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    Trial 1
    (Heterozygous F508del/Other Specific)

    Trial 1
    (Heterozygous F508del/
    Other Specific)

    On this Page:
    Study Design Summary of Results
    On this Page:
    Study Design Summary of Results

    STUDY DESIGN

    TRIAL 1: A double-blind, placebo-controlled, Phase 3 trial in patients heterozygous for the F508del mutation and a specific mutation1,2

    • Phase 3, 24-week, double-blind, placebo-controlled study assessing the efficacy of TRIKAFTA1,a
    • Patients were randomized 1:1
      • 200 patients received TRIKAFTA: elexacaftor 200 mg/tezacaftor 100 mg/ivacaftor 150 mg qam and ivacaftor 150 mg qpm with fat-containing food
      • 203 patients received placebo q12h with fat-containing food
    • All patients remained on their standard-of-care CF therapies.

    Please see additional safety information based on this trial in the safety profile.

    aAll patients who completed the study were eligible to roll over into a 192-week, open-label Extension Study.1,3

    Key Inclusion Criteria1,2,b

    • Confirmed CF diagnosis, clinically stable, and at least 12 years of age
    • Heterozygous for the F508del mutation and one of approximately 200 other mutations in the CFTR gene that resulted in either:
      • No CFTR protein
      • A CFTR protein that lacks baseline function and is not responsive to ivacaftor and tezacaftor/ivacaftor
    • ppFEV1 between 40% and 90% at screening

    bKey exclusion criteria included clinically significant cirrhosis with or without portal hypertension, lung infection with organisms associated with a more rapid decline in pulmonary status (including, but not limited to, Burkholderia cenocepacia, Burkholderia dolosa, and Mycobacterium abscessus), and solid organ or hematologic transplantation.1,2

    Primary Endpoint1

    • Absolute change in ppFEV1 from baseline at Week 4
      • Preplanned interim analysis was conducted after ≥140 patients completed the Week 4 visit and ≥100 patients completed the Week 12 visit
      • There were 403 patients included in the preplanned interim analysis at Week 4

    Select Secondary Endpoints1,c

    • Absolute change from baseline through week 24 in ppFEV1
    • Number of pulmonary exacerbations through week 24d
    • Absolute change from baseline through week 24 in sweat chloride
    • Absolute change from baseline through week 24 and at week 4 in CFQ-R Respiratory Domain score
    • Absolute change from baseline at week 24 in BMI

    cA hierarchical testing procedure was performed for key secondary endpoints. For an endpoint to be significant, both it and all previous tests in the hierarchy had to achieve P<0.05.2

    dIn the trial, a pulmonary exacerbation was defined as a change in antibiotic therapy (IV, inhaled, or oral) as a result of 4 or more of 12 prespecified sinopulmonary signs/symptoms.1

    Baseline Characteristics4

     TRIKAFTA
    (N=200)    		Placebo
    (N=203)
    Sex, female, %48.048.3
    Mean age, years (range)25.6 (12.1-59.9)26.8 (12.3-64.0)
    Mean BMI, kg/m2 (range)21.49 (15.01-30.86)21.31 (14.42-33.80)
    Mean ppFEV1 (range)61.6 (33.8-97.1)61.3 (32.3-93.7)
    Mean SwCI, mmol/L (range)102.3 (22.5-156.0)102.9 (68.5-137.0)
     TRIKAFTA
    (N=200)    		Placebo
    (N=203)
    Sex, female, %48.048.3
    Mean age, years (range)25.6
    (12.1-59.9)    		26.8
    (12.3-64.0)
    Mean BMI, kg/m2 (range)21.49
    (15.01-30.86)    		21.31
    (14.42-33.80)
    Mean ppFEV1 (range)61.6
    (33.8-97.1)    		61.3
    (32.3-93.7)
    Mean SwCI, mmol/L (range)102.3
    (22.5-156.0)    		102.9
    (68.5-137.0)

    SUMMARY OF RESULTS

    Trial outcomes for patients aged 12 years and older (heterozygous F508del/other specific)

    Primary Endpoint2

    ABSOLUTE CHANGE IN ppFEV1 FROM BASELINE AT WEEK 4
    13.8 Percentage Points
    SIGNIFICANT IMPROVEMENT IN LUNG FUNCTION SUSTAINED THROUGH WEEK 24 VS PLACEBO
    in mean absolute change in ppFEV1 from baseline at Week 4 based on preplanned interim analysis (95% CI: 12.1, 15.4; P<0.0001)

    Select Secondary Endpoints

    ABSOLUTE CHANGE IN ppFEV1 FROM BASELINE THROUGH WEEK 241
    14.3 Percentage Points
    IMPROVEMENT VS PLACEBO BASED ON THE AVERAGE OF WEEKS 4, 8, 12, 16, AND 24
    (95% CI: 12.7, 15.8; P<0.0001)
    Graph showing significant improvement in lung function at Week 4, sustained through Week 24 Graph showing significant improvement in lung function at Week 4, sustained through Week 24
    • Improvements in ppFEV1 were seen regardless of age, ppFEV1 at baseline, geographic region, and sex1
    In Trial 1, mean baseline ppFEV1 was 61.6 percentage points (range: 33.8, 97.1) for patients receiving TRIKAFTA and 61.3 percentage points (range: 32.3, 93.7) for patients receiving placebo.4
    ANNUALIZED RATE OF PULMONARY EXACERBATIONS1,5,e,f
    63 Percentage Points
    REDUCTION THROUGH WEEK 24
    (RR: 0.37, [95% CI: 0.25, 0.55]; P<0.0001)
    Graph showing reduction in rate of pulmonary exacerbations through Week 24 Graph showing reduction in rate of pulmonary exacerbations through Week 24

    eIn Trial 1, the number of pulmonary exacerbation events was 113 (0.98) for placebo vs 41 (0.37) for TRIKAFTA.1

    fIn Trial 1, the number of pulmonary exacerbations is expressed as a rate over 48 weeks based on 24 weeks of observation.1

    MEAN ABSOLUTE CHANGE IN SWEAT CHLORIDE1,5
    41.8 mmol/L
    SIGNIFICANT REDUCTION IN SWEAT CHLORIDE
    vs placebo through Week 24 (95% CI: -44.4, -39.3; P<0.0001)
    Graph showing significant reduction in sweat chloride through Week 24 Graph showing significant reduction in sweat chloride through Week 24
    In Trial 1, mean baseline sweat chloride was 102.3 mmol/L (range: 22.5, 156.0) for patients receiving TRIKAFTA and 102.9 mmol/L (range: 68.5, 137.0) for those receiving placebo.4
    ABSOLUTE CHANGE FROM BASELINE IN CFQ-R RESPIRATORY DOMAIN SCORE THROUGH WEEK 241,5
    20.2 Points
    SIGNIFICANT IMPROVEMENT IN CFQ-R RESPIRATORY DOMAIN SCORE
    vs placebo at week 4, maintained through Week 24 (95% CI: 17.5, 23.0; P<0.0001)
    Graph showing significant reduction in sweat chloride through Week 24 Graph showing significant reduction in sweat chloride through Week 24
    • In Trial 1, significant improvement in CFQ-R Respiratory Domain score was seen as early as Week 4
      • 20.1-point improvement vs placebo (95% CI: 16.9, 23.2; P<0.0001)
    The MCID threshold for CFQ-R Respiratory Domain score is 4 points in patients with CF with stable respiratory symptoms and represents the minimal change a patient can detect.7
    In Trial 1, mean baseline CFQ-R Respiratory Domain score was 68.3 for patients receiving TRIKAFTA and 70.0 for those receiving placebo.5
    CFQ-R Respiratory Domain score measured composite patient-reported outcomes in the following respiratory symptoms8:
    • Waking up from coughing
    • Wheezing
    • Coughing
    • Congestion
    • Difficulty breathing
    • Mucus production
    • Congestion
    • Difficulty breathing
    • Mucus production
    ABSOLUTE CHANGE FROM BASELINE IN BMI1,2
    1.04 kg/m2
    SIGNIFICANT INCREASE IN BMI VS PLACEBO AT WEEK 24
    95% CI: 0.85, 1.23; P<0.0001)
    Graph showing significant increase in BMI at Week 24 Graph showing significant increase in BMI at Week 24
    For example, a patient who began TRIKAFTA in the trial at 130 lb and 5'5" tall with a BMI of 22 may have completed the trial with a 6-lb increase in weight.9
    In Trial 1, mean baseline BMI was 21.49 kg/m2 (range: 15.01, 30.86) for patients receiving TRIKAFTA and 21.31 kg/m2 (range: 14.42, 33.80) for patients receiving placebo.4
    ADDITIONAL ENDPOINTS IN TRIAL 15,6
    ADDITIONAL ENDPOINTS IN TRIAL 15,6
    71%
    REDUCTION IN EVENT RATE  leading to HOSPITALIZATION (32 events for placebo vs 9 events for TRIKAFTA [RR: 0.29, 95% CI: 0.14, 0.61])
    78%
    REDUCTION IN EVENT RATE leading to IV ANTIBIOTIC USE (51 events for placebo vs 11 events for TRIKAFTA [RR: 0.22, 95% CI: 0.11, 0.43])
    • Power for additional endpoints was limited. Analysis of additional endpoints was not adjusted for multiplicity. These additional endpoints are not included in the TRIKAFTA full Prescribing Information

    BMI, body mass index; CF, cystic fibrosis; CFQ-R, Cystic Fibrosis Questionnaire-Revised; CFTR, cystic fibrosis transmembrane conductance regulator; CI, confidence interval; IV, intravenous; lb, pounds; LS, least squares; MCID, minimal clinically important difference; ppFEV1, percent predicted forced expiratory volume in 1 second; q12h, every 12 hours; qam, every morning; qpm, every evening; RR, rate ratio, SE, standard error; SwCl, sweat chloride; WK, week.

    Trial 2
    (Homozygous F508del Mutation)

    Trial 2
    (Homozygous F508del Mutation)

    On this Page:
    Study Design Summary of Results
    On this Page:
    Study Design Summary of Results

    STUDY DESIGN

    TRIAL 2: A double-blind, active-controlled, head-to-head Phase 3 trial in patients homozygous for the F508del mutation1,2

    • Phase 3, 4-week, double-blind, active-controlled, head-to-head study assessing the efficacy of TRIKAFTA1,a
    • Prior to the run-in period, all patients in this study discontinued previous CFTR modulator therapies, but remained on their standard-of-care CF therapies.1
    • During the 4-week, open-label run-in period, all patients received tezacaftor 100 mg daily/ivacaftor 150 mg q12h
    • During the 4-week, double-blind treatment period, patients were randomized 1:1
      • 55 patients received TRIKAFTA: elexacaftor 200 mg/tezacaftor 100 mg/ivacaftor 150 mg qam and ivacaftor 150 mg qpm with fat-containing food
      • 52 patients received an active comparator: tezacaftor 100 mg/ivacaftor 150 mg qam and ivacaftor 150 mg qpm with fat-containing food

    aAll patients who completed the study were eligible to roll over into a 192-week, open-label Extension Study.1,3

    Key Inclusion Criteria1,2,b

    • Confirmed CF diagnosis, clinically stable, and at least 12 years of age
    • Homozygous for the F508del mutation
    • ppFEV1 between 40% and 90% at screening

    bKey exclusion criteria included clinically significant cirrhosis with or without portal hypertension, lung infection with organisms associated with a more rapid decline in pulmonary status (including, but not limited to, Burkholderia cenocepacia, Burkholderia dolosa, and Mycobacterium abscessus), and solid organ or hematologic transplantation.1,4

    Primary Endpoint1

    • Absolute change in ppFEV1 from baseline at Week 4

    Select Secondary Endpoints1,c

    • Absolute change from baseline at Week 4 in sweat chloride
    • Absolute change from baseline at Week 4 in CFQ-R Respiratory Domain score

    cA hierarchical testing procedure was performed for key secondary endpoints. For an endpoint to be significant, both it and all previous tests in the hierarchy had to achieve a hierarchy of P<0.05.5

    Baseline Characteristics4

     TRIKAFTA 
    (N=55)    		Tezacaftor/ivacaftor and ivacaftor
    (N=52)
    Sex, female, %56.453.8
    Mean age, years (range)28.8 (12.7-54.1)27.9 (12.4-60.5)
    Mean BMI, kg/m2 (range)21.8 (16.0-28.4)21.9 (15.6-34.6)
    Mean ppFEV1 (range)61.6 (35.0-87.4)60.2 (35.0-89.0)
    Mean SwCI, mmol/L (range)91.4 (67.0-114.0)90.0 (60.5-112.0)
     TRIKAFTA 
    (N=55)    		Tezacaftor/
    ivacaftor and ivacaftor
    (N=52)
    Sex, female, %56.453.8
    Mean age, years (range)28.8
    (12.7-54.1)    		27.9
    (12.4-60.5)
    Mean BMI, kg/m2 (range)21.8
    (16.0-28.4)    		21.9
    (15.6-34.6)
    Mean ppFEV1 (range)61.6
    (35.0-87.4)    		60.2
    (35.0-89.0)
    Mean SwCI, mmol/L (range)91.4
    (67.0-114.0)    		90.0
    (60.5-112.0)

    SUMMARY OF RESULTS

    Trial outcomes for patients aged 12 years and older (homozygous F508del mutation)

    Primary Endpoint2

    ABSOLUTE CHANGE IN ppFEV1 FROM BASELINE
    10.0 Percentage Points
    IMPROVEMENT
    vs tezacaftor/ivacaftor and ivacaftor at Week 4 (95% CI: 7.4, 12.6; P<0.0001)
    Graph showing significant improvements in lung function and sweat chloride vs active comparator Graph showing significant improvements in lung function and sweat chloride vs active comparator
    In Trial 2, mean baseline ppFEV1 was 61.6 percentage points (range: 35.0, 87.4) for patients receiving TRIKAFTA and 60.2 percentage points (range: 35.0, 89.0) for patients receiving the active comparator.6

    Select Secondary Endpoints

    ABSOLUTE CHANGE IN SWEAT CHLORIDE1
    45.1 mmol/L
    SIGNIFICANT REDUCTION IN SWEAT CHLORIDE
    Compared with tezacaftor/ivacaftor and ivacaftor at Week 4 (95% CI: -50.1, -40.1; P<0.0001)
    SIGNIFICANT REDUCTION IN SWEAT CHLORIDE
    Compared with tezacaftor/
    ivacaftor and ivacaftor at Week 4 (95% CI: -50.1, -40.1; P<0.0001)
    In Trial 2, mean baseline sweat chloride was 91.4 mmol/L (range: 67.0, 114.0) for patients receiving TRIKAFTA and 90.0 mmol/L (range: 60.5, 112.0) for patients receiving the active comparator.6
    MEAN ABSOLUTE CHANGE FROM BASELINE IN CFQ-R RESPIRATORY DOMAIN SCORE1,2
    17.4 Points
    SIGNIFICANT IMPROVEMENT IN CFQ-R RESPIRATORY DOMAIN SCORE
    vs tezacaftor/ivacaftor and ivacaftor at Week 4 LS-mean absolute difference (95% CI: 11.8, 23.0; P<0.0001)
    Graph showing significant improvement in CFQ-R Respiratory Domain score at Week 4, maintained through Week 24 Graph showing significant improvement in CFQ-R Respiratory Domain score at Week 4, maintained through Week 24
    The MCID threshold for CFQ-R Respiratory Domain score is 4 points in patients with CF with stable respiratory symptoms and represents the minimal change a patient can detect.7
    In Trial 2, mean baseline CFQ-R Respiratory Domain score was 70.6 points for patients receiving TRIKAFTA and 72.6 points for those receiving the active comparator.6
    CFQ-R Respiratory Domain score measured composite patient-reported outcomes in the following respiratory symptoms8:
    • Waking up from coughing
    • Wheezing
    • Coughing
    • Congestion
    • Difficulty breathing
    • Mucus production
    • Congestion
    • Difficulty breathing
    • Mucus production

    BMI, body mass index; CF, cystic fibrosis; CFTR, cystic fibrosis transmembrane conductance regulator; CFQ-R, Cystic Fibrosis Questionnaire-Revised; CI, confidence interval; IV, intravenous; LS, least square; MCID, minimal clinically important difference; ppFEV1, percent predicted forced expiratory volume in 1 second; q12h, every 12 hours; qam, every morning; qpm, every evening; RR, rate ratio, SE, standard error; SwCl, sweat chloride; WK, week.

    See the results in patients aged 2 to <6 years

    See the safety profile of TRIKAFTA

    IMPORTANT SAFETY INFORMATION

    WARNINGS AND PRECAUTIONS

    Elevated Transaminases and Hepatic Injury

    • Liver failure leading to transplantation has been reported in a patient with cirrhosis and portal hypertension while receiving TRIKAFTA. Avoid use of TRIKAFTA in patients with pre-existing advanced liver disease (e.g., as evidenced by cirrhosis, portal hypertension, ascites, hepatic encephalopathy) unless the benefits are expected to outweigh the risks. If used in these patients, they should be closely monitored after the initiation of treatment
    • Isolated elevations of transaminases or bilirubin have been observed in patients with CF treated with TRIKAFTA. In some instances, transaminase elevations have been associated with concomitant elevations in total bilirubin and/or international normalized ratio (INR) and have resulted in patients being hospitalized for intervention, including in patients without a history of pre-existing liver disease

    INDICATIONS AND USAGE

    TRIKAFTA is indicated for the treatment of cystic fibrosis (CF) in patients aged 2 years and older who have at least one F508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene or a mutation in the CFTR gene that is responsive based on in vitro data.

    If the patient’s genotype is unknown, an FDA-cleared CF mutation test should be used to confirm the presence of at least one F508del mutation or a mutation that is responsive based on in vitro data.

    • Assessments of liver function tests (ALT, AST, and bilirubin) are recommended prior to initiating TRIKAFTA, every 3 months during the first year of treatment, and annually thereafter
    • In the event of significant elevations in liver function tests, e.g. ALT or AST >5x the upper limit of normal (ULN) or ALT or AST >3x ULN with bilirubin >2x ULN, dosing should be interrupted and laboratory tests closely followed until the abnormalities resolve. Following the resolution of liver function test elevations, consider the benefits and risks of resuming treatment
    • For patients with a history of hepatobiliary disease or liver function test elevations, more frequent monitoring should be considered

    Hypersensitivity Reactions, Including Anaphylaxis

    • Hypersensitivity reactions, including cases of angioedema and anaphylaxis, have been reported in the postmarketing setting. If signs or symptoms of serious hypersensitivity reactions develop during treatment, discontinue TRIKAFTA and institute appropriate therapy. Consider the benefits and risks for the individual patient to determine whether to resume treatment with TRIKAFTA

    Concomitant Use With CYP3A Inducers

    • Exposure to ivacaftor is significantly decreased and exposure to elexacaftor and tezacaftor are expected to decrease by the concomitant use of strong CYP3A inducers, which may reduce the therapeutic effectiveness of TRIKAFTA. Co‑administration with strong CYP3A inducers is not recommended

    Concomitant Use With CYP3A Inhibitors

    • Exposure to elexacaftor, tezacaftor, and ivacaftor are increased when co-administered with strong or moderate CYP3A inhibitors. The dose of TRIKAFTA should be reduced when used concomitantly with moderate or strong CYP3A inhibitors

    Cataracts

    • Cases of non-congenital lens opacities have been reported in pediatric patients treated with ivacaftor-containing regimens. Baseline and follow‑up ophthalmological examinations are recommended in pediatric patients initiating treatment with TRIKAFTA

    ADVERSE REACTIONS

    Serious Adverse Reactions

    • Serious adverse reactions that occurred more frequently in patients treated with TRIKAFTA compared to placebo were rash (1% vs <1%) and influenza (1% vs 0)

    Most Common Adverse Reactions

    • The most common adverse reactions occurring in ≥5% of patients treated with TRIKAFTA (N=202) and higher than placebo (N=201) by ≥1% in the 24-week placebo-controlled, parallel-group Phase 3 trial (Trial 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, and blood bilirubin increased
    • The safety profile for the patients with CF receiving TRIKAFTA (N=55) enrolled in the 4-week, randomized, double-blind, active-controlled Phase 3 trial (Trial 2) was similar to that observed in Trial 1
    • The safety profile in patients age 6 through 11 years from an open-label trial (Trial 3; N=66) was similar to that observed in Trial 1. The safety profile in patients age 2 through 5 years from an open-label trial (Trial 4; N=75) was similar to that observed in Trial 1

    USE IN SPECIFIC POPULATIONS

    Pediatric Use

    • The safety and effectiveness of TRIKAFTA in patients with CF younger than 2 years of age have not been established

    Click here to access full Prescribing Information for TRIKAFTA.

     

    Important Safety Information and Indication

    EXPAND

    COLLAPSE

    INDICATIONS AND USAGE

    TRIKAFTA is indicated for the treatment of cystic fibrosis (CF) in patients aged 2 years and older who have at least one F508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene or a mutation in the CFTR gene that is responsive based on in vitro data.

    If the patient’s genotype is unknown, an FDA-cleared CF mutation test should be used to confirm the presence of at least one F508del mutation or a mutation that is responsive based on in vitro data.

    INDICATIONS AND USAGE

    TRIKAFTA is indicated for the treatment of cystic fibrosis (CF) in patients aged 2 years and older who have at least one F508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene or a mutation in the CFTR gene that is responsive based on in vitro data.

    If the patient’s genotype is unknown, an FDA-cleared CF mutation test should be used to confirm the presence of at least one F508del mutation or a mutation that is responsive based on in vitro data.

    IMPORTANT SAFETY INFORMATION

    WARNINGS AND PRECAUTIONS

    Elevated Transaminases and Hepatic Injury

    • Liver failure leading to transplantation has been reported in a patient with cirrhosis and portal hypertension while receiving TRIKAFTA. Avoid use of TRIKAFTA in patients with pre-existing advanced liver disease (e.g., as evidenced by cirrhosis, portal hypertension, ascites, hepatic encephalopathy) unless the benefits are expected to outweigh the risks. If used in these patients, they should be closely monitored after the initiation of treatment
    • Isolated elevations of transaminases or bilirubin have been observed in patients with CF treated with TRIKAFTA. In some instances, transaminase elevations have been associated with concomitant elevations in total bilirubin and/or international normalized ratio (INR) and have resulted in patients being hospitalized for intervention, including in patients without a history of pre-existing liver disease

    INDICATIONS AND USAGE

    TRIKAFTA is indicated for the treatment of cystic fibrosis (CF) in patients aged 2 years and older who have at least one F508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene or a mutation in the CFTR gene that is responsive based on in vitro data.

    If the patient’s genotype is unknown, an FDA-cleared CF mutation test should be used to confirm the presence of at least one F508del mutation or a mutation that is responsive based on in vitro data.

    IMPORTANT SAFETY INFORMATION

    WARNINGS AND PRECAUTIONS

    Elevated Transaminases and Hepatic Injury

    • Liver failure leading to transplantation has been reported in a patient with cirrhosis and portal hypertension while receiving TRIKAFTA. Avoid use of TRIKAFTA in patients with pre-existing advanced liver disease (e.g., as evidenced by cirrhosis, portal hypertension, ascites, hepatic encephalopathy) unless the benefits are expected to outweigh the risks. If used in these patients, they should be closely monitored after the initiation of treatment
    • Isolated elevations of transaminases or bilirubin have been observed in patients with CF treated with TRIKAFTA. In some instances, transaminase elevations have been associated with concomitant elevations in total bilirubin and/or international normalized ratio (INR) and have resulted in patients being hospitalized for intervention, including in patients without a history of pre-existing liver disease
    • Assessments of liver function tests (ALT, AST, and bilirubin) are recommended prior to initiating TRIKAFTA, every 3 months during the first year of treatment, and annually thereafter
    • In the event of significant elevations in liver function tests, e.g. ALT or AST >5x the upper limit of normal (ULN) or ALT or AST >3x ULN with bilirubin >2x ULN, dosing should be interrupted and laboratory tests closely followed until the abnormalities resolve. Following the resolution of liver function test elevations, consider the benefits and risks of resuming treatment
    • For patients with a history of hepatobiliary disease or liver function test elevations, more frequent monitoring should be considered

    Hypersensitivity Reactions, Including Anaphylaxis

    • Hypersensitivity reactions, including cases of angioedema and anaphylaxis, have been reported in the postmarketing setting. If signs or symptoms of serious hypersensitivity reactions develop during treatment, discontinue TRIKAFTA and institute appropriate therapy. Consider the benefits and risks for the individual patient to determine whether to resume treatment with TRIKAFTA

    Concomitant Use With CYP3A Inducers

    • Exposure to ivacaftor is significantly decreased and exposure to elexacaftor and tezacaftor are expected to decrease by the concomitant use of strong CYP3A inducers, which may reduce the therapeutic effectiveness of TRIKAFTA. Co‑administration with strong CYP3A inducers is not recommended

    Concomitant Use With CYP3A Inhibitors

    • Exposure to elexacaftor, tezacaftor, and ivacaftor are increased when co-administered with strong or moderate CYP3A inhibitors. The dose of TRIKAFTA should be reduced when used concomitantly with moderate or strong CYP3A inhibitors

    Cataracts

    • Cases of non-congenital lens opacities have been reported in pediatric patients treated with ivacaftor-containing regimens. Baseline and follow‑up ophthalmological examinations are recommended in pediatric patients initiating treatment with TRIKAFTA

    ADVERSE REACTIONS

    Serious Adverse Reactions

    • Serious adverse reactions that occurred more frequently in patients treated with TRIKAFTA compared to placebo were rash (1% vs <1%) and influenza (1% vs 0)

    Most Common Adverse Reactions

    • The most common adverse reactions occurring in ≥5% of patients treated with TRIKAFTA (N=202) and higher than placebo (N=201) by ≥1% in the 24-week placebo-controlled, parallel-group Phase 3 trial (Trial 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, and blood bilirubin increased
    • The safety profile for the patients with CF receiving TRIKAFTA (N=55) enrolled in the 4-week, randomized, double-blind, active-controlled Phase 3 trial (Trial 2) was similar to that observed in Trial 1
    • The safety profile in patients age 6 through 11 years from an open-label trial (Trial 3; N=66) was similar to that observed in Trial 1. The safety profile in patients age 2 through 5 years from an open-label trial (Trial 4; N=75) was similar to that observed in Trial 1

    USE IN SPECIFIC POPULATIONS

    Pediatric Use

    • The safety and effectiveness of TRIKAFTA in patients with CF younger than 2 years of age have not been established

    Click here to access full Prescribing Information for TRIKAFTA.

    References:
    1. TRIKAFTA [prescribing information]. Boston, MA: Vertex Pharmaceuticals Incorporated; August 2023. 2. Heijerman HG, McKone EF, Downey DG, et al. Efficacy and safety of the elexacaftor plus tezacaftor plus ivacaftor combination regimen in people with cystic fibrosis homozygous for the F508del mutation: a double-blind, randomised, phase 3 trial [published correction appears in Lancet. 2020;395(10238):1694]. Lancet. 2019;394(10212):1940-1948. doi:10.1016/S0140-6736(19)32597-8. 3. Data on file. Vertex Pharmaceuticals Incorporated. Boston, MA. REF-6056 (v1.0); 2020. 4. Heijerman HG, McKone EF, Downey DG, et al. Efficacy and safety of the elexacaftor plus tezacaftor plus ivacaftor combination regimen in people with cystic fibrosis homozygous for the F508del mutation: a double-blind, randomised, phase 3 trial. Lancet (suppl). 2019;394(10212):1940-1948. 5. Middleton PG, Mall MA, Drevinek P, et al. Elexacaftor–tezacaftor–ivacaftor for cystic fibrosis with a single Phe508del allele. N Engl J Med. 2019;381(19)(suppl):1809-1819. 6. Data on file. Vertex Pharmaceuticals Incorporated. Boston, MA. REF-3497 (v1.0); 2019. 7. Quittner AL, Modi AC, Wainwright C, et al. Determination of the minimal clinically important difference scores for the Cystic Fibrosis Questionnaire-Revised respiratory symptom scale in two populations of patients with cystic fibrosis and chronic Pseudomonas aeruginosa airway infection. Chest. 2009;135(6):1610-1618. 8. CFQ-R Cystic Fibrosis Questionnaire-Revised. Cystic Fibrosis Foundation. Quittner, Modi, Watrous and Messer, 2000. Revised 2002. English version 2.0. 

     

    • Assessments of liver function tests (ALT, AST, and bilirubin) are recommended prior to initiating TRIKAFTA, every 3 months during the first year of treatment, and annually thereafter
    • In the event of significant elevations in liver function tests, e.g. ALT or AST >5x the upper limit of normal (ULN) or ALT or AST >3x ULN with bilirubin >2x ULN, dosing should be interrupted and laboratory tests closely followed until the abnormalities resolve. Following the resolution of liver function test elevations, consider the benefits and risks of resuming treatment
    • For patients with a history of hepatobiliary disease or liver function test elevations, more frequent monitoring should be considered

    Hypersensitivity Reactions, Including Anaphylaxis

    • Hypersensitivity reactions, including cases of angioedema and anaphylaxis, have been reported in the postmarketing setting. If signs or symptoms of serious hypersensitivity reactions develop during treatment, discontinue TRIKAFTA and institute appropriate therapy. Consider the benefits and risks for the individual patient to determine whether to resume treatment with TRIKAFTA

    Concomitant Use With CYP3A Inducers

    • Exposure to ivacaftor is significantly decreased and exposure to elexacaftor and tezacaftor are expected to decrease by the concomitant use of strong CYP3A inducers, which may reduce the therapeutic effectiveness of TRIKAFTA. Co‑administration with strong CYP3A inducers is not recommended

    Concomitant Use With CYP3A Inhibitors

    • Exposure to elexacaftor, tezacaftor, and ivacaftor are increased when co-administered with strong or moderate CYP3A inhibitors. The dose of TRIKAFTA should be reduced when used concomitantly with moderate or strong CYP3A inhibitors

    Cataracts

    • Cases of non-congenital lens opacities have been reported in pediatric patients treated with ivacaftor-containing regimens. Baseline and follow‑up ophthalmological examinations are recommended in pediatric patients initiating treatment with TRIKAFTA

    ADVERSE REACTIONS

    Serious Adverse Reactions

    • Serious adverse reactions that occurred more frequently in patients treated with TRIKAFTA compared to placebo were rash (1% vs <1%) and influenza (1% vs 0)

    Most Common Adverse Reactions

    • The most common adverse reactions occurring in ≥5% of patients treated with TRIKAFTA (N=202) and higher than placebo (N=201) by ≥1% in the 24-week placebo-controlled, parallel-group Phase 3 trial (Trial 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, and blood bilirubin increased
    • The safety profile for the patients with CF receiving TRIKAFTA (N=55) enrolled in the 4-week, randomized, double-blind, active-controlled Phase 3 trial (Trial 2) was similar to that observed in Trial 1
    • The safety profile in patients age 6 through 11 years from an open-label trial (Trial 3; N=66) was similar to that observed in Trial 1. The safety profile in patients age 2 through 5 years from an open-label trial (Trial 4; N=75) was similar to that observed in Trial 1

    USE IN SPECIFIC POPULATIONS

    Pediatric Use

    • The safety and effectiveness of TRIKAFTA in patients with CF younger than 2 years of age have not been established

    Click here to access full Prescribing Information for TRIKAFTA.

    References:
    1. TRIKAFTA [prescribing information]. Boston, MA: Vertex Pharmaceuticals Incorporated; August 2023. 2. Heijerman HG, McKone EF, Downey DG, et al. Efficacy and safety of the elexacaftor plus tezacaftor plus ivacaftor combination regimen in people with cystic fibrosis homozygous for the F508del mutation: a double-blind, randomised, phase 3 trial [published correction appears in Lancet. 2020;395(10238):1694]. Lancet. 2019;394(10212):1940-1948. doi:10.1016/S0140-6736(19)32597-8. 3. Data on file. Vertex Pharmaceuticals Incorporated. Boston, MA. REF-6056 (v1.0); 2020. 4. Heijerman HG, McKone EF, Downey DG, et al. Efficacy and safety of the elexacaftor plus tezacaftor plus ivacaftor combination regimen in people with cystic fibrosis homozygous for the F508del mutation: a double-blind, randomised, phase 3 trial. Lancet (suppl). 2019;394(10212):1940-1948. 5. Middleton PG, Mall MA, Drevinek P, et al. Elexacaftor–tezacaftor–ivacaftor for cystic fibrosis with a single Phe508del allele. N Engl J Med. 2019;381(19)(suppl):1809-1819. 6. Data on file. Vertex Pharmaceuticals Incorporated. Boston, MA. REF-3497 (v1.0); 2019. 7. Quittner AL, Modi AC, Wainwright C, et al. Determination of the minimal clinically important difference scores for the Cystic Fibrosis Questionnaire-Revised respiratory symptom scale in two populations of patients with cystic fibrosis and chronic Pseudomonas aeruginosa airway infection. Chest. 2009;135(6):1610-1618. 8. CFQ-R Cystic Fibrosis Questionnaire-Revised. Cystic Fibrosis Foundation. Quittner, Modi, Watrous and Messer, 2000. Revised 2002. English version 2.0.