Trikafta

If the patient's genotype is unknown, an FDA-cleared CF mutation test should be used to confirm the presence of at least one indicated mutation

Prior to initiating TRIKAFTA obtain liver function tests (ALT, AST, alkaline phosphatase, and bilirubin) in all patients. Monitor liver function tests every month during the first 6 months of treatment, then every 3 months during the next 12 months, then at least annually thereafter. (

• Should not be used in patients with severe hepatic impairment. Use not recommended in patients with moderate hepatic impairment unless the benefit outweighs the risk. Reduce dose if used in patients with moderate hepatic impairment. Liver function tests should be closely monitored. (
  2.3 Recommended Dosage for Patients with Hepatic Impairment

  • Severe Hepatic Impairment (Child-Pugh Class C):
    Should not be used. TRIKAFTA has not been studied 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
    [see Warnings and Precautions (5.1), Adverse Reactions (6), Use in Specific Populations (8.7)and Clinical Pharmacology (12.3)]
    .
  • Moderate Hepatic Impairment (Child-Pugh Class B)
    : Treatment is not recommended. Use of TRIKAFTA in patients with moderate hepatic impairment should only be considered when there is a clear medical need, and the benefit outweighs the risk. If used, TRIKAFTA should be used with caution at a reduced dose (see Table 2)
    [see Use in Specific Populations (8.7)and Clinical Pharmacology (12.3)]
    . Liver function tests should be closely monitored
    [see Dosage and Administration (2.1)and Warnings and Precautions (5.1)].
    Recommended dosage for patients with moderate hepatic impairment (Child-Pugh Class B) is provided in Table 2.

  Table 2: Recommended Dosage of TRIKAFTA, if used, in Patients with Moderate Hepatic Impairment (Child-Pugh Class B)

  Age	Weight	Oral Morning Dose	Oral Evening Dose
  2 to less than 6 years	Less than 14 kg	Weekly dosing schedule is as follows: Days 1-3: One packet (containing elexacaftor 80 mg/tezacaftor 40 mg/ivacaftor 60 mg) oral granules each day Day 4: no dose Days 5-6: One packet (containing elexacaftor 80 mg/tezacaftor 40 mg/ivacaftor 60 mg) oral granules each day Day 7: no dose	No evening dose of ivacaftor oral granules.
  	14 kg or more	Weekly dosing schedule is as follows: Days 1-3: One packet (containing elexacaftor 100 mg/tezacaftor 50 mg/ivacaftor 75 mg) oral granules each day Day 4: no dose Days 5-6: One packet (containing elexacaftor 100 mg/tezacaftor 50 mg/ivacaftor 75 mg) oral granules each day Day 7: no dose	No evening dose of ivacaftor oral granules.
  6 to less than 12 years	Less than 30 kg	Alternating daily dosing schedule is as follows: Day 1: Two tablets of elexacaftor 50 mg/tezacaftor 25 mg/ivacaftor 37.5 mg (total dose of elexacaftor 100 mg/tezacaftor 50 mg/ivacaftor 75 mg) Day 2: One tablet of elexacaftor 50 mg/tezacaftor 25 mg/ivacaftor 37.5 mg	No evening ivacaftor tablet dose.
  	30 kg or more	Alternating daily dosing schedule is as follows: Day 1: Two tablets of elexacaftor 100 mg/tezacaftor 50 mg/ivacaftor 75 mg (total dose of elexacaftor 200 mg/tezacaftor 100 mg/ivacaftor 150 mg) Day 2: One tablet elexacaftor 100 mg/tezacaftor 50 mg/ivacaftor 75 mg	No evening ivacaftor tablet dose.
  12 years and older	—	Alternating daily dosing schedule is as follows: Day 1: Two tablets of elexacaftor 100 mg/tezacaftor 50 mg/ivacaftor 75 mg (total dose of elexacaftor 200 mg/tezacaftor 100 mg/ivacaftor 150 mg) Day 2: One tablet elexacaftor 100 mg/tezacaftor 50 mg/ivacaftor 75 mg	No evening ivacaftor tablet dose.

  • Mild Hepatic Impairment (Child-Pugh Class A):
    No dose adjustment is recommended
    [see Use in Specific Populations (8.7)and Clinical Pharmacology (12.3)]
    . See Table 1for recommended dosage of TRIKAFTA. Liver function tests should be closely monitored
    [see Dosage and Administration (2.1)and Warnings and Precautions (5.1)].
  ,
  5.1 Drug-Induced Liver Injury and Liver Failure

  TRIKAFTA can cause serious and potentially fatal drug-induced liver injury. Cases of liver failure leading to transplantation and death have been reported in patients with and without a history of liver disease taking TRIKAFTA, in both clinical trials and the postmarketing setting

  [see Adverse Reactions (6)]

  . Liver injury has been reported within the first month of therapy and up to 15 months following initiation of TRIKAFTA.

  Assess liver function tests (ALT, AST, alkaline phosphatase, and bilirubin) in all patients prior to initiating TRIKAFTA. Assess liver function tests every month during the first 6 months of treatment, then every 3 months for the next 12 months, then at least annually thereafter. Consider more frequent monitoring for patients with a history of liver disease or liver function test elevations at baseline

  [see Dosage and Administration (2.1), Adverse Reactions (6), and Use in Specific Populations (8.7)]

  .

  Interrupt TRIKAFTA in the event of signs or symptoms of liver injury. These may include:

  • Significant elevations in liver function tests (e.g., ALT or AST >5 × the upper limit of normal (ULN) or ALT or AST >3 × ULN with bilirubin >2 × ULN)
  • Clinical symptoms suggestive of liver injury (e.g., jaundice, right upper quadrant pain, nausea, vomiting, altered mental status, ascites).

  Consider referral to a hepatologist and follow patients closely with clinical and laboratory monitoring until abnormalities resolve. If abnormalities resolve and if the benefit is expected to outweigh the risk, resume TRIKAFTA treatment with close monitoring.

  TRIKAFTA should not be used in patients with severe hepatic impairment (Child-Pugh Class C). TRIKAFTA is not recommended in patients with moderate hepatic impairment (Child-Pugh Class B) and should only be considered when there is a clear medical need, and the benefit outweighs the risk. If used, use with caution at a reduced dosage and monitor patients closely

  [see Dosage and Administration (2.3), Use in Specific Populations (8.7)and Clinical Pharmacology (12.3)]

  .
  ,
  6 ADVERSE REACTIONS

  The following clinically significant adverse reactions are discussed in greater detail in other sections of the labeling:

  • Drug-Induced Liver Injury and Liver Failure
    [see Warnings and Precautions (5.1)]
  • Hypersensitivity Reactions, Including Anaphylaxis
    [see Warnings and Precautions (5.2)]
  • Intracranial Hypertension
    [see Warnings and Precautions (5.3)]
  • Cataracts
    [see Warnings and Precautions (5.6)]

  The most common adverse drug reactions to TRIKAFTA (≥5% of patients and at a frequency higher than placebo by ≥1%) were headache, upper respiratory tract infection, abdominal pain, diarrhea, rash, alanine aminotransferase increased, nasal congestion, blood creatine phosphokinase increased, aspartate aminotransferase increased, rhinorrhea, rhinitis, influenza, sinusitis, blood bilirubin increased and constipation.

  
  
  

  To report SUSPECTED ADVERSE REACTIONS, contact Vertex Pharmaceuticals Incorporated at 1-877-634-8789 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

  6.1 Clinical Trials Experience

  Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

  Patients with Cystic Fibrosis with at Least One

  F508del

  Mutation

  The safety profile of TRIKAFTA in patients with CF with at least one

  F508del

  mutation is based on data from 510 patients aged 12 years and older in two double-blind, controlled trials of 24 weeks and 4 weeks treatment duration (Trials 1 and 2, respectively). Eligible patients were also able to participate in an open-label extension safety study (up to 96 weeks of TRIKAFTA). In the two controlled trials, a total of 257 patients aged 12 years and older received at least one dose of TRIKAFTA.

  In Trial 1, the proportion of patients who discontinued study drug prematurely due to adverse events was 1% for TRIKAFTA-treated patients and 0% for placebo-treated patients.

  In Trial 1, serious adverse reactions that occurred more frequently in TRIKAFTA-treated patients compared to placebo were rash (1% vs <1%) and influenza (1% vs 0%). There were no deaths.

  Table 4 shows adverse reactions occurring in ≥5% of TRIKAFTA-treated patients and higher than placebo by ≥1% in the 24-week, placebo-controlled, parallel-group trial (Trial 1).

  Table 4: Adverse Reactions Occurring in ≥5% of TRIKAFTA-Treated Patients and Higher than Placebo by ≥1% in Trial 1

  Adverse Reactions	TRIKAFTA N=202 n (%)	Placebo N=201 n (%)
  Headache	35 (17)	30 (15)
  Upper respiratory tract infectionIncludes upper respiratory tract infection and viral upper respiratory tract infection.	32 (16)	25 (12)
  Abdominal painIncludes abdominal pain, abdominal pain upper, abdominal pain lower.	29 (14)	18 (9)
  Diarrhea	26 (13)	14 (7)
  RashIncludes rash, rash generalized, rash erythematous, rash macular, rash pruritic.	21 (10)	10 (5)
  Alanine aminotransferase increased	20 (10)	7 (3)
  Nasal congestion	19 (9)	15 (7)
  Blood creatine phosphokinase increased	19 (9)	9 (4)
  Aspartate aminotransferase increased	19 (9)	4 (2)
  Rhinorrhea	17 (8)	6 (3)
  Rhinitis	15 (7)	11 (5)
  Influenza	14 (7)	3 (1)
  Sinusitis	11 (5)	8 (4)
  Blood bilirubin increased	10 (5)	2 (1)

  Additional adverse reactions that occurred in TRIKAFTA-treated patients at a frequency of 2% to <5% and higher than placebo by ≥1% include the following: flatulence, abdominal distension, conjunctivitis, pharyngitis, respiratory tract infection, tonsillitis, urinary tract infection, c-reactive protein increased, hypoglycemia, dizziness, dysmenorrhea, acne, eczema and pruritus.

  In addition, the following clinical trials have also been conducted

  [see Use in Specific Populations (8.4), Clinical Pharmacology (12.3)and Clinical Studies (14)]:

  • a 24-week, open-label trial in 66 patients with CF aged 6 to less than 12 years who were either homozygous for the
    F508del
    mutation or heterozygous for the
    F508del
    mutation, and a mutation on the second allele that results in either no CFTR protein or a CFTR protein that is not responsive to ivacaftor and tezacaftor/ivacaftor (Trial 3).
  • a 24-week, open-label trial in 75 patients with CF aged 2 to less than 6 years. Patients who had at least one
    F508del
    mutation or a mutation known to be responsive to TRIKAFTA were eligible for the study (Trial 4).

  The safety profile for the CF patients enrolled in Trials 2, 3, and 4 was consistent to that observed in Trial 1.

  Patients with Cystic Fibrosis with at Least One Qualifying Non-

  F508del

  Mutation

  The safety of TRIKAFTA in patients with CF with at least one non-

  F508del

  mutation is based on data from 307 patients aged 6 years and older with at least one qualifying non-

  F508del

  CFTR mutation that was TRIKAFTA-responsive. Trial 5 was a randomized, double blind, placebo-controlled trial for a 24-week treatment duration in which 205 patients received at least one dose of TRIKAFTA. Eligible patients were also able to participate in an open-label extension safety study.

  In Trial 5, the proportion of patients who discontinued study drug prematurely due to adverse reactions was 2% for TRIKAFTA-treated patients and 0% for placebo-treated patients.

  Table 5 shows adverse reactions occurring in ≥5% of TRIKAFTA-treated patients and higher than placebo by ≥1% in the 24-week, placebo-controlled, parallel-group trial (Trial 5).

  Table 5: Adverse Reactions Occurring in ≥5% of TRIKAFTA-Treated Patients and Higher than Placebo by ≥1% in Trial 5

  Adverse Reactions	TRIKAFTA N=205 n (%)	Placebo N=102 n (%)
  RashIncludes rash, rash maculo-papular, rash erythematous, rash papular	48 (23)	2 (2)
  Headache	37 (18)	13 (13)
  Diarrhea	26 (13)	10 (10)
  Rhinitis	20 (10)	6 (6)
  Influenza	18 (9)	2 (2)
  Constipation	15 (7)	4 (4)

  Specific Adverse Reactions

  Liver Function Test Elevations

  In Trial 1, the incidence of maximum transaminase (ALT or AST) >8, >5, or >3 × ULN was 1%, 2%, and 8% in TRIKAFTA-treated patients and 1%, 1%, and 5% in placebo-treated patients. The incidence of adverse reactions of transaminase elevations (AST and/or ALT) was 11% in TRIKAFTA-treated patients and 4% in placebo-treated patients.

  In Trial 1, the incidence of maximum total bilirubin elevation >2 × ULN was 4% in TRIKAFTA-treated patients and <1% in placebo-treated patients. Maximum indirect and direct bilirubin elevations >1.5 × ULN occurred in 11% and 3% of TRIKAFTA-treated patients, respectively. No TRIKAFTA-treated patients developed maximum direct bilirubin elevation >2 × ULN.

  During Trial 3, in patients aged 6 to less than 12 years, the incidence of maximum transaminase (ALT or AST) >8, >5, and >3 × ULN were 0%, 1.5%, and 10.6%, respectively. No TRIKAFTA-treated patients had transaminase elevation >3 × ULN associated with elevated total bilirubin >2 × ULN or discontinued treatment due to transaminase elevations.

  During Trial 4 in patients aged 2 to less than 6 years, the incidence of maximum transaminase (ALT or AST) >8, >5, and >3 × ULN were 1.3%, 2.7%, and 8.0%, respectively. No TRIKAFTA-treated patients had transaminase elevation >3 × ULN associated with elevated total bilirubin >2 × ULN. One patient required treatment interruption during Trial 4 and later discontinued TRIKAFTA during the open label extension due to transaminase elevations.

  In Trial 5, the incidence of maximum transaminase (ALT or AST) >8, >5, and >3 × ULN were 2.0%, 2.0%, and 6.3%, respectively, and led to treatment discontinuation in 0.5% and treatment interruptions in 1.5% of TRIKAFTA-treated patients. There were no transaminase elevations >3 × ULN in placebo-treated patients.

  Rash

  In Trial 1, the overall incidence of rash was 10% in TRIKAFTA-treated and 5% in placebo-treated patients (see Table 4). The incidence of rash was higher in female TRIKAFTA-treated patients (16%) than in male TRIKAFTA-treated patients (5%).

  In Trial 5, the overall incidence of rash was 23% in TRIKAFTA-treated and 2% in placebo-treated patients (see Table 5). The incidence of rash was higher in female TRIKAFTA-treated patients (27%) than in male TRIKAFTA-treated patients (20%).

  A role of hormonal contraceptives in the occurrence of rash cannot be excluded

  [see Drug Interactions (7.3)]

  .

  Increased Creatine Phosphokinase

  In Trial 1, the incidence of maximum creatine phosphokinase elevation >5 × ULN was 10% in TRIKAFTA-treated and 5% in placebo-treated patients. Among the TRIKAFTA-treated patients with creatine phosphokinase elevation >5 × ULN, 14% (3/21) required treatment interruption and none discontinued treatment.

  In Trial 5, the incidence of maximum creatine phosphokinase elevation >5 × ULN was 5.4% (11/205) in TRIKAFTA-treated patients and 1% (1/102) in placebo-treated patients. The incidence of maximum creatine phosphokinase elevation >10 × ULN was 2.4% (5/205) in TRIKAFTA-treated patients and 1% (1/102) in placebo-treated patients. There were no interruptions or discontinuations among the TRIKAFTA-treated patients with creatine phosphokinase elevation >5 × ULN. Among the TRIKAFTA-treated patients with creatine phosphokinase elevation > 10 × ULN, two patients, who had exercised within the preceding 72 hours, developed rhabdomyolysis without evidence of renal involvement resulting in treatment interruption in 1 patient.

  Increased Blood Pressure

  In Trial 1, the maximum increase from baseline in mean systolic and diastolic blood pressure was 3.5 mmHg and 1.9 mmHg, respectively for TRIKAFTA-treated patients (baseline: 113 mmHg systolic and 69 mmHg diastolic) and 0.9 mmHg and 0.5 mmHg, respectively for placebo-treated patients (baseline: 114 mmHg systolic and 70 mmHg diastolic).

  The proportion of patients who had systolic blood pressure >140 mmHg and 10 mmHg increase from baseline on at least two occasions was 4% in TRIKAFTA-treated patients and 1% in placebo-treated patients. The proportion of patients who had diastolic blood pressure >90 mmHg and 5 mmHg increase from baseline on at least two occasions was 1% in TRIKAFTA-treated patients and 2% in placebo-treated patients.

  With the exception of sex differences in rash, the safety profile of TRIKAFTA was generally similar across all subgroups of patients, including analysis by age, sex, baseline percent predicted FEV₁(ppFEV₁) and geographic regions.

  6.2 Postmarketing Experience

  The following adverse reactions have been identified during postapproval use of TRIKAFTA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

  Hepatobiliary

  : liver injury, fatal liver failure, liver transplantation

  Immune System Disorders

  : anaphylaxis, angioedema

  Nervous System Disorders

  : intracranial hypertension
  ,
  8.7 Hepatic Impairment

  • Severe Hepatic Impairment (Child-Pugh Class C):
    Should not be used. TRIKAFTA has not been studied 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
    [see Dosage and Administration (2.3), Warnings and Precautions (5.1), Adverse Reactions (6)and Clinical Pharmacology (12.3)]
    .
  • Moderate Hepatic Impairment (Child-Pugh Class B):
    Treatment is not recommended. Use of TRIKAFTA in patients with moderate hepatic impairment should only be considered when there is a clear medical need, and the benefit outweighs the risk. If used in patients with moderate hepatic impairment, TRIKAFTA should be used at a reduced dose. Liver function tests should be closely monitored
    [see Dosage and Administration (2.1, 2.3)and Warnings and Precautions (5.1)]
    .
    
    In a clinical study of 11 subjects with moderate hepatic impairment, one subject developed total and direct bilirubin elevations >2 × ULN, and a second subject developed direct bilirubin elevation >4.5 × ULN
    [see Clinical Pharmacology (12.3)]
    .
  • Mild Hepatic Impairment (Child-Pugh Class A):
    No dose modification is recommended. Liver function tests should be closely monitored
    [see Dosage and Administration (2.1)and Warnings and Precautions (5.1)]
    .
  ,
  12.3 Pharmacokinetics

  The pharmacokinetics of elexacaftor, tezacaftor and ivacaftor are similar between healthy adult subjects and patients with CF. The pharmacokinetic parameters for elexacaftor, tezacaftor and ivacaftor in patients with CF aged 12 years and older are shown in Table 7.

  Table 7: Pharmacokinetic Parameters of TRIKAFTA Components

  	Elexacaftor	Tezacaftor	Ivacaftor
  AUCss: area under the concentration versus time curve at steady state; SD: Standard Deviation; Cmax: maximum observed concentration; Tmax: time of maximum concentration; AUC: area under the concentration versus time curve.
  General Information
  AUCss(SD), mcg∙h/mLBased on elexacaftor 200 mg and tezacaftor 100 mg once daily/ivacaftor 150 mg every 12 hours at steady state in patients with CF aged 12 years and older.	162 (47.5)AUC0-24h.	89.3 (23.2)	11.7 (4.01)AUC0-12h.
  Cmax(SD), mcg/mL	9.2 (2.1)	7.7 (1.7)	1.2 (0.3)
  Time to Steady State, days	Within 7 days	Within 8 days	Within 3-5 days
  Accumulation Ratio	2.2	2.07	2.4
  Absorption
  Absolute Bioavailability	80%	Not determined	Not determined
  Median Tmax(range), hours	6 (4 to 12)	3 (2 to 4)	4 (3 to 6)
  Effect of Food	AUC increases 1.9- to 2.5-fold (moderate-fat meal)	No clinically significant effect	Exposure increases 2.5- to 4-fold
  Distribution
  Mean (SD) Apparent Volume of Distribution, LElexacaftor, tezacaftor and ivacaftor do not partition preferentially into human red blood cells.	53.7 (17.7)	82.0 (22.3)	293 (89.8)
  Protein BindingElexacaftor and tezacaftor bind primarily to albumin. Ivacaftor primarily bind to albumin, alpha 1-acid glycoprotein and human gamma-globulin.	>99%	approximately 99%	approximately 99%
  Elimination
  Mean (SD) Effective Half-Life, hoursMean (SD) terminal half-lives of elexacaftor, tezacaftor and ivacaftor are approximately 24.7 (4.87) hours, 60.3 (15.7) hours and 13.1 (2.98) hours, respectively.	27.4 (9.31)	25.1 (4.93)	15.0 (3.92)
  Mean (SD) Apparent Clearance, L/hours	1.18 (0.29)	0.79 (0.10)	10.2 (3.13)
  Metabolism
  Primary Pathway	CYP3A4/5	CYP3A4/5	CYP3A4/5
  Active Metabolites	M23-ELX	M1-TEZ	M1-IVA
  Metabolite Potency Relative to Parent	Similar	Similar	approximately 1/6thof parent
  ExcretionFollowing radiolabeled doses.
  Primary Pathway	Feces: 87.3% (primarily as metabolites) Urine: 0.23%	Feces: 72% (unchanged or as M2-TEZ) Urine: 14% (0.79% unchanged)	Feces: 87.8% Urine: 6.6%

  Specific Populations

  Pediatric Patients 2 to Less Than 12 Years of Age

  Elexacaftor, tezacaftor and ivacaftor exposures observed in patients aged 2 to less than 12 years as determined using population PK analysis are presented by age group and dose administered in Table 8. Elexacaftor, tezacaftor and ivacaftor exposures in this patient population are within the range observed in patients aged 12 years and older.

  Table 8: Mean (SD) Elexacaftor, Tezacaftor and Ivacaftor Exposures Observed at Steady State by Age Group and Dose Administered

  Age Group	Dose	Elexacaftor AUC0-24h,ss (µg∙h/mL)	Tezacaftor AUC0-24h,ss (µg∙h/mL)	Ivacaftor AUC0-12h,ss (µg∙h/mL)
  SD: Standard Deviation; AUCss: area under the concentration versus time curve at steady state.
  Patients aged 2 to less than 6 years weighing less than 14 kg (N = 16)	elexacaftor 80 mg qd/tezacaftor 40 mg qd/ivacaftor 60 mg qAM and ivacaftor 59.5 mg qPM	128 (24.8)	87.3 (17.3)	11.9 (3.86)
  Patients aged 2 to less than 6 years weighing 14 kg or more (N = 59)	elexacaftor 100 mg qd/tezacaftor 50 mg qd/ivacaftor 75 mg q12h	138 (47.0)	90.2 (27.9)	13.0 (6.11)
  Patients aged 6 to less than 12 years weighing less than 30 kg (N = 36)	elexacaftor 100 mg qd/tezacaftor 50 mg qd/ivacaftor 75 mg q12h	116 (39.4)	67.0 (22.3)	9.78 (4.50)
  Patients aged 6 to less than 12 years weighing 30 kg or more (N = 30)	elexacaftor 200 mg qd/ tezacaftor 100 mg qd/ ivacaftor 150 mg q12h	195 (59.4)	103 (23.7)	17.5 (4.97)

  Pediatric Patients 12 to Less Than 18 Years of Age

  The following conclusions about exposures between adults and the pediatric population are based on population pharmacokinetic (PK) analyses. Following oral administration of TRIKAFTA to patients 12 to less than 18 years of age (elexacaftor 200 mg qd/tezacaftor 100 mg qd/ivacaftor 150 mg q12h), the mean (±SD) AUC_sswas 147 (36.8) mcg∙h/mL, 88.8 (21.8) mcg∙h/mL and 10.6 (3.35) mcg∙h/mL, respectively for elexacaftor, tezacaftor and ivacaftor, similar to the AUC_ssin adult patients.

  Patients with Renal Impairment

  Renal excretion of elexacaftor, tezacaftor and ivacaftor is minimal. Elexacaftor alone or in combination with tezacaftor and ivacaftor has not been studied in subjects with severe (eGFR <30 mL/min/1.73 m²) renal impairment or end-stage renal disease. Based on population PK analyses, the clearance of elexacaftor and tezacaftor was similar in subjects with mild (eGFR 60 to <90 mL/min/1.73 m²) or moderate (eGFR 30 to <60 mL/min/1.73 m²) renal impairment relative to patients with normal renal function

  [see Use in Specific Populations (8.6)]

  .

  Patients with Hepatic Impairment

  Elexacaftor alone or in combination with tezacaftor and ivacaftor has not been studied in subjects with severe hepatic impairment (Child-Pugh Class C, score 10-15). In a clinical study, following multiple doses of elexacaftor, tezacaftor and ivacaftor for 10 days, subjects with moderately impaired hepatic function (Child-Pugh Class B, score 7-9) had 25% higher AUC and 12% higher C_maxfor elexacaftor, 73% higher AUC and 70% higher C_maxfor M23-ELX, 36% higher AUC and 24% higher C_maxfor combined elexacaftor and M23-ELX, 20% higher AUC but similar C_maxfor tezacaftor and 1.5-fold higher AUC and 10% higher C_maxfor ivacaftor compared with healthy subjects matched for demographics

  [see Dosage and Administration (2.3), Warnings and Precautions (5.1), Adverse Reactions (6)and Use in Specific Populations (8.7)]

  .

  Tezacaftor and Ivacaftor

  Following multiple doses of tezacaftor and ivacaftor for 10 days, subjects with moderately impaired hepatic function had an approximately 36% higher AUC and a 10% higher in C_maxfor tezacaftor and a 1.5-fold higher AUC but similar C_maxfor ivacaftor compared with healthy subjects matched for demographics.

  Ivacaftor

  In a study with ivacaftor alone, subjects with moderately impaired hepatic function had similar ivacaftor C_max, but an approximately 2.0-fold higher ivacaftor AUC_0-∞compared with healthy subjects matched for demographics.

  Male and Female Patients

  Based on population PK analysis, the exposures of elexacaftor, tezacaftor and ivacaftor are similar in males and females.

  Drug Interaction Studies

  Drug interaction studies were performed with elexacaftor, tezacaftor and/or ivacaftor and other drugs likely to be co-administered or drugs commonly used as probes for pharmacokinetic interaction studies

  [see Drug Interactions (7)]

  .

  Potential for Elexacaftor, Tezacaftor and/or Ivacaftor to Affect Other Drugs

  Based on in vitro results, elexacaftor and tezacaftor have a low potential to inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A4, whereas ivacaftor has the potential to inhibit CYP2C8, CYP2C9 and CYP3A. However, clinical studies showed that the combination regimen of tezacaftor/ivacaftor is not an inhibitor of CYP3A and ivacaftor is not an inhibitor of CYP2C8 or CYP2D6.

  Based on in vitro results, elexacaftor, tezacaftor and ivacaftor are not likely to induce CYP3A, CYP1A2 and CYP2B6.

  Based on in vitro results, elexacaftor and tezacaftor have a low potential to inhibit the transporter P-gp, while ivacaftor has the potential to inhibit P-gp. Co-administration of tezacaftor/ivacaftor with digoxin, a sensitive P-gp substrate, increased digoxin exposure by 1.3-fold in a clinical study. Based on in vitro results, elexacaftor and M23-ELX may inhibit OATP1B1 and OATP1B3 uptake. Tezacaftor has a low potential to inhibit BCRP, OCT2, OAT1, or OAT3. Ivacaftor is not an inhibitor of the transporters OCT1, OCT2, OAT1, or OAT3.

  The effects of elexacaftor, tezacaftor and/or ivacaftor on the exposure of co-administered drugs are shown in Table 9

  [see Drug Interactions (7)]

  .

  Table 9: Impact of Elexacaftor, Tezacaftor and/or Ivacaftor on Other Drugs

  Dose and Schedule		Effect on Other Drug PK	Geometric Mean Ratio (90% CI) of Other Drug No Effect=1.0
  			AUC	Cmax
  ↑ = increase, ↓ = decrease, ↔ = no change.
  AUC: area under the concentration versus time curve; CI: Confidence Interval; ELX: elexacaftor; Cmax: maximum observed concentration; TEZ: tezacaftor; IVA: ivacaftor; PK: Pharmacokinetics.
  Midazolam 2 mg single oral dose	TEZ 100 mg qd/IVA 150 mg q12h	↔ Midazolam	1.12 (1.01, 1.25)	1.13 (1.01, 1.25)
  Digoxin 0.5 mg single dose	TEZ 100 mg qd/IVA 150 mg q12h	↑ Digoxin	1.30 (1.17, 1.45)	1.32 (1.07, 1.64)
  Oral Contraceptive Ethinyl estradiol 30 µg/Levonorgestrel 150 µg qd	ELX 200 mg qd/TEZ 100 mg qd/IVA 150 mg q12h	↑ Ethinyl estradiolEffect is not clinically significant [see Drug Interactions (7.3)] .	1.33 (1.20, 1.49)	1.26 (1.14, 1.39)
  		↑ Levonorgestrel	1.23 (1.10, 1.37)	1.10 (0.985, 1.23)
  Rosiglitazone 4 mg single oral dose	IVA 150 mg q12h	↔ Rosiglitazone	0.975 (0.897, 1.06)	0.928 (0.858, 1.00)
  Desipramine 50 mg single dose	IVA 150 mg q12h	↔ Desipramine	1.04 (0.985, 1.10)	1.00 (0.939, 1.07)

  Potential for Other Drugs to Affect Elexacaftor, Tezacaftor and/or Ivacaftor

  In vitro studies showed that elexacaftor, tezacaftor and ivacaftor are all metabolized by CYP3A. Exposure to elexacaftor, tezacaftor and ivacaftor may be reduced by concomitant CYP3A inducers and increased by concomitant CYP3A inhibitors.

  In vitro studies showed that elexacaftor and tezacaftor are substrates for the efflux transporter P-gp, but ivacaftor is not. Elexacaftor and ivacaftor are not substrates for OATP1B1 or OATP1B3; tezacaftor is a substrate for OATP1B1, but not OATP1B3. Tezacaftor is a substrate for BCRP.

  The effects of co-administered drugs on the exposure of elexacaftor, tezacaftor and/or ivacaftor are shown in Table 10

  [see Dosage and Administration (2.4)and Drug Interactions (7)]

  .

  Table 10: Impact of Other Drugs on Elexacaftor, Tezacaftor and/or Ivacaftor

  Dose and Schedule		Effect on ELX, TEZ and/or IVA PK	Geometric Mean Ratio (90% CI) of Elexacaftor, Tezacaftor and Ivacaftor No Effect = 1.0
  			AUC	Cmax
  ↑ = increase, ↓ = decrease, ↔ = no change.
  AUC: area under the concentration versus time curve; CI: Confidence Interval; Cmax: maximum observed concentration; ELX: elexacaftor; TEZ: tezacaftor; IVA: ivacaftor; PK: Pharmacokinetics.
  Itraconazole 200 mg q12h on Day 1, followed by 200 mg qd	TEZ 25 mg qd + IVA 50 mg qd	↑ Tezacaftor	4.02 (3.71, 4.63)	2.83 (2.62, 3.07)
  		↑ Ivacaftor	15.6 (13.4, 18.1)	8.60 (7.41, 9.98)
  Itraconazole 200 mg qd	ELX 20 mg + TEZ 50 mg single dose	↑ Elexacaftor	2.83 (2.59, 3.10)	1.05 (0.977, 1.13)
  		↑ Tezacaftor	4.51 (3.85, 5.29)	1.48 (1.33, 1.65)
  Ketoconazole 400 mg qd	IVA 150 mg single dose	↑ Ivacaftor	8.45 (7.14, 10.0)	2.65 (2.21, 3.18)
  Ciprofloxacin 750 mg q12h	TEZ 50 mg q12h + IVA 150 mg q12h	↔ Tezacaftor	1.08 (1.03, 1.13)	1.05 (0.99, 1.11)
  		↑ IvacaftorEffect is not clinically significant [see Drug Interactions (7.3)] .	1.17 (1.06, 1.30)	1.18 (1.06, 1.31)
  Rifampin 600 mg qd	IVA 150 mg single dose	↓ Ivacaftor	0.114 (0.097, 0.136)	0.200 (0.168, 0.239)
  Fluconazole 400 mg single dose on Day 1, followed by 200 mg qd	IVA 150 mg q12h	↑ Ivacaftor	2.95 (2.27, 3.82)	2.47 (1.93, 3.17)
  )
• See full prescribing information for dosage modifications due to drug interactions with TRIKAFTA. (
  2.4 Dosage Modification for Patients Taking Drugs that are CYP3A Inhibitors

  Table 3 describes the recommended dosage modification for TRIKAFTA when used concomitantly with strong (e.g., ketoconazole, itraconazole, posaconazole, voriconazole, telithromycin, and clarithromycin) or moderate (e.g., fluconazole, erythromycin) CYP3A inhibitors. Administer TRIKAFTA orally with fat-containing food

  [see Dosage and Administration (2.2)].

  Avoid food or drink containing grapefruit during TRIKAFTA treatment

  [see Warnings and Precautions (5.5), Drug Interactions (7.1)and Clinical Pharmacology (12.3)]

  .

  Table 3: Dosage Modification for Concomitant Use of TRIKAFTA with Moderate and Strong CYP3A Inhibitors

  Age	Weight	Moderate CYP3A Inhibitors	Strong CYP3A Inhibitors
  2 to less than 6 years	Less than 14 kg	Alternating daily dosing schedule is as follows: Day 1: One packet (containing elexacaftor 80 mg/tezacaftor 40 mg/ivacaftor 60 mg) in the morning Day 2: One packet (containing ivacaftor 59.5 mg) oral granules in the morning No evening packet of ivacaftor oral granules.	One packet (containing elexacaftor 80 mg/tezacaftor 40 mg/ivacaftor 60 mg) in the morning twice a week, approximately 3 to 4 days apart. No evening packet of ivacaftor oral granules.
  	14 kg or more	Alternating daily dosing schedule is as follows: Day 1: One packet (containing elexacaftor 100 mg/tezacaftor 50 mg/ivacaftor 75 mg) in the morning Day 2: One packet (containing ivacaftor 75 mg) oral granules in the morning No evening packet of ivacaftor oral granules.	One packet (containing elexacaftor 100 mg/tezacaftor 50 mg/ivacaftor 75 mg) in the morning twice a week, approximately 3 to 4 days apart. No evening packet of ivacaftor oral granules.
  6 to less than 12 years	Less than 30 kg	Alternating daily dosing schedule is as follows: Day 1: Two tablets of elexacaftor 50 mg/tezacaftor 25 mg/ivacaftor 37.5 mg (total dose of elexacaftor 100 mg/tezacaftor 50 mg/ivacaftor 75 mg) in the morning Day 2: One tablet of ivacaftor 75 mg in the morning No evening ivacaftor tablet dose.	Two tablets of elexacaftor 50 mg/tezacaftor 25 mg/ivacaftor 37.5 mg (total dose of elexacaftor 100 mg/tezacaftor 50 mg/ivacaftor 75 mg) in the morning twice a week, approximately 3 to 4 days apart. No evening ivacaftor tablet dose.
  	30 kg or more	Alternating daily dosing schedule is as follows: Day 1: Two tablets elexacaftor 100 mg/tezacaftor 50 mg/ivacaftor 75 mg (total dose of elexacaftor 200 mg/tezacaftor100 mg/ivacaftor 150 mg) in the morning Day 2: One tablet of ivacaftor 150 mg in the morning No evening ivacaftor tablet dose.	Two tablets elexacaftor 100 mg/tezacaftor 50 mg/ivacaftor 75 mg (total dose of elexacaftor 200 mg/tezacaftor 100 mg/ivacaftor 150 mg) in the morning twice a week, approximately 3 to 4 days apart. No evening ivacaftor tablet dose.
  12 years and older		Alternating daily dosing schedule is as follows: Day 1: Two tablets elexacaftor 100 mg/tezacaftor 50 mg/ivacaftor 75 mg (total dose of elexacaftor 200 mg/tezacaftor 100 mg/ivacaftor 150 mg) in the morning Day 2: One tablet of ivacaftor 150 mg in the morning No evening ivacaftor tablet dose.	Two tablets elexacaftor 100 mg/tezacaftor 50 mg/ivacaftor 75 mg (total dose of elexacaftor 200 mg/tezacaftor 100 mg/ivacaftor 150 mg) in the morning twice a week, approximately 3 to 4 days apart. No evening ivacaftor tablet dose.
  ,
  5.5 Concomitant Use with CYP3A Inhibitors

  Exposure to elexacaftor, tezacaftor and ivacaftor are increased when used concomitantly with strong or moderate CYP3A inhibitors. Therefore, the dose of TRIKAFTA should be reduced when used concomitantly with moderate or strong CYP3A inhibitors

  [see Dosage and Administration (2.4), Drug Interactions (7.1)and Clinical Pharmacology (12.3)]

  .
  ,
  7.1 Effect of Other Drugs and Grapefruit on TRIKAFTA

  Strong CYP3A Inducers

  Concomitant use of TRIKAFTA with strong CYP3A inducers is not recommended. Elexacaftor, tezacaftor and ivacaftor are substrates of CYP3A (ivacaftor is a sensitive substrate of CYP3A). Concomitant use of CYP3A inducers may result in reduced exposures and thus reduced TRIKAFTA efficacy

  [see Warnings and Precautions (5.4)]

  . Concomitant use of ivacaftor with rifampin, a strong CYP3A inducer, significantly decreased ivacaftor area under the curve (AUC) by 89%. Elexacaftor and tezacaftor exposures are expected to decrease during concomitant use with strong CYP3A inducers

  [see Clinical Pharmacology (12.3)]

  .

  Examples of strong CYP3A inducers include:

  • rifampin, rifabutin, phenobarbital, carbamazepine, phenytoin and St. John's wort (
    Hypericum perforatum
    )

  Strong or Moderate CYP3A Inhibitors

  The dosage of TRIKAFTA should be reduced when used concomitantly with strong CYP3A inhibitors

  [see Dosage and Administration (2.4)and Warnings and Precautions (5.5)]

  . Concomitant use with itraconazole, a strong CYP3A inhibitor, increased elexacaftor AUC by 2.8-fold and tezacaftor AUC by 4.0- to 4.5-fold. When used concomitantly with itraconazole and ketoconazole, ivacaftor AUC increased by 15.6-fold and 8.5-fold, respectively

  [see Clinical Pharmacology (12.3)]

  .

  Examples of strong CYP3A inhibitors include:

  • ketoconazole, itraconazole, posaconazole and voriconazole
  • telithromycin and clarithromycin

  The dosage of TRIKAFTA should be reduced when used concomitantly with moderate CYP3A inhibitors

  [see Dosage and Administration (2.4)and Warnings and Precautions (5.5)].

  Simulations indicated that concomitant use with moderate CYP3A inhibitors may increase elexacaftor and tezacaftor AUC by approximately 1.9- to 2.3-fold and 2.1-fold, respectively. Concomitant use of fluconazole increased ivacaftor AUC by 2.9-fold

  [see Clinical Pharmacology (12.3)]

  .

  Examples of moderate CYP3A inhibitors include:

  • fluconazole
  • erythromycin

  Grapefruit

  Concomitant use of TRIKAFTA with grapefruit juice, which contains one or more components that moderately inhibit CYP3A, may increase exposure of elexacaftor, tezacaftor and ivacaftor; therefore, food or drink containing grapefruit should be avoided during treatment with TRIKAFTA

  [see Dosage and Administration (2.4)]

  .
  ,
  12.3 Pharmacokinetics

  The pharmacokinetics of elexacaftor, tezacaftor and ivacaftor are similar between healthy adult subjects and patients with CF. The pharmacokinetic parameters for elexacaftor, tezacaftor and ivacaftor in patients with CF aged 12 years and older are shown in Table 7.

  Table 7: Pharmacokinetic Parameters of TRIKAFTA Components

  	Elexacaftor	Tezacaftor	Ivacaftor
  AUCss: area under the concentration versus time curve at steady state; SD: Standard Deviation; Cmax: maximum observed concentration; Tmax: time of maximum concentration; AUC: area under the concentration versus time curve.
  General Information
  AUCss(SD), mcg∙h/mLBased on elexacaftor 200 mg and tezacaftor 100 mg once daily/ivacaftor 150 mg every 12 hours at steady state in patients with CF aged 12 years and older.	162 (47.5)AUC0-24h.	89.3 (23.2)	11.7 (4.01)AUC0-12h.
  Cmax(SD), mcg/mL	9.2 (2.1)	7.7 (1.7)	1.2 (0.3)
  Time to Steady State, days	Within 7 days	Within 8 days	Within 3-5 days
  Accumulation Ratio	2.2	2.07	2.4
  Absorption
  Absolute Bioavailability	80%	Not determined	Not determined
  Median Tmax(range), hours	6 (4 to 12)	3 (2 to 4)	4 (3 to 6)
  Effect of Food	AUC increases 1.9- to 2.5-fold (moderate-fat meal)	No clinically significant effect	Exposure increases 2.5- to 4-fold
  Distribution
  Mean (SD) Apparent Volume of Distribution, LElexacaftor, tezacaftor and ivacaftor do not partition preferentially into human red blood cells.	53.7 (17.7)	82.0 (22.3)	293 (89.8)
  Protein BindingElexacaftor and tezacaftor bind primarily to albumin. Ivacaftor primarily bind to albumin, alpha 1-acid glycoprotein and human gamma-globulin.	>99%	approximately 99%	approximately 99%
  Elimination
  Mean (SD) Effective Half-Life, hoursMean (SD) terminal half-lives of elexacaftor, tezacaftor and ivacaftor are approximately 24.7 (4.87) hours, 60.3 (15.7) hours and 13.1 (2.98) hours, respectively.	27.4 (9.31)	25.1 (4.93)	15.0 (3.92)
  Mean (SD) Apparent Clearance, L/hours	1.18 (0.29)	0.79 (0.10)	10.2 (3.13)
  Metabolism
  Primary Pathway	CYP3A4/5	CYP3A4/5	CYP3A4/5
  Active Metabolites	M23-ELX	M1-TEZ	M1-IVA
  Metabolite Potency Relative to Parent	Similar	Similar	approximately 1/6thof parent
  ExcretionFollowing radiolabeled doses.
  Primary Pathway	Feces: 87.3% (primarily as metabolites) Urine: 0.23%	Feces: 72% (unchanged or as M2-TEZ) Urine: 14% (0.79% unchanged)	Feces: 87.8% Urine: 6.6%

  Specific Populations

  Pediatric Patients 2 to Less Than 12 Years of Age

  Elexacaftor, tezacaftor and ivacaftor exposures observed in patients aged 2 to less than 12 years as determined using population PK analysis are presented by age group and dose administered in Table 8. Elexacaftor, tezacaftor and ivacaftor exposures in this patient population are within the range observed in patients aged 12 years and older.

  Table 8: Mean (SD) Elexacaftor, Tezacaftor and Ivacaftor Exposures Observed at Steady State by Age Group and Dose Administered

  Age Group	Dose	Elexacaftor AUC0-24h,ss (µg∙h/mL)	Tezacaftor AUC0-24h,ss (µg∙h/mL)	Ivacaftor AUC0-12h,ss (µg∙h/mL)
  SD: Standard Deviation; AUCss: area under the concentration versus time curve at steady state.
  Patients aged 2 to less than 6 years weighing less than 14 kg (N = 16)	elexacaftor 80 mg qd/tezacaftor 40 mg qd/ivacaftor 60 mg qAM and ivacaftor 59.5 mg qPM	128 (24.8)	87.3 (17.3)	11.9 (3.86)
  Patients aged 2 to less than 6 years weighing 14 kg or more (N = 59)	elexacaftor 100 mg qd/tezacaftor 50 mg qd/ivacaftor 75 mg q12h	138 (47.0)	90.2 (27.9)	13.0 (6.11)
  Patients aged 6 to less than 12 years weighing less than 30 kg (N = 36)	elexacaftor 100 mg qd/tezacaftor 50 mg qd/ivacaftor 75 mg q12h	116 (39.4)	67.0 (22.3)	9.78 (4.50)
  Patients aged 6 to less than 12 years weighing 30 kg or more (N = 30)	elexacaftor 200 mg qd/ tezacaftor 100 mg qd/ ivacaftor 150 mg q12h	195 (59.4)	103 (23.7)	17.5 (4.97)

  Pediatric Patients 12 to Less Than 18 Years of Age

  The following conclusions about exposures between adults and the pediatric population are based on population pharmacokinetic (PK) analyses. Following oral administration of TRIKAFTA to patients 12 to less than 18 years of age (elexacaftor 200 mg qd/tezacaftor 100 mg qd/ivacaftor 150 mg q12h), the mean (±SD) AUC_sswas 147 (36.8) mcg∙h/mL, 88.8 (21.8) mcg∙h/mL and 10.6 (3.35) mcg∙h/mL, respectively for elexacaftor, tezacaftor and ivacaftor, similar to the AUC_ssin adult patients.

  Patients with Renal Impairment

  Renal excretion of elexacaftor, tezacaftor and ivacaftor is minimal. Elexacaftor alone or in combination with tezacaftor and ivacaftor has not been studied in subjects with severe (eGFR <30 mL/min/1.73 m²) renal impairment or end-stage renal disease. Based on population PK analyses, the clearance of elexacaftor and tezacaftor was similar in subjects with mild (eGFR 60 to <90 mL/min/1.73 m²) or moderate (eGFR 30 to <60 mL/min/1.73 m²) renal impairment relative to patients with normal renal function

  [see Use in Specific Populations (8.6)]

  .

  Patients with Hepatic Impairment

  Elexacaftor alone or in combination with tezacaftor and ivacaftor has not been studied in subjects with severe hepatic impairment (Child-Pugh Class C, score 10-15). In a clinical study, following multiple doses of elexacaftor, tezacaftor and ivacaftor for 10 days, subjects with moderately impaired hepatic function (Child-Pugh Class B, score 7-9) had 25% higher AUC and 12% higher C_maxfor elexacaftor, 73% higher AUC and 70% higher C_maxfor M23-ELX, 36% higher AUC and 24% higher C_maxfor combined elexacaftor and M23-ELX, 20% higher AUC but similar C_maxfor tezacaftor and 1.5-fold higher AUC and 10% higher C_maxfor ivacaftor compared with healthy subjects matched for demographics

  [see Dosage and Administration (2.3), Warnings and Precautions (5.1), Adverse Reactions (6)and Use in Specific Populations (8.7)]

  .

  Tezacaftor and Ivacaftor

  Following multiple doses of tezacaftor and ivacaftor for 10 days, subjects with moderately impaired hepatic function had an approximately 36% higher AUC and a 10% higher in C_maxfor tezacaftor and a 1.5-fold higher AUC but similar C_maxfor ivacaftor compared with healthy subjects matched for demographics.

  Ivacaftor

  In a study with ivacaftor alone, subjects with moderately impaired hepatic function had similar ivacaftor C_max, but an approximately 2.0-fold higher ivacaftor AUC_0-∞compared with healthy subjects matched for demographics.

  Male and Female Patients

  Based on population PK analysis, the exposures of elexacaftor, tezacaftor and ivacaftor are similar in males and females.

  Drug Interaction Studies

  Drug interaction studies were performed with elexacaftor, tezacaftor and/or ivacaftor and other drugs likely to be co-administered or drugs commonly used as probes for pharmacokinetic interaction studies

  [see Drug Interactions (7)]

  .

  Potential for Elexacaftor, Tezacaftor and/or Ivacaftor to Affect Other Drugs

  Based on in vitro results, elexacaftor and tezacaftor have a low potential to inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A4, whereas ivacaftor has the potential to inhibit CYP2C8, CYP2C9 and CYP3A. However, clinical studies showed that the combination regimen of tezacaftor/ivacaftor is not an inhibitor of CYP3A and ivacaftor is not an inhibitor of CYP2C8 or CYP2D6.

  Based on in vitro results, elexacaftor, tezacaftor and ivacaftor are not likely to induce CYP3A, CYP1A2 and CYP2B6.

  Based on in vitro results, elexacaftor and tezacaftor have a low potential to inhibit the transporter P-gp, while ivacaftor has the potential to inhibit P-gp. Co-administration of tezacaftor/ivacaftor with digoxin, a sensitive P-gp substrate, increased digoxin exposure by 1.3-fold in a clinical study. Based on in vitro results, elexacaftor and M23-ELX may inhibit OATP1B1 and OATP1B3 uptake. Tezacaftor has a low potential to inhibit BCRP, OCT2, OAT1, or OAT3. Ivacaftor is not an inhibitor of the transporters OCT1, OCT2, OAT1, or OAT3.

  The effects of elexacaftor, tezacaftor and/or ivacaftor on the exposure of co-administered drugs are shown in Table 9

  [see Drug Interactions (7)]

  .

  Table 9: Impact of Elexacaftor, Tezacaftor and/or Ivacaftor on Other Drugs

  Dose and Schedule		Effect on Other Drug PK	Geometric Mean Ratio (90% CI) of Other Drug No Effect=1.0
  			AUC	Cmax
  ↑ = increase, ↓ = decrease, ↔ = no change.
  AUC: area under the concentration versus time curve; CI: Confidence Interval; ELX: elexacaftor; Cmax: maximum observed concentration; TEZ: tezacaftor; IVA: ivacaftor; PK: Pharmacokinetics.
  Midazolam 2 mg single oral dose	TEZ 100 mg qd/IVA 150 mg q12h	↔ Midazolam	1.12 (1.01, 1.25)	1.13 (1.01, 1.25)
  Digoxin 0.5 mg single dose	TEZ 100 mg qd/IVA 150 mg q12h	↑ Digoxin	1.30 (1.17, 1.45)	1.32 (1.07, 1.64)
  Oral Contraceptive Ethinyl estradiol 30 µg/Levonorgestrel 150 µg qd	ELX 200 mg qd/TEZ 100 mg qd/IVA 150 mg q12h	↑ Ethinyl estradiolEffect is not clinically significant [see Drug Interactions (7.3)] .	1.33 (1.20, 1.49)	1.26 (1.14, 1.39)
  		↑ Levonorgestrel	1.23 (1.10, 1.37)	1.10 (0.985, 1.23)
  Rosiglitazone 4 mg single oral dose	IVA 150 mg q12h	↔ Rosiglitazone	0.975 (0.897, 1.06)	0.928 (0.858, 1.00)
  Desipramine 50 mg single dose	IVA 150 mg q12h	↔ Desipramine	1.04 (0.985, 1.10)	1.00 (0.939, 1.07)

  Potential for Other Drugs to Affect Elexacaftor, Tezacaftor and/or Ivacaftor

  In vitro studies showed that elexacaftor, tezacaftor and ivacaftor are all metabolized by CYP3A. Exposure to elexacaftor, tezacaftor and ivacaftor may be reduced by concomitant CYP3A inducers and increased by concomitant CYP3A inhibitors.

  In vitro studies showed that elexacaftor and tezacaftor are substrates for the efflux transporter P-gp, but ivacaftor is not. Elexacaftor and ivacaftor are not substrates for OATP1B1 or OATP1B3; tezacaftor is a substrate for OATP1B1, but not OATP1B3. Tezacaftor is a substrate for BCRP.

  The effects of co-administered drugs on the exposure of elexacaftor, tezacaftor and/or ivacaftor are shown in Table 10

  [see Dosage and Administration (2.4)and Drug Interactions (7)]

  .

  Table 10: Impact of Other Drugs on Elexacaftor, Tezacaftor and/or Ivacaftor

  Dose and Schedule		Effect on ELX, TEZ and/or IVA PK	Geometric Mean Ratio (90% CI) of Elexacaftor, Tezacaftor and Ivacaftor No Effect = 1.0
  			AUC	Cmax
  ↑ = increase, ↓ = decrease, ↔ = no change.
  AUC: area under the concentration versus time curve; CI: Confidence Interval; Cmax: maximum observed concentration; ELX: elexacaftor; TEZ: tezacaftor; IVA: ivacaftor; PK: Pharmacokinetics.
  Itraconazole 200 mg q12h on Day 1, followed by 200 mg qd	TEZ 25 mg qd + IVA 50 mg qd	↑ Tezacaftor	4.02 (3.71, 4.63)	2.83 (2.62, 3.07)
  		↑ Ivacaftor	15.6 (13.4, 18.1)	8.60 (7.41, 9.98)
  Itraconazole 200 mg qd	ELX 20 mg + TEZ 50 mg single dose	↑ Elexacaftor	2.83 (2.59, 3.10)	1.05 (0.977, 1.13)
  		↑ Tezacaftor	4.51 (3.85, 5.29)	1.48 (1.33, 1.65)
  Ketoconazole 400 mg qd	IVA 150 mg single dose	↑ Ivacaftor	8.45 (7.14, 10.0)	2.65 (2.21, 3.18)
  Ciprofloxacin 750 mg q12h	TEZ 50 mg q12h + IVA 150 mg q12h	↔ Tezacaftor	1.08 (1.03, 1.13)	1.05 (0.99, 1.11)
  		↑ IvacaftorEffect is not clinically significant [see Drug Interactions (7.3)] .	1.17 (1.06, 1.30)	1.18 (1.06, 1.31)
  Rifampin 600 mg qd	IVA 150 mg single dose	↓ Ivacaftor	0.114 (0.097, 0.136)	0.200 (0.168, 0.239)
  Fluconazole 400 mg single dose on Day 1, followed by 200 mg qd	IVA 150 mg q12h	↑ Ivacaftor	2.95 (2.27, 3.82)	2.47 (1.93, 3.17)
  )