G314E§
  • G551D§
  • G551S§
  • G576A§
  • G576A;R668C‡§
  • G622D§
  • G970D§
  • G1069R§
  • G1244E§
  • G1249R§
  • G1349D§
  • H939R§
  • H1054D§
  • H1375P§
  • I148T§
  • I175V§
  • I336K§
  • I601F§
  • I618T§
  • I807M§
  • I980K§
  • I1027T§
  • I1139V§
  • I1269N§
  • I1366N§
  • K1060T
  • L15P§
  • L206W*
  • L320V§
  • L346P§
  • L967S§
  • L997F§
  • L1324P§
  • L1335P§
  • L1480P§
  • M152V§
  • M265R§
  • M952I§
  • M952T§
  • P5L§
  • P67L*
  • P205S§
  • Q98R§
  • Q237E§
  • Q237H§
  • Q359R§
  • Q1291R§
  • R31L§
  • R74Q§
  • R74W
  • R74W; D1270N‡§
  • R74W;V201M‡§
  • R74W;V201M;D1270N‡§
  • R75Q§
  • R117C*§
  • R117G§
  • R117H§
  • R117L§
  • R117P§
  • R170H§
  • R258G§
  • R334L§
  • R334Q§
  • R347H*§
  • R347L§
  • R347P§
  • R352Q*§
  • R352W§
  • R553Q§
  • R668C§
  • R751L§
  • R792G§
  • R933G§
  • R1066H§
  • R1070Q§
  • R1070W*
  • R1162L§
  • R1283M§
  • R1283S§
  • S549N§
  • S549R§
  • S589N§
  • S737F§
  • S912L§
  • S945L*
  • S977F*
  • S1159F§
  • S1159P§
  • S1251N§
  • S1255P§
  • T338I§
  • T1036N§
  • T1053I§
  • V201M§
  • V232D§
  • V562I§
  • V754M§
  • V1153E§
  • V1240G§
  • V1293G§
  • W1282R§
  • Y109N§
  • Y161S§
  • Y1014C§
  • Y1032C§

Legend:

  • § = Mutations approved in December 2020
  • * = Clinical data for these mutations appear in sections 14.1 and 14.2 of the Prescribing Information.
  • † = A patient must have 2 copies of the F508del mutation or at least 1 copy of a responsive mutation listed above in this table to be indicated for Symdeko®.
  • ‡ = Complex/compound mutations in which a single allele of the CFTR gene has multiple mutations; these exist independent of the presence of mutations on the other allele.

Trikafta® is a combination product of elexacaftor, tezacaftor, and ivacaftor that is FDA approved for the treatment of cystic fibrosis patients 6 years of age and older who have at least one F508del mutation in the CFTR gene or a mutation in the CFTR gene that is responsive based on in vitro data. If the patient’s genotype is unknown, then an FDA-cleared cystic fibrosis test should be used to confirm the presence of at least one F508del mutation or a responsive mutation based on in vitro data1,2,10.

Both elexacaftor and tezacaftor increase the amount of mature CFTR at the cell surface by facilitating cellular processing and trafficking of normal and select mutant forms of CFTR, while ivacaftor enhances channel-opening probability of CFTR proteins at the cell surface. Combined therapy improves CFTR function at the cell surface, increases chloride transport, and results in clinical benefit1-3, 7-9. A list of CFTR gene mutations that are responsive to Trikafta® therapy are listed below10.

List of CFTR Gene Mutations that are Responsive to Trikafta®

  • 3141del9   
  • 546insCTA 
  • A46D 
  • A120T 
  • A234D 
  • A349V 
  • A455E 
  • A554E 
  • A1006E 
  • A1067T 
  • D110E 
  • D110H 
  • D192G 
  • D443Y 
  • D443Y;G576A;R668C†  
  • D579G 
  • D614G 
  • D836Y 
  • D924N 
  • D979V   
  • D1152H 
  • D1270N 
  • E56K 
  • E60K 
  • E92K 
  • E116K 
  • E193K   
  • E403D  
  • E474K 
  • E588V 
  • E822K
  • F191V 
  • F311del 
  • F311L 
  • F508C 
  • F508C;S1251N† 
  • F508del* 
  • F575Y 
  • F1016S 
  • F1052V 
  • F1074L 
  • F1099L 
  • G27R 
  • G85E  
  • G126D
  • G178E 
  • G178R 
  • G194R 
  • G194V 
  • G314E
  • G463V 
  • G480C 
  • G551D 
  • G551S 
  • G576A 
  • G576A;R668C† 
  • G622D
  • G628R 
  • G970D 
  • G1061R 
  • G1069R
  • G1244E 
  • G1249R 
  • G1349D 
  • H139R 
  • H199Y 
  • H939R 
  • H1054D 
  • H1085P 
  • H1085R 
  • H1375P 
  • I148T 
  • I175V 
  • I336K
  • I502T 
  • I601F 
  • I618T 
  • I807M 
  • I980K 
  • I1027T
  • I1139V 
  • I1269N 
  • I1366N  
  • K1060T 
  • L15P 
  • L165S 
  • L206W
  • L320V
  • L346P  
  • L453S 
  • L967S
  • L997F 
  • L1077P 
  • L1324P 
  • L1335P 
  • L1480P 
  • M152V 
  • M265R 
  • M952I 
  • M952T 
  • M1101K 
  • P5L 
  • P67L 
  • P205S 
  • P574H 
  • Q98R 
  • Q237E 
  • Q237H 
  • Q359R  
  • Q1291R 
  • R31L 
  • R74Q 
  • R74W
  • R74W;D1270N†
  • R74W;V201M†
  • R74W;V201M;D1270N†
  • R75Q 
  • R117C  
  • R117G
  • R117H 
  • R117L
  • R117P 
  • R170H 
  • R258G 
  • R334L 
  • R334Q 
  • R347H 
  • R347L
  • R347P 
  • R352Q
  • R352W 
  • R553Q 
  • R668C 
  • R751L 
  • R792G 
  • R933G 
  • R1066H 
  • R1070Q 
  • R1070W
  • R1162L 
  • R1283M 
  • R1283S 
  • S13F
  • S341P 
  • S364P 
  • S492F 
  • S549N 
  • S549R
  • S589N
  • S737F
  • S912L
  • S945L
  • S977F
  • S1159F
  • S1159P
  • S1251N
  • S1255P
  • T338I
  • T1036N
  • T1053I
  • V201M
  • V232D
  • V456A
  • V456F
  • V562I
  • V754M
  • V1153E
  • V1240G
  • V1293G
  • W361R
  • W1098C
  • W1282R
  •  Y109N
  • Y161D
  • Y161S
  • Y563N
  • Y1014C
  • Y1032C

Legend:

  • * = F508del is a responsive CFTR mutation based on both clinical and in vitro data.
  • † = Complex/ compound mutations where a single allele of the CFTR gene has multiple mutations; these exist independent of the presence of mutations on the other allele.

1.1. Adults

Recommended adult ivacaftor doses as monotherapy and combination therapy are summarized in Tables 4 and 5. Dosage adjustments for ivacaftor monotherapy and combination therapy when administered adjunctively with cytochrome P450 3A4 inhibitors are summarized in Table 6 1-3, 4, 6, 7, 10. Dosages in patient profiles exceeding these recommendations will be reviewed.

Table 4. Maximum Recommended Adult Ivacaftor Dosages: Monotherapy1-4
Treatment Indication Drug Name Dosage Form/Strength Maximum Recommended Dosage
CF (patients with one mutation in CFTR gene responsive to ivacaftor potentiation) ivacaftor (Kalydeco®) 150 mg oral tablets 150 mg orally every 12 hours with fat-containing food

Legend:

  • CF = cystic fibrosis
  • CFTR = cystic fibrosis transmembrane conductance regulator
Table 5. Maximum Recommended Adult Ivacaftor Dosages: Combination Therapy1-3, 6, 7, 10
Treatment Indication Drug Name Dosage Form/Strength Maximum Recommended Dosage
CF (patients homozygous for F508del mutation in the CFTR gene) lumacaftor/ivacaftor (Orkambi®) 200 mg/125 mg oral tablets 400 mg/250 mg (2 x 200 mg lumacaftor/125 mg ivacaftor tablets) orally every 12 hours with fat-containing food
CF (patients homozygous for F508del mutation or have at least one mutation in the CFTR gene responsive to tezacaftor/ivacaftor) tezacaftor/ivacaftor (Symdeko®) tezacaftor 100 mg/ivacaftor 150 mg; ivacaftor 150 mg oral tablets tezacaftor 100 mg/ivacaftor 150 mg in morning and ivacaftor 150 mg in evening approximately 12 hours apart with fat-containing food
CF (patients have at least one F508del mutation in the CFTR gene or have at least one mutation in the CFTR gene responsive to elexacaftor/tezacaftor/ivacaftor)
 		 elexacaftor/tezacaftor/ivacaftor (Trikafta®) elexacaftor 100 mg/ tezacaftor 50 mg/ ivacaftor 75 mg oral tablet; ivacaftor 150 mg oral tablet 2 tablets (elexacaftor 100 mg/ tezacaftor 50 mg/ ivacaftor 75 mg) in morning and one ivacaftor 150 mg tablet in evening approximately 12 hours apart with fat-containing food

Legend:

  • CF = cystic fibrosis
  • CFTR = cystic fibrosis transmembrane conductance regulator
Table 6. Ivacaftor Adult Dosage Adjustments with Concurrent CYP3A4 Inhibitor Therapy1-4, 6, 7, 10
Ivacaftor Drug Name Concurrent CYP3A4 Inhibitor Therapy Dosage Recommendations*
ivacaftor (Kalydeco®) strong CYP3A inhibitors (e.g., ketoconazole) ivacaftor dosages should be reduced to 150 mg twice weekly
ivacaftor (Kalydeco®) moderate CYP3A inhibitors (e.g., erythromycin, fluconazole) ivacaftor dosages should be reduced to 150 mg once daily
lumacaftor/ivacaftor (Orkambi®) strong CYP3A inhibitors (e.g., ketoconazole) lumacaftor/ivacaftor dosages should be reduced to 200 mg/125 mg once daily in patients receiving strong CYP3A inhibitors for the first week, followed by lumacaftor 400 mg/ivacaftor 250 mg every 12 hours thereafter; no dosage adjustments are needed if CYP3A inhibitors are initiated in patients already taking lumacaftor/ivacaftor
lumacaftor/ivacaftor (Orkambi®) moderate CYP3A inhibitors (e.g., erythromycin, fluconazole) no dosage adjustments recommended
tezacaftor/ivacaftor (Symdeko®) strong CYP3A inhibitors (e.g., ketoconazole)

Day 1: tezacaftor/ivacaftor 100 mg/150 once daily in morning

Days 2 and 3: no dosages administered

Day 4: tezacaftor/ivacaftor 100 mg/150 once daily in morning

The evening ivacaftor dose should NOT be given

Continue twice weekly (morning) administration schedule, with 3-4 days between dosages
tezacaftor/ivacaftor (Symdeko®) moderate CYP3A inhibitors (e.g., erythromycin, fluconazole)

Day 1: tezacaftor/ivacaftor 100 mg/150 once daily in morning

Day 2: ivacaftor 150 mg once daily in morning

The evening ivacaftor dose should NOT be given

Continue alternate day (morning) administration schedule
elexacaftor/tezacaftor/ivacaftor (Trikafta®) strong CYP3A inhibitors (e.g., ketoconazole)

2 tablets (elexacaftor 100 mg/ tezacaftor 50 mg/ ivacaftor 75 mg) in morning twice weekly, with 3-4 days between dosages

The evening ivacaftor dose should NOT be given
elexacaftor/tezacaftor/ivacaftor (Trikafta®) moderate CYP3A inhibitors (e.g., erythromycin, fluconazole)

Day 1: 2 tablets (elexacaftor 100 mg/tezacaftor 50 mg/ivacaftor 75 mg) in morning

Day 2: ivacaftor 150 mg once daily in morning

The evening ivacaftor dose should NOT be given

Continue alternate day (morning) administration schedule

Legend:

  • CYP3A/3A4 = cytochrome P450 3A/3A4
  • *all dosages should be given with a fat-containing meal

1.2. Pediatrics

Tables 7 and 8 summarize ivacaftor dosing recommendations as monotherapy and combination therapy for pediatric patients. Ivacaftor is not recommended in patients less than 4 months of age1-4. Safety and efficacy of lumacaftor/ivacaftor combination therapy in children less than 2 years of age have not been established1-3, 6. Tezacaftor/ivacaftor safety and efficacy have not been determined in children below 6 years of age, while elexacaftor/tezacaftor/ivacaftor efficacy/safety have not been established in children younger than 6 years of age1-3, 7, 10. Dosage adjustments for ivacaftor monotherapy and combination therapy when administered concomitantly with cytochrome P450 3A4 inhibitors are summarized in Table 9. Ivacaftor is not recommended for use concurrently with CYP3A strong inducers.

Table 7. Maximum Recommended Pediatric Ivacaftor Dosages: Monotherapy1-4
Treatment Indication Drug Name Dosage Form/Strength Maximum Recommended Dosage
CF (patients with one mutation in CFTR gene responsive to ivacaftor potentiation) ivacaftor (Kalydeco®)

25 mg, 50 mg, 75 mg oral granules

150 mg oral tablets

children/adolescents 6-17 years: 150 mg orally every 12 hours with fat-containing food

infants/children 6 months to less than 6 years (greater than 14 kg): 75 mg as oral granules every 12 hours with fat-containing food

infants/children 6 months to less than 6 years (7 kg to less than 14 kg): 50 mg as oral granules every 12 hours with fat-containing food

infants/children 6 months to less than 6 years (5 kg to less than 7 kg): 25 mg as oral granules every 12 hours with fat-containing food

infants 4 to 5 months weighing 5 kg or more: 25 mg as oral granules every 12 hours with fat-containing food

Legend:

  • CF = cystic fibrosis
  • CFTR = cystic fibrosis transmembrane conductance regulator
Table 8. Maximum Recommended Pediatric Ivacaftor Dosages: Combination Therapy1-3, 6, 7, 10
Treatment Indication Drug Name Dosage Form/Strength Maximum Recommended Dosage 
CF (patients homozygous for F508del mutation in the CFTR gene) lumacaftor/ivacaftor (Orkambi®)

100 mg/ 125 mg, 150 mg/188 mg oral granules

100 mg/125 mg, 200 mg/125 mg oral tablets
  • children/adolescents 12 years and older:
    • 400 mg/250 mg (2 x 200 mg lumacaftor/125 mg ivacaftor tablets) orally every 12 hours with fat-containing food
  • children 6-11 years:
    • 200 mg/250 mg (2 x 100 mg lumacaftor/125 mg ivacaftor tablets) orally every 12 hours with fat-containing food
  • children 2-5 years (greater than 14 kg):
    • 150 mg/188 mg oral granules every 12 hours with fat-containing food
  • children 2-5 years (less than 14 kg):
    • 100 mg/125 mg oral granules every 12 hours with fat-containing food
CF (patients homozygous for F508del mutation or have at least one mutation in the CFTR gene responsive to tezacaftor/ivacaftor) tezacaftor/ivacaftor (Symdeko®)

tezacaftor 50 mg/ivacaftor 75 mg oral tablet; ivacaftor 75 mg oral tablet

tezacaftor 100 mg/ivacaftor 150 mg oral tablet; ivacaftor 150 mg oral tablet
  • children/adolescents 12-17 years:
    • tezacaftor 100 mg/ivacaftor 150 mg in morning and ivacaftor 150 mg in evening approximately 12 hours apart with fat-containing food
  • children 6-11 years (greater than 30 kg):
    • tezacaftor 100 mg/ ivacaftor 150 mg in morning and ivacaftor 150 mg in evening approximately 12 hours apart with fat-containing food
  • children 6-11 years (less than 30 kg):
    • tezacaftor 50 mg/ ivacaftor 75 mg in morning and ivacaftor 75 mg in evening approximately 12 hours apart with fat-containing food
CF (patients have at least one F508del mutation in the CFTR gene) elexacaftor/tezacaftor/ivacaftor (Trikafta®)

elexacaftor 100 mg/ tezacaftor 50 mg/ ivacaftor 75 mg oral tablet; ivacaftor 150 mg oral tablet

elexacaftor 50 mg/ tezacaftor 25 mg/ ivacaftor 37.5 mg oral tablet; ivacaftor 75 mg oral tablet
  • children/adolescents 12-17 years:
    • 2 tablets (elexacaftor 100 mg/ tezacaftor 50 mg/ ivacaftor 75 mg) in morning and one ivacaftor 150 mg tablet in evening approximately 12 hours apart with fat-containing food
  • children 6-11 years greater than or equal to 30 kg):
    • 2 tablets (elexacaftor 100 mg/ tezacaftor 50 mg/ ivacaftor 75 mg) in the morning and one ivacaftor 150 mg tablet in the evening approximately 12 hours apart with fat-containing food
  • children 6-11 years (less than 30 kg):
    • 2 tablets (elexacaftor 50 mg/ tezacaftor 25 mg/ ivacaftor 37.5 mg) in the morning and one ivacaftor 75 mg tablet in the evening approximately 12 hours apart with fat-containing food

 Legend:

  • CF = cystic fibrosis
  • CFTR = cystic fibrosis transmembrane conductance regulator
Table 9. Ivacaftor Pediatric Dosage Adjustments with Concurrent CYP3A4 Inhibitor Therapy
Ivacaftor Drug Name Concurrent CYP3A4 Inhibitor Therapy Dosage Recommendations*
ivacaftor (Kalydeco®) strong CYP3A inhibitors (e.g., ketoconazole)
  • greater than 6 years of age:
    • 150 mg twice weekly
  • 6 months to less than 6 years of age:
    • greater than 14 kg:
      • 75 mg granule packet twice weekly
  • 7 to less than 14 kg:
    • 50 mg granule packet twice weekly
  • 5 to less than 7 kg:
    • 25 mg granule packet twice weekly
  • 4 months to less than 6 months of age:
    • Use not recommended
ivacaftor (Kalydeco®) moderate CYP3A inhibitors (e.g., erythromycin, fluconazole)
  • greater than 6 years of age:
    • 150 mg orally once daily
  • 6 months to less than 6 years of age:
    • greater than 14 kg:
      • 75 mg granule packet orally once daily
  • 7 to less than 14 kg:
    • 50 mg granule packet orally once daily
  • 5 to less than 7 kg:
    • 25 mg granule packet orally once daily
  • 4 months to less than 6 months of age:
    • Use not recommended
lumacaftor/ivacaftor (Orkambi®) strong CYP3A inhibitors (e.g., ketoconazole)
  • greater than or equal to 12 years:
    • lumacaftor/ivacaftor dosages should be reduced to 200 mg/125 mg once daily for the first week, followed by 2 tablets (lumacaftor 400 mg/ivacaftor 250 mg) every 12 hours thereafter; no dosage adjustments are needed if CYP3A inhibitors are initiated in patients already taking lumacaftor/ivacaftor
  • 6 to 11 years:
    • lumacaftor/ivacaftor dosages should be reduced to 100 mg/125 mg once daily for the first week, followed by 2 tablets (lumacaftor 200 mg/ivacaftor 250 mg) every 12 hours thereafter; no dosage adjustments are needed if CYP3A inhibitors are initiated in patients already taking lumacaftor/ivacaftor
lumacaftor/ivacaftor (Orkambi®) strong CYP3A inhibitors (e.g., ketoconazole)
  • 2 to 5 years (greater than or equal to 14 kg):
    • lumacaftor/ivacaftor dosages should be reduced to 1 granule packet (150 mg/188 mg) every other day for the first week, followed by 1 granule packet (lumacaftor 150 mg/ivacaftor 188 mg) every 12 hours thereafter; no dosage adjustments are needed if CYP3A inhibitors are initiated in patients already taking lumacaftor/ivacaftor
  • 2 to 5 years (less than 14 kg):
    • lumacaftor/ivacaftor dosages should be reduced to 1 granule packet (100 mg/125 mg) every other day for the first week, followed by 1 granule packet (lumacaftor 100 mg/ivacaftor 125 mg) every 12 hours thereafter; no dosage adjustments are needed if CYP3A inhibitors are initiated in patients already taking lumacaftor/ivacaftor
lumacaftor/ivacaftor (Orkambi®) moderate CYP3A inhibitors (e.g., erythromycin, fluconazole) no dosage adjustments recommended
tezacaftor/ivacaftor (Symdeko®) strong CYP3A inhibitors (e.g., ketoconazole)
  • greater than or equal to 6 years to less than 12 years greater than or equal to 30 kg;
    • children/ adolescents greater than or equal to 12 years:
      • Day 1: tezacaftor/ivacaftor 100 mg/150 once daily in morning
      • Days 2 and 3: no dosages administered
      • Day 4: tezacaftor/ivacaftor 100 mg/150 once daily in morning 
    • The evening ivacaftor dose should NOT be given
  • Continue twice weekly (morning) administration schedule, with 3-4 days between dosages
  • Greater than or equal to 6 years to less than 12 years less than 30 kg:
    • Day 1: tezacaftor/ivacaftor 50 mg/75 once daily in morning
    • Days 2 and 3: no dosages administered
    • Day 4: tezacaftor/ivacaftor 50 mg/75 once daily in morning 
    • The evening ivacaftor dose should NOT be given
  • Continue twice weekly (morning) administration schedule, with 3-4 days between dosages
tezacaftor/ivacaftor (Symdeko®) moderate CYP3A inhibitors (e.g., erythromycin, fluconazole)
  • greater than or equal to 6 years to less than 12 years
    • Greater than or equal to 30 kg;
    • children/adolescents greater than or equal to 12 years:
      • Day 1: tezacaftor/ivacaftor 100 mg/150 once daily in morning
      • Day 2: ivacaftor 150 mg once daily in morning
      • The evening ivacaftor dose should NOT be given
      • Continue alternate day (morning) administration schedule
  • Greater than or equal to 6 years to less than 12 years
    • Less than 30 kg:
      • Day 1: tezacaftor/ivacaftor 50 mg/75 once daily in morning
      • Day 2:  ivacaftor 75 mg once daily in morning
  • The evening ivacaftor dose should NOT be given
  • Continue alternate day (morning) administration schedule
elexacaftor/tezacaftor/ivacaftor (Trikafta®) strong CYP3A inhibitors (e.g., ketoconazole)
  • 6-11 years of age: 
    • Weight less than 30 kg:
      • 2 tablets (elexacaftor 50 mg/ tezacaftor 25 mg/ ivacaftor 37.5 mg) in morning twice weekly, with 3-4 days between doses
    • The evening ivacaftor dose should NOT be given
  • 6-11 years of age:
    • Weight greater than or equal to 30 kg:
      • 2 tablets (elexacaftor 100 mg/ tezacaftor 50 mg/ ivacaftor 75 mg) in morning twice weekly, with 3-4 days between doses 
    • The evening ivacaftor dose should NOT be given
  • Greater than or equal to 12 years of age: 
    • 2 tablets (elexacaftor 100 mg/ tezacaftor 50 mg/ ivacaftor 75 mg) in morning twice weekly, with 3-4 days between dosages
    • The evening ivacaftor dose should NOT be given
elexacaftor/tezacaftor/ivacaftor (Trikafta®) moderate CYP3A inhibitors (e.g., erythromycin, fluconazole)
  • 6-11 years of age:
    • Weight less than 30 kg:
      • Day 1: 2 tablets (elexacaftor 50 mg/ tezacaftor 25 mg/ ivacaftor 37.5 mg) in morning
      • Day 2: ivacaftor 75 mg once daily in morning
    • The evening ivacaftor dose should NOT be given
    • Continue alternate day (morning) administration schedule
  • 6-11 years of age:
    • Weight greater than or equal to 30 kg:
      • Day 1: 2 tablets (elexacaftor 100 mg/ tezacaftor 50 mg/ ivacaftor 75 mg) in morning
      • Day 2: ivacaftor 75 mg once daily in morning
    • The evening ivacaftor dose should NOT be given
    • Continue alternate day (morning) administration schedule
  • Greater than or equal to 12 years of age:
    • Day 1: 2 tablets (elexacaftor 100 mg/ tezacaftor 50 mg/ ivacaftor 75 mg) in morning
    • Day 2: ivacaftor 150 mg once daily in morning
    • The evening ivacaftor dose should NOT be given
    • Continue alternate day (morning) administration schedule

Legend:

  • CYP3A = cytochrome P450 3A

1.3. Dosing in Renal Impairment

Because ivacaftor, lumacaftor/ivacaftor, tezacaftor/ivacaftor, and elexacaftor/tezacaftor/ivacaftor have not been studied in patients with renal insufficiency, these medications should be used cautiously in patients with CrCl less than or equal to 30 mL/min 1-4, 6, 7, 10.

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