2.1 Recommended Dosage in Adults and Pediatric Patients Aged 2 Years and Older

Recommended dosage for adult and pediatric patients aged 2 years and older is provided in Table 1. The morning and the evening dose should be taken approximately 12 hours apart. TRIKAFTA is for oral use.

2.2 Recommended Dosage for Patients with Hepatic Impairment

• 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 1 for recommended dosage of TRIKAFTA. Liver function tests should be closely monitored [see Warnings and Precautions (5.1) and Adverse Reactions (6)].
• 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 exceeds 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 Warnings and Precautions (5.1) and Adverse Reactions (6)]. Recommended dosage for patients with moderate hepatic impairment (Child-Pugh Class B) is provided in Table 2.

• 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)].

2.3 Dosage Modification for Patients Taking Drugs that are CYP3A Inhibitors

Table 3 describes the recommended dosage modification for TRIKAFTA when co-administered with strong (e.g., ketoconazole, itraconazole, posaconazole, voriconazole, telithromycin, and clarithromycin) or moderate (e.g., fluconazole, erythromycin) CYP3A inhibitors. Avoid food or drink containing grapefruit during TRIKAFTA treatment [see Warnings and Precautions (5.4), Drug Interactions (7.2) and Clinical Pharmacology (12.3)].

2.4 Recommendations Regarding Missed Dose(s)

If 6 hours or less have passed since the missed morning or evening dose, the patient should take the missed dose as soon as possible and continue on the original schedule.

If more than 6 hours have passed since:

• the missed morning dose, the patient should take the missed dose as soon as possible and should not take the evening dose. The next scheduled morning dose should be taken at the usual time.
• the missed evening dose, the patient should not take the missed dose. The next scheduled morning dose should be taken at the usual time.

Morning and evening doses should not be taken at the same time.

2.5 Administration Information

Administer TRIKAFTA tablets or oral granules with fat-containing food. Examples of meals or snacks that contain fat are those prepared with butter or oils or those containing eggs, peanut butter, cheeses, nuts, whole milk, or meats [see Clinical Pharmacology (12.3)].

Tablets:

Fixed-dose combination containing elexacaftor 50 mg, tezacaftor 25 mg, and ivacaftor 37.5 mg co-packaged with ivacaftor 75 mg:

• Elexacaftor, tezacaftor and ivacaftor tablets are light orange, capsule-shaped and debossed with "T50" on one side and plain on the other
• Ivacaftor tablets are light blue, capsule-shaped, and printed with "V 75" in black ink on one side and plain on the other

Fixed-dose combination containing elexacaftor 100 mg, tezacaftor 50 mg, and ivacaftor 75 mg co-packaged with ivacaftor 150 mg:

• Elexacaftor, tezacaftor and ivacaftor tablets are orange, capsule-shaped and debossed with "T100" on one side and plain on the other
• Ivacaftor tablets are light blue, capsule-shaped, and printed with "V 150" in black ink on one side and plain on the other

Oral Granules:

Fixed-dose combination oral granules containing elexacaftor 100 mg, tezacaftor 50 mg, and ivacaftor 75 mg co-packaged with ivacaftor 75 mg oral granules:

• Elexacaftor, tezacaftor, and ivacaftor oral granules are white to off-white, sweetened, unflavored granules approximately 2 mm in diameter contained in a white and orange unit-dose packet
• Ivacaftor oral granules are white to off-white, sweetened, unflavored granules approximately 2 mm in diameter contained in a white and pink unit-dose packet

Fixed-dose combination oral granules containing elexacaftor 80 mg, tezacaftor 40 mg, ivacaftor 60 mg co-packaged with ivacaftor 59.5 mg oral granules:

• Elexacaftor, tezacaftor, and ivacaftor oral granules are white to off-white, sweetened, unflavored granules approximately 2 mm in diameter contained in a white and blue unit-dose packet
• Ivacaftor oral granules are white to off-white, sweetened, unflavored granules approximately 2 mm in diameter contained in a white and green unit-dose packet

5.1 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 [see Dosage and Administration (2.2), Adverse Reactions (6), Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)].

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 for all patients 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 >5 × the upper limit of normal (ULN) or ALT or AST >3 × ULN with bilirubin >2 × 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 [see Dosage and Administration (2.2), Adverse Reactions (6), Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)].

5.2 Hypersensitivity Reactions, Including Anaphylaxis

Hypersensitivity reactions, including cases of angioedema and anaphylaxis, have been reported in the postmarketing setting [see Adverse Reactions (6.2)]. 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.

5.3 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. Therefore, co-administration with strong CYP3A inducers is not recommended [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)].

5.4 Concomitant Use with CYP3A Inhibitors

Exposure to elexacaftor, tezacaftor and ivacaftor are increased when co-administered 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 (2.3), Drug Interactions (7.2) and Clinical Pharmacology (12.3)].

5.5 Cataracts

Cases of non-congenital lens opacities have been reported in pediatric patients treated with ivacaftor-containing regimens. Although other risk factors were present in some cases (such as corticosteroid use, exposure to radiation), a possible risk attributable to treatment with ivacaftor cannot be excluded. Baseline and follow-up ophthalmological examinations are recommended in pediatric patients initiating treatment with TRIKAFTA [see Use in Specific Populations (8.4)].

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.

The safety profile of TRIKAFTA is based on data from 510 CF patients aged 12 years and older in two double-blind, controlled trials of 24 weeks and 4 weeks treatment duration (Trials 1 and 2). 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 addition, the following clinical trials have also been conducted [see Use in Specific Populations (8.4) and Clinical Pharmacology (12.3)]:

• 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).

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 in Trials 1, 2, 3 and 4.

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).

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.

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

6.2 Postmarketing Experience

The following adverse reactions have been identified during post approval 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.

7.1 Inducers of CYP3A

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. Co-administration 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 co-administration with strong CYP3A inducers. Therefore, co-administration of TRIKAFTA with strong CYP3A inducers is not recommended [see Warnings and Precautions (5.3) and Clinical Pharmacology (12.3)].

Examples of strong CYP3A inducers include:

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

7.2 Inhibitors of CYP3A

Co-administration with itraconazole, a strong CYP3A inhibitor, increased elexacaftor AUC by 2.8-fold and tezacaftor AUC by 4.0- to 4.5-fold. When co-administered with itraconazole and ketoconazole, ivacaftor AUC increased by 15.6-fold and 8.5-fold, respectively. The dosage of TRIKAFTA should be reduced when co-administered with strong CYP3A inhibitors [see Dosage and Administration (2.3), Warnings and Precautions (5.4) and Clinical Pharmacology (12.3)].

Examples of strong CYP3A inhibitors include:

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

Simulations indicated that co-administration with moderate CYP3A inhibitors may increase elexacaftor and tezacaftor AUC by approximately 1.9- to 2.3-fold and 2.1-fold, respectively. Co-administration of fluconazole increased ivacaftor AUC by 2.9-fold. The dosage of TRIKAFTA should be reduced when co-administered with moderate CYP3A inhibitors [see Dosage and Administration (2.3), Warnings and Precautions (5.4) and Clinical Pharmacology (12.3)].

Examples of moderate CYP3A inhibitors include:

• fluconazole
• erythromycin

Co-administration 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 (2.3)].

7.3 Ciprofloxacin

Ciprofloxacin had no clinically relevant effect on the exposure of tezacaftor or ivacaftor and is not expected to affect the exposure of elexacaftor. Therefore, no dose adjustment is necessary during concomitant administration of TRIKAFTA with ciprofloxacin [see Clinical Pharmacology (12.3)].

Potential for elexacaftor/tezacaftor/ivacaftor to affect other drugs

7.4 CYP2C9 Substrates

Ivacaftor may inhibit CYP2C9; therefore, monitoring of the international normalized ratio (INR) during co-administration of TRIKAFTA with warfarin is recommended. Other medicinal products for which exposure may be increased by TRIKAFTA include glimepiride and glipizide; these medicinal products should be used with caution [see Clinical Pharmacology (12.3)].

7.5 Transporters

Co-administration of ivacaftor or tezacaftor/ivacaftor with digoxin, a sensitive P-gp substrate, increased digoxin AUC by 1.3-fold, consistent with weak inhibition of P-gp by ivacaftor. Administration of TRIKAFTA may increase systemic exposure of medicinal products that are sensitive substrates of P-gp, which may increase or prolong their therapeutic effect and adverse reactions. When used concomitantly with digoxin or other substrates of P-gp with a narrow therapeutic index such as cyclosporine, everolimus, sirolimus and tacrolimus, caution and appropriate monitoring should be used [see Clinical Pharmacology (12.3)].

Elexacaftor and M23-ELX inhibit uptake by OATP1B1 and OATP1B3 in vitro. Co-administration of TRIKAFTA may increase exposures of medicinal products that are substrates of these transporters, such as statins, glyburide, nateglinide and repaglinide. When used concomitantly with substrates of OATP1B1 or OATP1B3, caution and appropriate monitoring should be used [see Clinical Pharmacology (12.3)]. Bilirubin is an OATP1B1 and OATP1B3 substrate.

7.6 Hormonal Contraceptives

TRIKAFTA has been studied with ethinyl estradiol/levonorgestrel and was found to have no clinically relevant effect on the exposures of the oral contraceptive. TRIKAFTA is not expected to have an impact on the efficacy of oral contraceptives.

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

The safety and effectiveness of TRIKAFTA for the treatment of CF have been established in pediatric patients aged 2 to less than 18 years who have at least one F508del mutation in the CFTR gene or a mutation in the CFTR gene that is responsive based on in vitro data. Use of TRIKAFTA for this indication for pediatric patients 12 years of age and older was supported by evidence from two adequate and well-controlled studies (Trials 1 and 2) in CF patients aged 12 years and older [see Adverse Reactions (6.1) and Clinical Studies (14)].

Use of TRIFAFTA for this indication in pediatric patients 2 to less than 12 years of age is based on the following:

• Trial 1, 56 pediatric patients aged 12 to less than 18 years who had an F508del mutation on one allele 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 [see Adverse Reactions (6) and Clinical Studies (14)].
• Trial 2, 16 pediatric patients aged 12 to less than 18 years who were homozygous for the F508del mutation [see Adverse Reactions (6) and Clinical Studies (14)].
• Trial 3, 66 pediatric patients aged 6 to less than 12 years who were homozygous for the F508del mutation or heterozygous for the F508del mutation with 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 [see Adverse Reactions (6) and Clinical Pharmacology (12.3)].
• Trial 4, 75 pediatric patients aged 2 to less than 6 years who had at least one F508del mutation or a mutation known to be responsive to TRIKAFTA [see Adverse Reactions (6) and Clinical Pharmacology (12.3)].

The effectiveness of TRIKAFTA in patients aged 2 to less than 12 years was extrapolated from patients aged 12 years and older with support from population pharmacokinetic analyses showing elexacaftor, tezacaftor, and ivacaftor exposure levels in patients aged 2 to less than 12 years within the range of exposures observed in patients aged 12 years and older [see Clinical Pharmacology (12.3)]. Safety of TRIKAFTA in patients aged 6 to less than 12 years was derived from a 24-week, open-label, clinical trial in 66 patients aged 6 to less than 12 years (mean age at baseline 9.3 years) administered either a total dose of elexacaftor 100 mg/tezacaftor 50 mg/ivacaftor 75 mg in the morning and ivacaftor 75 mg in the evening (for patients weighing less than 30 kg) or a total dose of elexacaftor 200 mg/tezacaftor 100 mg/ivacaftor 150 mg in the morning and ivacaftor 150 mg in the evening (for patients weighing 30 kg or more) (Trial 3). Safety of TRIKAFTA in patients aged 2 to less than 6 years was derived from a 24-week, open-label, clinical trial in 75 patients aged 2 to less than 6 years (mean age at baseline 4.1 years) administered either a total dose of elexacaftor 80 mg/tezacaftor 40 mg/ivacaftor 60 mg in the morning and ivacaftor 59.5 mg in the evening (for patients weighing 10 kg to less than 14 kg) or a total dose of elexacaftor 100 mg/tezacaftor 50 mg/ivacaftor 75 mg in the morning and ivacaftor 75 mg in the evening (for patients weighing 14 kg or more) (Trial 4). The safety profile of patients in these trials was similar to that observed in Trial 1 [see Adverse Reactions (6)].

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

8.5 Geriatric Use

Clinical studies of TRIKAFTA did not include any patients aged 65 years and older.

8.6 Renal Impairment

TRIKAFTA has not been studied in patients with severe renal impairment or end-stage renal disease. No dosage adjustment is recommended in patients with mild (eGFR 60 to <90 mL/min/1.73 m2) or moderate (eGFR 30 to <60 mL/min/1.73 m2) renal impairment. Use with caution in patients with severe (eGFR <30 mL/min/1.73 m2) renal impairment or end-stage renal disease [see Clinical Pharmacology (12.3)].

8.7 Hepatic Impairment

• Mild Hepatic Impairment (Child-Pugh Class A): No dose modification is recommended. Liver function tests should be closely monitored.
• 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 exceeds the risk. If used in patients with moderate hepatic impairment, TRIKAFTA should be used at a reduced dose [see Dosage and Administration (2.2)]. Liver function tests should be closely monitored.
  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)].
• 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 (2.2), Warnings and Precautions (5.1), Adverse Reactions (6) and Clinical Pharmacology (12.3)].

8.8 Patients with Severe Lung Dysfunction

Trial 1 included a total of 18 patients receiving TRIKAFTA with ppFEV1 <40 at baseline. The safety and efficacy in this subgroup were comparable to those observed in the overall population.

Elexacaftor

Elexacaftor is a white solid that is practically insoluble in water (<1 mg/mL). Its chemical name is N-(1,3-dimethyl-1H-pyrazole-4-sulfonyl)-6-[3-(3,3,3-trifluoro-2,2-dimethylpropoxy)-1H-pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide. Its molecular formula is C26H34N7O4SF3 and its molecular weight is 597.66. Elexacaftor has the following structural formula:

Tezacaftor

Tezacaftor is a white to off-white solid that is practically insoluble in water (<5 microgram/mL). Its chemical name is 1-(2,2-difluoro-2H-1,3-benzodioxol-5-yl)-N-{1-[(2R)-2,3-dihydroxypropyl]-6-fluoro-2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl}cyclopropane-1-carboxamide. Its molecular formula is C26H27N2F3O6 and its molecular weight is 520.50. Tezacaftor has the following structural formula:

Ivacaftor

Ivacaftor is a white to off-white crystalline solid that is practically insoluble in water (<0.05 microgram/mL). Pharmacologically it is a CFTR potentiator. Its chemical name is N-(2,4-di-tert-butyl-5-hydroxyphenyl)-1,4-dihydro-4-oxoquinoline-3-carboxamide. Its molecular formula is C24H28N2O3 and its molecular weight is 392.49. Ivacaftor has the following structural formula:

12.1 Mechanism of Action

Elexacaftor and tezacaftor bind to different sites on the CFTR protein and have an additive effect in facilitating the cellular processing and trafficking of select mutant forms of CFTR (including F508del-CFTR) to increase the amount of CFTR protein delivered to the cell surface compared to either molecule alone. Ivacaftor potentiates the channel open probability (or gating) of the CFTR protein at the cell surface.

The combined effect of elexacaftor, tezacaftor and ivacaftor is increased quantity and function of CFTR at the cell surface, resulting in increased CFTR activity as measured by CFTR mediated chloride transport.

12.2 Pharmacodynamics

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 6.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No studies of carcinogenicity, mutagenicity, or impairment of fertility were conducted with the combination of elexacaftor, tezacaftor and ivacaftor; however, separate studies of elexacaftor, tezacaftor and ivacaftor are described below.

Efficacy:

The efficacy of TRIKAFTA in patients with CF aged 12 years and older was evaluated in two double-blind, controlled trials (Trials 1 and 2).

Trial 1 was a 24-week, randomized, double-blind, placebo-controlled study in patients who had an F508del mutation on one allele 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. An interim analysis was planned when at least 140 patients completed Week 4 and at least 100 patients completed Week 12.

Trial 2 was a 4-week, randomized, double-blind, active-controlled study in patients who are homozygous for the F508del mutation. Patients received tezacaftor 100 mg qd/ivacaftor 150 mg q12h during a 4-week, open-label run-in period and were then randomized and dosed to receive TRIKAFTA or tezacaftor 100 mg qd/ivacaftor 150 mg q12h during a 4-week, double-blind treatment period.

Patients in Trials 1 and 2 had a confirmed diagnosis of CF and at least one F508del mutation. Patients discontinued any previous CFTR modulator therapies, but continued on their other standard-of-care CF therapies (e.g., bronchodilators, inhaled antibiotics, dornase alfa and hypertonic saline). Patients had a ppFEV1 at screening between 40-90%. Patients with a history of colonization with organisms associated with a more rapid decline in pulmonary status, including but not limited to Burkholderia cenocepacia, Burkholderia dolosa, or Mycobacterium abscessus, or who had an abnormal liver function test at screening (ALT, AST, ALP, or GGT ≥3 × ULN, or total bilirubin ≥2 × ULN), were excluded from the trials. Patients in Trials 1 and 2 were eligible to roll over into a 96-week, open-label extension study.

14.1 Trial 1

Trial 1 evaluated 403 patients (200 TRIKAFTA, 203 placebo) with CF aged 12 years and older (mean age 26.2 years). The mean ppFEV1 at baseline was 61.4% (range: 32.3%, 97.1%). The primary endpoint assessed at the time of interim analysis was mean absolute change in ppFEV1 from baseline at Week 4. The final analysis tested all key secondary endpoints in the 403 patients who completed the 24-week study participation, including absolute change in ppFEV1 from baseline through Week 24; absolute change in sweat chloride from baseline at Week 4 and through Week 24; number of pulmonary exacerbations through Week 24; absolute change in BMI from baseline at Week 24, and absolute change in CFQ-R Respiratory Domain Score (a measure of respiratory symptoms relevant to patients with CF, such as cough, sputum production and difficulty breathing) from baseline at Week 4 and through Week 24.

Of the 403 patients included in the interim analysis, the treatment difference between TRIKAFTA and placebo for the mean absolute change from baseline in ppFEV1 at Week 4 was 13.8 percentage points (95% CI: 12.1, 15.4; P<0.0001).

The treatment difference between TRIKAFTA and placebo for mean absolute change in ppFEV1 from baseline through Week 24 was 14.3 percentage points (95% CI: 12.7, 15.8; P<0.0001). Mean improvement in ppFEV1 was observed at the first assessment on Day 15 and sustained through the 24-week treatment period (see Figure 1). Improvements in ppFEV1 were observed regardless of age, baseline ppFEV1, sex and geographic region. See Table 10 for a summary of primary and key secondary outcomes in Trial 1.

Figure 1: Absolute Change from Baseline in Percent Predicted FEV1 at Each Visit in Trial 1

14.2 Trial 2

Trial 2 evaluated 107 patients with CF aged 12 years and older (mean age 28.4 years). The mean ppFEV1 at baseline, following the 4-week, open-label run-in period with tezacaftor/ivacaftor was 60.9% (range: 35.0%, 89.0%). The primary endpoint was mean absolute change in ppFEV1 from baseline at Week 4 of the double-blind treatment period. The key secondary efficacy endpoints were absolute change in sweat chloride and CFQ-R Respiratory Domain Score from baseline at Week 4. Treatment with TRIKAFTA compared to tezacaftor/ivacaftor resulted in a statistically significant improvement in ppFEV1 of 10.0 percentage points (95% CI: 7.4, 12.6; P<0.0001). Mean improvement in ppFEV1 was observed at the first assessment on Day 15. Improvements in ppFEV1 were observed regardless of age, sex, baseline ppFEV1 and geographic region. See Table 11 for a summary of primary and key secondary outcomes.

Store at 20°C - 25°C (68°F - 77°F); excursions permitted to 15°C - 30°C (59°F - 86°F) [see USP Controlled Room Temperature].

Elevated Transaminases and Hepatic Injury

Inform the patients that liver failure leading to transplantation has been reported in a patient with cirrhosis with portal hypertension while receiving TRIKAFTA. Avoid use of TRIKAFTA in patients with pre-existing advanced liver disease (e.g., 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 [see Dosage and Administration (2.2), Warnings and Precautions (5.1), Adverse Reactions (6), Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)].

Inform patients that isolated elevation of transaminases or bilirubin have occurred in patients treated with TRIKAFTA. In some instances, transaminase elevations have been associated with concomitant elevations in total bilirubin and/or INR and have resulted in patients being hospitalized for intervention, including in patients without a history of pre-existing liver disease. Liver function tests (ALT, AST and bilirubin) should be assessed prior to initiating TRIKAFTA, every 3 months during the first year of treatment, and annually thereafter. More frequent monitoring should be considered in patients with a history of hepatobiliary disease or liver function test elevations [see Dosage and Administration (2.2), Warnings and Precautions (5.1), Adverse Reactions (6), Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)].

Drug Interactions with CYP3A Inducers and Inhibitors

Ask patients to tell you all the medications they are taking including any herbal supplements or vitamins. Co-administration of TRIKAFTA with strong CYP3A inducers (e.g., rifampin, St. John's wort) is not recommended, as they may reduce the efficacy of TRIKAFTA. Dose reduction to two elexacaftor/tezacaftor/ivacaftor tablets or one elexacaftor/tezacaftor/ivacaftor oral granules packet twice a week, taken approximately 3 to 4 days apart is recommended when co-administered with strong CYP3A inhibitors, such as ketoconazole. Advise the patient not to take the evening dose of ivacaftor. Dose reduction to two elexacaftor/tezacaftor/ivacaftor tablets or one elexacaftor/tezacaftor/ivacaftor oral granules packet and one ivacaftor tablet or ivacaftor oral granules packet, taken on alternate days, is recommended when co-administered with moderate CYP3A inhibitors, such as fluconazole. Advise the patient not to take the evening dose of ivacaftor. Food or drink containing grapefruit should be avoided [see Dosage and Administration (2.3), Warnings and Precautions (5), Drug Interactions (7) and Clinical Pharmacology (12.3)].

Use in Patients with Hepatic Impairment

No dose adjustment is recommended for patients with mild hepatic impairment (Child-Pugh Class A, score 5-6). See Table 2. Liver function tests should be closely monitored.

Treatment is not recommended for patients with moderate hepatic impairment (Child-Pugh Class B, score 7-9). Use of TRIKAFTA in patients with moderate hepatic impairment should only be considered when there is a clear medical need, and the benefit exceeds the risk. If used in patients with moderate hepatic impairment, TRIKAFTA should be used with caution at a reduced dose (see Table 2). Liver function tests should be closely monitored.

TRIKAFTA has not been studied in patients with severe hepatic impairment (Child-Pugh Class C, score 10-15), but the exposure is expected to be higher than in patients with moderate hepatic impairment. TRIKAFTA should not be used in patients with severe hepatic impairment. Inquire and/or assess whether patients have liver impairment [see Dosage and Administration (2.2), Warnings and Precautions (5.1), Adverse Reactions (6), Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)].

Hypersensitivity Reactions, Including Anaphylaxis

Hypersensitivity reactions including angioedema and anaphylaxis are possible with use of TRIKAFTA. Inform patients of the early signs of hypersensitivity reactions including rash, hives, itching, facial swelling, tightness of the chest and wheezing. Advise patients to discontinue use of TRIKAFTA immediately and contact their physician or go to the emergency department if these symptoms occur.

Cataracts

Inform patients that abnormality of the eye lens (cataract) has been noted in some children and adolescents receiving ivacaftor-containing regimens. Baseline and follow-up ophthalmological examinations should be performed in pediatric patients initiating treatment with TRIKAFTA [see Warnings and Precautions (5.5) and Use in Specific Populations (8.4)].

Administration

Inform patients that TRIKAFTA is best absorbed by the body when taken with food that contains fat. A typical CF diet will satisfy this requirement. Examples include eggs, butter, peanut butter, whole-milk dairy products (such as whole milk, cheese and yogurt), etc. [see Dosage and Administration (2.5) and Clinical Pharmacology (12.3)].

Patients should be informed about what to do in the event they miss a dose [see Dosage and Administration (2.4)] of TRIKAFTA:

• If 6 hours or less have passed since the missed morning or evening dose is usually taken, patients should be instructed to take the prescribed dose with fat-containing food as soon as possible.
• If more than 6 hours have passed since:
  • the time the morning dose is usually taken, patients should be instructed to take the morning dose as soon as possible, and not take the evening dose. Patients should take the next scheduled morning dose at the usual time.
  • the time the evening dose is usually taken, patients should be instructed to not take the missed evening dose. Patients should take the next scheduled morning dose at the usual time.
• Patients should be instructed to not take the morning and evening doses at the same time.
• Patients should be advised to contact their health care provider if they have questions.