1 INDICATIONS AND USAGE TRIKAFTA is indicated for the treatment of cystic fibrosis (CF) in adult and pediatric patients aged 2 years and older who have a clinical diagnosis of CF and who have at least one variant in the cystic fibrosis transmembrane conductance regulator ( CFTR ) gene that is either responsive based on clinical and/or in vitro data (see Table 6 ) or results in production of CFTR protein [see Clinical Pharmacology (12.1) ] .

If the patient's genotype is unknown, an FDA-cleared CF genetic test should be used to confirm the presence of at least one variant in the CFTR gene that is either responsive based on clinical and/or in vitro data or results in production of CFTR protein.

TRIKAFTA is a combination of ivacaftor, a CFTR potentiator, tezacaftor, and elexacaftor indicated for the treatment of cystic fibrosis (CF) in adult and pediatric patients aged 2 years and older who have a clinical diagnosis of CF and who have at least one variant in the CFTR gene that is either responsive based on clinical and/or in vitro data or results in production of CFTR protein.

( 1 , 12.1 ) If the patient's genotype is unknown, an FDA-cleared CF genetic test should be used to confirm the presence of at least one variant in the CFTR gene that is either responsive based on clinical and/or in vitro data or results in production of CFTR protein.

( 1 )

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) ] Neuropsychiatric Events, Including Suicidal Thoughts and Behaviors [see Warnings and Precautions (5.4) ] Cataracts [see Warnings and Precautions (5.7) ] 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.

( 6.1 ) 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 Variant The safety profile of TRIKAFTA in patients with CF with at least one F508del variant 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 infection Includes upper respiratory tract infection and viral upper respiratory tract infection.

32 (16) 25 (12) Abdominal pain Includes abdominal pain, abdominal pain upper, abdominal pain lower.

29 (14) 18 (9) Diarrhea 26 (13) 14 (7) Rash Includes 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 variant or heterozygous for the F508del variant, and a variant 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 variant or a variant 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 Variant The safety of TRIKAFTA in patients with CF with at least one non- F508del variant is based on data from 307 patients aged 6 years and older with at least one qualifying non- F508del CFTR variant 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 (%) Rash Includes 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 FEV 1 (ppFEV 1 ) and geographic regions.

6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of TRIKAFTA or drugs containing the same or similar active ingredients as 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 Psychiatric Disorders : anxiety, depression, suicidal ideation and behavior, insomnia