Trikafta Kit
FDA Label NDC 51167-446

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), Warnings and Precautions (5.1), Adverse Reactions (6) and Use in Specific Populations (8.7)].

Interrupt TRIKAFTA for significant elevations in liver function tests or in the event of signs or symptoms of liver injury. Consider referral to a hepatologist. Follow patients closely with clinical and laboratory monitoring until abnormalities resolve. If abnormalities resolve, resume treatment only if the benefit is expected to outweigh the risk. Closer monitoring is advised after resuming TRIKAFTA [see Warnings and Precautions (5.1)].

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). If used, use with caution at a reduced dosage and monitor patients closely [see Dosage and Administration (2.3), Warnings and Precautions (5.1), Adverse Reactions (6), Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)].

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.

Prior to initiating TRIKAFTA, obtain liver function tests (ALT, AST, alkaline phosphatase, and bilirubin) for all patients. Monitor 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 Warnings and Precautions (5.1) and Use in Specific Populations (8.7)].

Recommended dosage for adult and pediatric patients aged 2 years and older is provided in Table 1. Administer TRIKAFTA tablets (swallow the tablets whole) or oral granules orally with fat-containing food, in the morning and in the evening approximately 12 hours apart. 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)].

Administer each dose of TRIKAFTA oral granules immediately before or after ingestion of fat-containing food. Mix entire contents of each packet of oral granules with one teaspoon (5 mL) of age-appropriate soft food or liquid that is at or below room temperature. Some examples of soft food or liquids include pureed fruits or vegetables, yogurt, applesauce, water, milk, or juice. Once mixed, the product should be consumed completely within one hour.

• 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 of 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 of 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 1 for recommended dosage of TRIKAFTA. Liver function tests should be closely monitored [see Dosage and Administration (2.1) and Warnings and Precautions (5.1)].

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 (5.6), Drug Interactions (7.1) and Clinical Pharmacology (12.3)].

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.

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, oblong-shaped and debossed with "T50" on one side and plain on the other
• Ivacaftor tablets are light blue, oblong-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, oblong-shaped and debossed with "T100" on one side and plain on the other
• Ivacaftor tablets are light blue, oblong-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, and 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

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 FEV₁ (ppFEV₁) and geographic regions.

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

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 (5.5)]. 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 (5.6)]. 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 (5.6)]. 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)].

CYP2C9 Substrates

Ivacaftor may inhibit CYP2C9; therefore, monitoring of the international normalized ratio (INR) during concomitant use 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)].

Transporters

Concomitant use 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. Concomitant use 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.

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)].

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.

Hormonal contraceptives may play a role in the occurrence of rash and cannot be excluded [see Adverse Reactions (6.1)]. For patients with CF taking hormonal contraceptives who develop rash, consider interrupting TRIKAFTA and hormonal contraceptives. Following the resolution of rash, consider resuming TRIKAFTA without the hormonal contraceptives. If rash does not recur, resumption of hormonal contraceptives can be considered.

Risk Summary

There are limited and incomplete human data from clinical trials on the use of TRIKAFTA or its individual components, elexacaftor, tezacaftor and ivacaftor, in pregnant women to inform a drug-associated risk. Although there are no animal reproduction studies with the concomitant administration of elexacaftor, tezacaftor and ivacaftor, separate reproductive and developmental studies were conducted with each active component of TRIKAFTA in pregnant rats and rabbits.

In animal embryo fetal development (EFD) studies oral administration of elexacaftor to pregnant rats and rabbits during organogenesis demonstrated no adverse developmental effects at doses that produced maternal exposures up to approximately 2 times the exposure at the maximum recommended human dose (MRHD) in rats and 4 times the MRHD in rabbits [based on summed AUCs of elexacaftor and its metabolite (for rat) and AUC of elexacaftor (for rabbit)]. Oral administration of tezacaftor to pregnant rats and rabbits during organogenesis demonstrated no adverse developmental effects at doses that produced maternal exposures up to approximately 3 times the exposure at the MRHD in rats and 0.2 times the MRHD in rabbits (based on summed AUCs of tezacaftor and M1-TEZ). Oral administration of ivacaftor to pregnant rats and rabbits during organogenesis demonstrated no adverse developmental effects at doses that produced maternal exposures up to approximately 5 and 14 times the exposure at the MRHD, respectively [based on summed AUCs of ivacaftor and its metabolites (for rat) and AUC of ivacaftor (for rabbit)]. No adverse developmental effects were observed after oral administration of elexacaftor, tezacaftor or ivacaftor to pregnant rats from the period of organogenesis through lactation at doses that produced maternal exposures approximately 1 time, approximately 1 time and 3 times the exposures at the MRHD, respectively [based on summed AUCs of parent and metabolite(s)] (see Data).

The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data

Animal Data

Elexacaftor

In an EFD study, pregnant rats were administered oral doses of elexacaftor at 15, 25, and 40 mg/kg/day during the period of organogenesis from gestation Days 6-17. Elexacaftor did not cause adverse developmental outcomes at exposures up to 9 times the MRHD (based on summed AUCs for elexacaftor and its metabolite at maternal doses up to 40 mg/kg/day). Lower mean fetal body weights were observed at doses ≥25 mg/kg/day that produced maternal exposures ≥4 times the MRHD. Maternal toxicity was observed at 40 mg/kg/day (9 times the MRHD). In an EFD study, pregnant rabbits were administered oral doses of elexacaftor at 50, 100, or 125 mg/kg/day during the period of organogenesis from gestation Days 7-20. Elexacaftor was not teratogenic at exposures up to 4 times the MRHD (based on AUC of elexacaftor at maternal doses up to 125 mg/kg/day). Maternal toxicity was observed at 125 mg/kg/day (4 times the MRHD). In a pre- and postnatal development (PPND), pregnant rats were administered elexacaftor at oral doses of 5, 7.5, and 10 mg/kg/day from gestation Day 6 through lactation Day 18. Elexacaftor did not cause adverse developmental outcomes in pups at maternal doses up to 10 mg/kg/day (approximately 1 time the MRHD based on summed AUCs of elexacaftor and its metabolite). Placental transfer of elexacaftor was observed in pregnant rats.

Tezacaftor

In an EFD study, pregnant rats were administered tezacaftor at oral doses of 25, 50, or 100 mg/kg/day during the period of organogenesis from gestation Days 6-17. Tezacaftor did not cause adverse developmental effects at exposures up to 3 times the MRHD (based on summed AUCs of tezacaftor and M1-TEZ). Maternal toxicity in rats was observed at greater than or equal to 50 mg/kg/day (approximately greater than or equal to 1 time the MRHD). In an EFD study, pregnant rabbits were administered tezacaftor at oral doses of 10, 25, or 50 mg/kg/day during the period of organogenesis from gestation Days 7-20. Tezacaftor did not affect fetal developmental outcomes at exposures up to 0.2 times the MRHD (based on summed AUCs of tezacaftor and M1-TEZ). Lower fetal body weights were observed in rabbits at a maternally toxic dose that produced exposures approximately 1 time the MRHD (based on summed AUCs of tezacaftor and M1-TEZ at a maternal dose of 50 mg/kg/day). In a PPND study, pregnant rats were administered tezacaftor at oral doses of 25, 50, or 100 mg/kg/day from gestation Day 6 through lactation Day 18. Tezacaftor had no adverse developmental effects on pups at an exposure of approximately 1 time the MRHD (based on summed AUCs for tezacaftor and M1-TEZ at a maternal dose of 25 mg/kg/day). Decreased fetal body weights and early developmental delays in pinna detachment, eye opening, and righting reflex occurred at a maternally toxic dose (based on maternal weight loss) that produced exposures approximately 2 times the exposure at the MRHD (based on summed AUCs for tezacaftor and M1-TEZ). Placental transfer of tezacaftor was observed in pregnant rats.

Ivacaftor

In an EFD study, pregnant rats were administered ivacaftor at oral doses of 50, 100, or 200 mg/kg/day during the period of organogenesis from gestation Days 7-17. Ivacaftor did not affect fetal survival at exposures up to 5 times the MRHD (based on summed AUCs of ivacaftor and its metabolites at maternal oral doses up to 200 mg/kg/day). Maternal toxicity was observed at 100 and 200 mg/kg/day (3 and 5 times the exposure at the MRHD) and was associated with a decrease in fetal body weights at a maternal dose of 200 mg/kg/day (5 times the MRHD). In an EFD study, pregnant rabbits were administered ivacaftor at oral doses of 25, 50, or 100 mg/kg/day during the period of organogenesis from gestation Days 7-19. Ivacaftor did not affect fetal development or survival at exposures up to 14 times the MRHD (on an ivacaftor AUC basis at maternal oral doses up to 100 mg/kg/day). Maternal toxicity (i.e., death, decreased food consumption, decreased mean body weight and body weight gain, decreased clinical condition, abortions) was observed at doses greater than or equal to 50 mg/kg/day (approximately 5 times the MRHD). In a PPND study, pregnant rats were administered ivacaftor at oral doses of 50, 100, or 200 mg/kg/day from gestation Day 7 through lactation Day 20. Ivacaftor had no effects on delivery or growth and development of offspring at exposures up to 3 times the MRHD (based on summed AUCs for ivacaftor and its metabolites at maternal oral doses up to 100 mg/kg/day). Decreased fetal body weights were observed at a maternally toxic dose that produced exposures 5 times the MRHD (based on summed AUCs of ivacaftor and its metabolites). Placental transfer of ivacaftor was observed in pregnant rats and rabbits.

Risk Summary

There is no information regarding the presence of elexacaftor, tezacaftor, or ivacaftor in human milk, the effects on the breastfed infant, or the effects on milk production. Elexacaftor, tezacaftor, and ivacaftor are excreted into the milk of lactating rats (see Data). The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for TRIKAFTA and any potential adverse effects on the breastfed child from TRIKAFTA or from the underlying maternal condition.

Data

Elexacaftor: Lacteal excretion of elexacaftor in rats was demonstrated following a single oral dose (10 mg/kg) of ¹⁴C-elexacaftor administered 6 to 10 days postpartum to lactating dams. Exposure of ¹⁴C-elexacaftor in milk was approximately 0.4 times the value observed in plasma (based on AUC_0-72h).

Tezacaftor: Lacteal excretion of tezacaftor in rats was demonstrated following a single oral dose (30 mg/kg) of ¹⁴C-tezacaftor administered 6 to 10 days postpartum to lactating dams. Exposure of ¹⁴C-tezacaftor in milk was approximately 3 times higher than in plasma (based on AUC_0-72h).

Ivacaftor: Lacteal excretion of ivacaftor in rats was demonstrated following a single oral dose (100 mg/kg) of ¹⁴C-ivacaftor administered 9 to 10 days postpartum to lactating dams. Exposure of ¹⁴C-ivacaftor in milk was approximately 1.5 times higher than in plasma (based on AUC_0-24h).

Juvenile Animal Toxicity Data

Findings of cataracts were observed in juvenile rats dosed from postnatal Day 7 through 35 with ivacaftor dose levels of 10 mg/kg/day and higher (0.21 times the MRHD based on systemic exposure of ivacaftor and its metabolites). This finding has not been observed in older animals [see Warnings and Precautions (5.7)].

Studies were conducted with tezacaftor in juvenile rats starting at postnatal day (PND) 21 and ranging up to PNDs 35 to 49. Findings of convulsions and death were observed in juvenile rats that received a tezacaftor dose level of 100 mg/kg/day (approximately equivalent to 1.9 times the MRHD based on summed AUCs of tezacaftor and its metabolite, M1-TEZ). A no-effect dose level was identified at 30 mg/kg/day (approximately equivalent to 0.8 times the MRHD based on summed AUCs of tezacaftor and its metabolite, M1-TEZ). Findings were dose related and generally more severe when dosing with tezacaftor was initiated earlier in the postnatal period (PND 7, which would be approximately equivalent to a human neonate). Tezacaftor and its metabolite, M1-TEZ, are substrates for P-glycoprotein. Lower brain levels of P-glycoprotein activity in younger rats resulted in higher brain levels of tezacaftor and M1-TEZ. These findings are not relevant for the indicated pediatric population, 2 years of age and older, for whom levels of P-glycoprotein activity are equivalent to levels observed in adults.

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:

Chemical Structure (Trikafta 01)

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:

Chemical Structure (Trikafta 02)

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:

Chemical Structure (Trikafta 03)

CFTR Chloride Transport Assay in Fischer Rat Thyroid Cells Expressing Mutant CFTR Protein

Effects of elexacaftor/tezacaftor/ivacaftor on chloride transport for mutant CFTR proteins was determined in Ussing chamber electrophysiology studies using a panel of Fischer Rat Thyroid (FRT) cell lines stably expressing individual mutant CFTR protein. Elexacaftor/tezacaftor/ivacaftor increased chloride transport in FRT cells expressing CFTR variants, as identified in Table 6.

The threshold that the treatment-induced increase in chloride transport must exceed for the mutant CFTR protein to be considered responsive is ≥10% of normal over baseline. This threshold was used because it is expected to predict clinical benefit. For individual variants, the magnitude of the net change over baseline in CFTR-mediated chloride transport in vitro is not correlated with the magnitude of clinical response.

CFTR Chloride Transport Assay in Human Bronchial Epithelial Cells Expressing Mutant CFTR Protein

Homozygous and heterozygous N1303K-Human Bronchial Epithelial (HBE) cells showed greater chloride transport in the presence of elexacaftor/tezacaftor/ivacaftor than F508del/F508del-HBE cells treated with tezacaftor/ivacaftor (which has shown clinical benefit in people homozygous for F508del).

Patient Selection

Select adult and pediatric patients 2 years of age and older for the treatment of CF with TRIKAFTA based on a clinical diagnosis of CF and 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 [see Indications and Usage (1)].

TRIKAFTA should only be used in patients with a clinical diagnosis of CF. The presence of eligible CFTR variant(s) should not be the sole determinant for using TRIKAFTA.

Table 6 lists CFTR variants responsive to TRIKAFTA based on clinical and/or in vitro data in FRT or HBE cells [see Clinical Studies (14)].

Table 6: List of CFTR Gene Variants Responsive to TRIKAFTA

The list of responsive CFTR variants is non-exhaustive. There may be protein-producing CFTR variants not listed that respond to treatment with TRIKAFTA.
Variants responsive to TRIKAFTA based on clinical data Clinical data obtained from Trials 1, 2, and 5.
2789+5G→A	D1152H This variant is also predicted to be responsive by FRT assay.	L206W	R1066H	S945L
3272-26A→G	F508del	L997F	R117C	T338I
3849+10kbC→T	G85E	M1101K	R347H	V232D
A455E	L1077P	P5L	R347P
Variants responsive to TRIKAFTA based on in vitro data The N1303K variant is predicted to be responsive by HBE assay. All other variants predicted to be responsive with in vitro data are supported by FRT assay.
1140-1151dup	E264V	H620P	N396Y	S1251N
1461insGAT	E282D	H620Q	N418S	S1255P
1507_1515del9	E292K	H939R	N900K	S13F
2055del9	E384K	H939R;H949L	P1013H	S13P
2183A→G	E403D	H954P	P1013L	S158N
2851A/G	E474K	I1023R	P1021L	S182R
293A→G	E527G	I1027T	P1021T	S18I
3007del6	E56K	I105N	P111L	S18N
3132T→G	E588V	I1139V	P1372T	S308P
3141del9	E60K	I1203V	P140S	S341P
3143del9	E822K	I1234L	P205S	S364P
314del9	E92K	I1234V del6aa	P439S	S434P
3331del6	F1016S	I125T	P499A	S492F
3410T→C	F1052V	I1269N	P574H	S50P
3523A→G	F1074L	I1366N	P67L	S519G
3601A→C	F1078S	I1366T	P750L	S531P
3761T→G	F1099L	I148L	P798S	S549I
3791C/T	F1107L	I148N	P988R	S549N
3850G→A	F191V	I148T	Q1012P	S549R
3978G→C	F200I	I175V	Q1209P	S557F
546insCTA	F311del	I331N	Q1291H	S589I
548insTAC	F311L	I336K	Q1291R	S589N
A1006E	F312del	I336L	Q1313K	S624R
A1025D	F433L	I444S	Q1352H	S686Y
A1067P	F508C	I497S	Q151K	S737F
A1067T	F508C;S1251N	I502T	Q179K	S821G
A1067V	F508del;R1438W	I506L	Q237E	S898R
A107G	F575Y	I506V	Q237H	S912L
A1081V	F587I	I506V;D1168G	Q237P	S912L;G1244V
A1087P	F587L	I521S	Q30P	S912T
A120T	F693L(TTG)	I530N	Q359K/T360K	S955P
A1319E	F87L	I556V	Q359R	S977F
A1374D	F932S	I586V	Q372H	S977F;R1438W
A141D	G1047D	I601F	Q493L	T1036N
A1466S	G1047R	I618N	Q493R	T1053I
A155P	G1061R	I618T	Q552P	T1057R
A234D	G1069R	I807M	Q98P	T1086A
A234V	G1123R	I86M	Q98R	T1086I
A238V	G1173S	I980K	R1048G	T1246I
A309D	G1237V	K1060T	R1066G	T1299I
A349V	G1244E	K162E	R1070P	T1299K
A357T	G1244R	K464E	R1070Q	T351I
A455V	G1247R	K464N	R1070W	T351S
A457T	G1249E	K522E	R1162L	T351S;R851L
A462P	G1249R	K522Q	R1162Q	T388M
A46D	G1265V	K951E	R117C;G576A;R668C	T465I
A534E	G126D	L1011S	R117G	T501A
A554E	G1298V	L102R;F1016S	R117H	T582S
A566D	G1349D	L1065R	R117L	T908N
A62P	G149R;G576A;R668C	L1227S	R117L;L997F	T990I
A872E	G178E	L1324P	R117P	V1008D
c.1367_1369dupTTG	G178R	L1335P	R1239S	V1010D
C225R	G194R	L137P	R1283G	V1153E
C491R	G194V	L1388P	R1283M	V11I
C590Y	G213E	L1480P	R1283S	V1240G
C866Y	G213E;R668C	L159S	R1438W	V1293G
D110E	G213V	L15P	R170H	V1293I
D110H	G226R	L15P;L1253F	R248K	V1415F
D110N	G239R	L165S	R258G	V201M
D1152A	G253R	L167R	R297Q	V232A
D1270N	G27E	L210P	R31C	V317A
D1270Y	G27R	L293P	R31L	V322M
D1312G	G314E	L320V	R334L	V392G
D1377H	G314R	L327P	R334Q	V456A
D1445N	G424S	L32P	R347L	V456F
D192G	G437D	L333F	R352Q	V520I
D192N	G461R	L333H	R352W	V562I
D373N	G461V	L346P	R516S	V562I;A1006E
D426N	G463V	L441P	R553Q	V562L
D443Y	G480C	L453S	R555G	V591A
D443Y;G576A;R668C	G480D	L467F	R600S	V603F
D529G	G480S	L558F	R668C	V754M
D565G	G500D	L619S	R709Q	V920L
D567N	G545R	L633P	R74Q	V920M
D579G	G551A	L636P	R74Q;R297Q	V93D
D58H	G551D	L88S	R74Q;V201M;D1270N	W1098C
D58V	G551R	L927P	R74W	W1282G
D614G	G551S	L967F;L1096R	R74W;D1270N	W1282R
D651H	G576A	L967S	R74W;R1070W;D1270N	W202C
D651N	G576A;R668C	L973F	R74W;S945L	W361R
D806G	G576A;S1359Y	M1137R	R74W;V201M	W496R
D836Y	G622D	M1137V	R74W;V201M;D1270N	Y1014C
D924N	G622V	M1210K	R74W;V201M;L997F	Y1032C
D979A	G628A	M150K	R751L	Y1032N
D979V	G628R	M150R	R75L	Y1073C
D985H	G930E	M152L	R75Q	Y1092H
D985Y	G970D	M152V	R75Q;L1065P	Y109H
D993A	G970S	M265R	R75Q;N1088D	Y109N
D993G	G970V	M348K	R75Q;S549N	Y122C
D993Y	H1054D	M394L	R792G	Y1381H
E1104K	H1079P	M469V	R792Q	Y161C
E1104V	H1085P	M498I	R810G	Y161D
E1126K	H1085R	M952I	R851L	Y161S
E116K	H1375N	M952T	R933G	Y301C
E116Q	H1375P	M961L	S1045Y	Y563N
E1221V	H139L	N1088D	S108F	Y89C
E1228K	H139R	N1195T	S1118F	Y913S
E1409K	H146R	N1303I	S1159F	Y919C
E1433K	H199Q	N1303K	S1159P
E193K	H199Y	N186K	S1188L
E217G	H609L	N187K	S1235R

Sweat Chloride Evaluation

In Trial 1 (patients with an F508del variant on one allele and a variant on the second allele that results in either no CFTR protein or a CFTR protein that is not responsive ivacaftor and tezacaftor/ivacaftor), a reduction in sweat chloride was observed from baseline at Week 4 and sustained through the 24-week treatment period [see Clinical Studies (14.1)]. In Trial 2 (patients homozygous for the F508del variant), a reduction in sweat chloride was observed from baseline at Week 4 [see Clinical Studies (14.2)]. In Trial 3 (patients aged 6 to less than 12 years who are 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), the mean absolute change in sweat chloride from baseline through Week 24 was -60.9 mmol/L (95% CI: -63.7, -58.2). In Trial 4 (patients aged 2 to less than 6 years who had at least one F508del variant or a variant known to be responsive to TRIKAFTA), the mean absolute change in sweat chloride from baseline through Week 24 was -57.9 mmol/L (95% CI: -61.3, -54.6). In Trial 5 (patients aged 6 years and older with at least one qualifying non-F508del elexacaftor/tezacaftor/ivacaftor-responsive CFTR variant), the mean absolute change in sweat chloride from baseline through Week 24 compared to placebo was -28.3 mmol/L (95% CI: -32.1, -24.5).

Cardiac Electrophysiology

At doses up to 2 times the maximum recommended dose of elexacaftor and 3 times the maximum recommended dose of tezacaftor and ivacaftor, the QT/QTc interval in healthy subjects was not prolonged to any clinically relevant extent.

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_ss was 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_ss in 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_max for elexacaftor, 73% higher AUC and 70% higher C_max for M23-ELX, 36% higher AUC and 24% higher C_max for combined elexacaftor and M23-ELX, 20% higher AUC but similar C_max for tezacaftor and 1.5-fold higher AUC and 10% higher C_max for 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_max for tezacaftor and a 1.5-fold higher AUC but similar C_max for 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 estradiol Effect 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)
		↑ Ivacaftor Effect 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)

Elexacaftor

A 6-month study in Tg.rasH2 transgenic mice showed no evidence of tumorigenicity at 50 mg/kg/day dose, the highest dose tested.

A two-year study was conducted in rats to assess the carcinogenic potential of elexacaftor. No evidence of tumorigenicity was observed in rats at elexacaftor oral doses up to 10 mg/kg/day (approximately 2 and 5 times the MRHD based on summed AUCs of elexacaftor and its metabolite in male and female rats, respectively).

Elexacaftor was negative for genotoxicity in the following assays: Ames test for bacterial gene variant, in vitro mammalian cell micronucleus assay in TK6 cells, and in vivo mouse micronucleus test.

Elexacaftor did not cause reproductive system toxicity in male rats at 55 mg/kg/day and female rats at 25 mg/kg/day, equivalent to approximately 6 times and 4 times the MRHD, respectively (based on summed AUCs of elexacaftor and its metabolite). Elexacaftor did not cause embryonic toxicity at 35 mg/kg/day which was the highest dose tested, equivalent to approximately 7 times the MRHD (based on summed AUCs of elexacaftor and its metabolite). Lower male and female fertility, male copulation and female conception indices were observed in males at 75 mg/kg/day and females at 35 mg/kg/day, equivalent to approximately 6 times and 7 times, respectively, the MRHD (based on summed AUCs of elexacaftor and its metabolite).

Tezacaftor

A two-year study in Sprague-Dawley rats and a 6-month study in Tg.rasH2 transgenic mice were conducted to assess the carcinogenic potential of tezacaftor. No evidence of tumorigenicity from tezacaftor was observed in male and female rats at oral doses up to 50 and 75 mg/kg/day (approximately 1 and 2 times the MRHD based on summed AUCs of tezacaftor and its metabolites in males and females, respectively). No evidence of tumorigenicity was observed in male and female Tg.rasH2 transgenic mice at tezacaftor doses up to 500 mg/kg/day.

Tezacaftor was negative for genotoxicity in the following assays: Ames test for bacterial gene variant, in vitro chromosomal aberration assay in Chinese hamster ovary cells and in vivo mouse micronucleus test.

There were no effects on male or female fertility and early embryonic development in rats at oral tezacaftor doses up to 100 mg/kg/day (approximately 3 times the MRHD based on summed AUC of tezacaftor and M1-TEZ).

Ivacaftor

Two-year studies were conducted in CD-1 mice and Sprague-Dawley rats to assess the carcinogenic potential of ivacaftor. No evidence of tumorigenicity from ivacaftor was observed in mice or rats at oral doses up to 200 mg/kg/day and 50 mg/kg/day, respectively (approximately equivalent to 2 and 7 times the MRHD, respectively, based on summed AUCs of ivacaftor and its metabolites).

Ivacaftor was negative for genotoxicity in the following assays: Ames test for bacterial gene variant, in vitro chromosomal aberration assay in Chinese hamster ovary cells and in vivo mouse micronucleus test.

Ivacaftor impaired fertility and reproductive performance indices in male and female rats at 200 mg/kg/day (approximately 7 and 5 times, respectively, the MRHD based on summed AUCs of ivacaftor and its metabolites). Increases in prolonged diestrus were observed in females at 200 mg/kg/day. Ivacaftor also increased the number of females with all nonviable embryos and decreased corpora lutea, implantations and viable embryos in rats at 200 mg/kg/day (approximately 5 times the MRHD based on summed AUCs of ivacaftor and its metabolites) when dams were dosed prior to and during early pregnancy. These impairments of fertility and reproductive performance in male and female rats at 200 mg/kg/day were attributed to severe toxicity.

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 11 for a summary of primary and key secondary outcomes in Trial 1.

Table 11: Primary and Key Secondary Efficacy Analyses (Trial 1)

Analysis	Statistic	Treatment Difference Treatment difference provided as the outcome measure for changes in ppFEV1, sweat chloride, CFQ-R and BMI; Rate ratio provided as the outcome measure for the number of pulmonary exacerbations. for TRIKAFTA (N=200) vs Placebo (N=203)
ppFEV1: percent predicted Forced Expiratory Volume in 1 second; CI: Confidence Interval; CFQ-R: Cystic Fibrosis Questionnaire-Revised; BMI: Body Mass Index.
Primary (Interim Full Analysis Set) Primary endpoint was based on interim analysis in 403 patients.
Absolute change in ppFEV1 from baseline at Week 4 (percentage points)	Treatment difference (95% CI) P value	13.8 (12.1, 15.4) P<0.0001
Key Secondary (Full Analysis Set) Key secondary endpoints were tested at the final analysis in 403 patients.
Absolute change in ppFEV1 from baseline through Week 24 (percentage points)	Treatment difference (95% CI) P value	14.3 (12.7, 15.8) P<0.0001
Number of pulmonary exacerbations from baseline through Week 24 A pulmonary exacerbation was defined as a change in antibiotic therapy (IV, inhaled, or oral) as a result of 4 or more of 12 pre-specified sino-pulmonary signs/symptoms. Number of pulmonary exacerbation events (event rate per year calculated based on 48 weeks per year) in the TRIKAFTA group were 41 (0.37) and 113 (0.98) in the placebo group.	Rate ratio (95% CI) P value	0.37 (0.25, 0.55) P<0.0001
Absolute change in sweat chloride from baseline through Week 24 (mmol/L)	Treatment difference (95% CI) P value	-41.8 (-44.4, -39.3) P<0.0001
Absolute change in CFQ-R respiratory domain score from baseline through Week 24 (points)	Treatment difference (95% CI) P value	20.2 (17.5, 23.0) P<0.0001
Absolute change in BMI from baseline at Week 24 (kg/m2)	Treatment difference (95% CI) P value	1.04 (0.85, 1.23) P<0.0001
Absolute change in sweat chloride from baseline at Week 4 (mmol/L)	Treatment difference (95% CI) P value	-41.2 (-44.0, -38.5) P<0.0001
Absolute change in CFQ-R respiratory domain score from baseline at Week 4 (points)	Treatment difference (95% CI) P value	20.1 (16.9, 23.2) P<0.0001

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



Figure 1 (Trikafta 04)

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 12 for a summary of primary and key secondary outcomes.

Table 12: Primary and Key Secondary Efficacy Analyses, Full Analysis Set (Trial 2)

Analysis Baseline for primary and key secondary endpoints is defined as the end of the 4-week tezacaftor/ivacaftor run-in period.	Statistic	Treatment Difference for TRIKAFTA (N=55) vs Tezacaftor/Ivacaftor Regimen of tezacaftor 100 mg qd/ivacaftor 150 mg q12h. (N=52)
ppFEV1: percent predicted Forced Expiratory Volume in 1 second; CI: Confidence Interval; CFQ-R: Cystic Fibrosis Questionnaire-Revised.
Primary
Absolute change in ppFEV1 from baseline at Week 4 (percentage points)	Treatment difference (95% CI) P value	10.0 (7.4, 12.6) P<0.0001
Key Secondary
Absolute change in sweat chloride from baseline at Week 4 (mmol/L)	Treatment difference (95% CI) P value	-45.1 (-50.1, -40.1) P<0.0001
Absolute change in CFQ-R respiratory domain score from baseline at Week 4 (points)	Treatment difference (95% CI) P value	17.4 (11.8, 23.0) P<0.0001

Drug-Induced Liver Injury and Liver Failure

Inform patients that TRIKAFTA is associated with a serious risk for drug-induced liver injury and that liver injury resulting in liver failure leading to liver transplantation or death have occurred, including in patients without a history of liver disease.

Advise all patients that liver function tests (ALT, AST, alkaline phosphatase, and bilirubin) should be assessed prior to initiating TRIKAFTA and then assessed every month during the first 6 months of treatment, then every 3 months for the next 12 months, then at least annually thereafter. Inform patients with a history of liver disease or liver function test elevations at baseline that more frequent monitoring may be necessary. Instruct patients to interrupt treatment with TRIKAFTA if symptoms of liver injury occur (e.g., jaundice, right upper quadrant pain, nausea, vomiting, altered mental status, ascites) and to notify their healthcare provider immediately. [see Dosage and Administration (2.1) and Warnings and Precautions (5.1)].

Drug Interactions with CYP3A Inducers and Inhibitors

Ask patients to tell you all the medications they are taking including any herbal supplements or vitamins. Inform patients that concomitant use 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 used concomitantly 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 used concomitantly 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 (2.4), Warnings and Precautions (5.5, 5.6), Drug Interactions (7.1) 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 [see Warnings and Precautions (5.2)].

Intracranial Hypertension

Inform patients that intracranial hypertension has occurred with the use of TRIKAFTA. Instruct patients to notify their healthcare provider right away if they experience signs and symptoms of intracranial hypertension, including headache, blurred vision, diplopia, and vision loss [see Warnings and Precautions (5.3)].

Neuropsychiatric Events, Including Suicidal Thoughts and Behaviors

Inform patients that neuropsychiatric symptoms, including anxiety, depression, suicidal thoughts and behaviors, and sleep disturbances (e.g., insomnia), have been reported with the use of TRIKAFTA or drugs containing the same or similar active ingredients as TRIKAFTA. The symptoms have been observed in patients with and without a history of similar symptoms and may occur within three months of TRIKAFTA initiation. Instruct patients to contact their healthcare provider immediately if changes in behavior or thinking that are not typical for the patient occur, or if the patient develops suicidal ideation or behavior [see Warnings and Precautions (5.4)].

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 (5.7) 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 (2.2) and Clinical Pharmacology (12.3)].

Patients should be informed about what to do in the event they miss a dose [see Dosage and Administration (2.5)] 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.

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None.

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)].

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.

Cases of intracranial hypertension (IH) have been reported in the postmarketing setting with the use of TRIKAFTA [see Adverse Reactions (6.2)]. Clinical manifestations of IH include headache, blurred vision, diplopia, and potential vision loss; papilledema can be found on fundoscopy. If an unusual headache or visual disturbances occur during treatment, and IH is suspected, interrupt TRIKAFTA and refer for prompt medical evaluation. Consider the benefits and risks for the individual patient to determine whether to resume treatment with TRIKAFTA. Patients should be monitored until IH resolution and for recurrence. Patients with elevated vitamin A levels may be at increased risk.

Serious neuropsychiatric events, including symptoms of anxiety, depression, suicidal ideation and behavior, and sleep disturbances, have been reported in the postmarketing setting in patients taking TRIKAFTA or drugs containing the same or similar active ingredients [see Adverse Reactions (6.2)]. The events were reported in adult and pediatric patients with and without a previous history of neuropsychiatric symptoms. Symptoms may occur within the first three months of treatment initiation.

Assess patients for baseline neuropsychiatric symptoms and monitor for new or worsening symptoms of anxiety, depression, suicidal ideation or behavior, or sleep disturbances. Consider the benefits and risks for the individual patient to determine if therapy with TRIKAFTA should be interrupted at the occurrence of neuropsychiatric symptoms and whether to resume therapy with symptom improvement.

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, concomitant use with strong CYP3A inducers is not recommended [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)].

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)].

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)].

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)]

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 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.

The safety and effectiveness of TRIKAFTA for the treatment of CF have been established in 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.

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 TRIKAFTA 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 variant on one allele 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 [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 variant [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 variant or heterozygous for the F508del variant with 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 [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 variant or a variant known to be responsive to TRIKAFTA [see Adverse Reactions (6) and Clinical Pharmacology (12.3)].
• Trial 5, 64 pediatric patients aged 6 years to less than 18 years who had at least one qualifying non-F508del TRIKAFTA-responsive variant and did not have an exclusionary variant [see Adverse Reactions (6) and Clinical Studies (14.2)].

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.

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

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)].

• 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)].

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.

Treatment of overdosage consists of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient.

TRIKAFTA is a co-package of elexacaftor, tezacaftor and ivacaftor fixed-dose combination tablets or granules and ivacaftor tablets or granules. Both tablets and granules are for oral administration.

The elexacaftor, tezacaftor and ivacaftor fixed-dose combination tablets are available as: orange, oblong-shaped, film-coated tablet containing 100 mg of elexacaftor, 50 mg of tezacaftor, 75 mg of ivacaftor, or light orange, oblong-shaped, film-coated tablet containing 50 mg of elexacaftor, 25 mg of tezacaftor, 37.5 mg of ivacaftor. The fixed-dose combination tablet contains the following inactive ingredients: croscarmellose sodium, hypromellose, hypromellose acetate succinate, magnesium stearate, microcrystalline cellulose, and sodium lauryl sulfate. The tablet film coat contains hydroxypropyl cellulose, hypromellose, iron oxide red, iron oxide yellow, talc, and titanium dioxide.

The ivacaftor tablet is available as a light blue, oblong-shaped, film-coated tablet containing 150 mg or 75 mg of ivacaftor and the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, hypromellose acetate succinate, lactose monohydrate, magnesium stearate, microcrystalline cellulose and sodium lauryl sulfate. The tablet film coat contains carnauba wax, FD&C Blue #2, PEG 3350, polyvinyl alcohol, talc, and titanium dioxide. The printing ink contains ammonium hydroxide, iron oxide black, propylene glycol, and shellac.

The elexacaftor, tezacaftor and ivacaftor fixed-dose combination oral granules are white to off-white, sweetened, unflavored granules approximately 2 mm in diameter enclosed in unit-dose packets. Each unit-dose packet contains 100 mg of elexacaftor, 50 mg of tezacaftor, 75 mg of ivacaftor or 80 mg of elexacaftor, 40 mg of tezacaftor, 60 mg of ivacaftor and the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, hypromellose, hypromellose acetate succinate, lactose monohydrate, magnesium stearate, mannitol, sodium lauryl sulfate, and sucralose.

The ivacaftor oral granules are white to off-white, sweetened, unflavored granules approximately 2 mm in diameter enclosed in unit-dose packets. Each unit-dose packet contains 75 mg or 59.5 mg of ivacaftor and the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, hypromellose acetate succinate, lactose monohydrate, magnesium stearate, mannitol, sodium lauryl sulfate, and sucralose.

The active ingredients of TRIKAFTA are described below.

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 both by CFTR-mediated chloride transport in vitro and by sweat chloride in patients with CF.

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.

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.

The efficacy of TRIKAFTA in patients aged 12 years and older with cystic fibrosis (CF) with at least one F508del variant was evaluated in two randomized, double-blind, controlled trials (Trials 1 and 2).

Trial 1 (NCT03525444) was a 24-week, randomized, double-blind, placebo-controlled study in patients who had an F508del variant on one allele 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. An interim analysis was planned when at least 140 patients completed Week 4 and at least 100 patients completed Week 12.

Trial 2 (NCT03525548) was a 4-week, randomized, double-blind, active-controlled study in patients who are homozygous for the F508del variant. 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 variant. 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 an open-label extension study.

The efficacy of TRIKAFTA in patients with cystic fibrosis (CF) without an F508del variant was evaluated in Trial 5.

Trial 5 (NCT05274269) was a 24-week, randomized, placebo-controlled, double-blind, parallel-group trial in 307 patients aged 6 years and older with CF (mean age 33.5 years). The mean baseline ppFEV1 was 67.7% (range: 34.0%, 108.7%). The trial included patients who had at least one qualifying non-F508del TRIKAFTA-responsive variant and did not have an exclusionary variant. Patients were randomized to TRIKAFTA or placebo. The dosage of TRIKAFTA was administered according to age and weight as follows:

• Patients aged 6 to less than 12 years, weighing less than 30 kg: total morning dose of elexacaftor 100 mg/ tezacaftor 50 mg/ ivacaftor 75 mg and evening dose of ivacaftor 75 mg
• Patients aged 6 to less than 12 years, weighing greater than or equal to 30 kg: total morning dose of elexacaftor 200 mg/ tezacaftor 100 mg/ ivacaftor 150 mg and evening dose of ivacaftor 150 mg
• Patients aged 12 years and older: total morning dose of elexacaftor 200 mg/ tezacaftor 100 mg/ ivacaftor 150 mg and evening dose of ivacaftor 150 mg

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 between 40-100% at screening. The mean ppFEV₁ at baseline was 68% (range: 34%, 109%). 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 Trial 5 were eligible to roll over into an open-label extension study.

In Trial 5, the primary efficacy endpoint was absolute change in ppFEV₁ from baseline through Week 24. Secondary efficacy endpoints were absolute change in sweat chloride through Week 24, absolute change in CFQ-R respiratory domain score through Week 24, absolute change in growth parameters (BMI, weight) at Week 24, and number of pulmonary exacerbation events through Week 24. Table 13 provides a summary of the primary and secondary efficacy results.

Table 13: Primary and Secondary Efficacy Analyses, Full Analysis Set (Trial 5)

Analysis	Statistic	Treatment Difference Treatment difference was provided as the outcome measure for changes in ppFEV1, sweat chloride, CFQ-R RD and BMI; Rate ratio provided as the outcome measure for the number of pulmonary exacerbations. for TRIKAFTA (N=205) vs Placebo (N=102)
BMI: body mass index; CFQ-R: Cystic Fibrosis Questionnaire-Revised; CI: confidence interval; N: total sample size; P: probability; ppFEV1: percent predicted forced expiratory volume in 1 second.
Primary
Absolute change in ppFEV1 from baseline through Week 24 (percentage points)	Treatment difference (95% CI) P value	9.2 (7.2, 11.3) P<0.0001
Secondary
Absolute change in sweat chloride from baseline through Week 24 (mmol/L)	Treatment difference (95% CI) P value	-28.3 (-32.1, -24.5) P<0.0001
Absolute change in CFQ-R respiratory domain score from baseline through Week 24 (points)	Treatment difference (95% CI) P value	19.5 (15.5, 23.5) P<0.0001
Absolute change from baseline in BMI at Week 24 (kg/m2)	Treatment difference (95% CI) P value	0.47 (0.24, 0.69) P<0.0001
Absolute change from baseline in weight at Week 24 (kg)	Treatment difference (95% CI) P value	1.3 (0.6, 1.9) P<0.0001
Number of pulmonary exacerbations through Week 24 Number of pulmonary exacerbation events (event rate per year calculated based on 48 weeks per year) in the TRIKAFTA group were 21 (0.17) and in the placebo group were 40 (0.63).	Rate ratio (95% CI) P value	0.28 (0.15, 0.51) P<0.0001

TRIKAFTA tablets are co-packaged blister pack sealed into a printed wallet, containing elexacaftor, tezacaftor and ivacaftor fixed-dose combination tablets and ivacaftor tablets. Four such wallets are placed in a printed outer carton. TRIKAFTA tablets are supplied as follows:

TRIKAFTA oral granules are supplied in morning and evening unit-dose packets. The morning dose packets contain a fixed-dose combination of elexacaftor, tezacaftor, and ivacaftor oral granules. The evening dose packets contain ivacaftor oral granules. The packets are placed into a printed wallet. Four such wallets are placed in a printed outer carton. TRIKAFTA granules are supplied as follows:

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].

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

NDC 51167-331-01
Rx Only

trikafta^®
(elexacaftor, tezacaftor and ivacaftor)
100 mg, 50 mg and 75 mg;
(ivacaftor) 150 mg tablets

ATTENTION PHARMACIST: Dispense enclosed
Medication Guide to each patient.

84 Tablets
4-wallets (each containing 14 tablets of elexacaftor, tezacaftor,
and ivacaftor and 7 tablets of ivacaftor)

LIFT HERE TO OPEN ►

Principal Display Panel (Kit Carton)

NDC 51167-106-02
Rx Only

trikafta^®
(elexacaftor, tezacaftor and ivacaftor)
50 mg, 25 mg and 37.5 mg;
(ivacaftor) 75 mg tablets

ATTENTION PHARMACIST: Dispense enclosed
Medication Guide to each patient.

84 Tablets
4-wallets (each containing 14 tablets of elexacaftor, tezacaftor,
and ivacaftor and 7 tablets of ivacaftor)

LIFT HERE TO OPEN →

Principal Display Panel (Kit Carton)

NDC 51167-445-01
Rx only

trikafta^®
(elexacaftor, tezacaftor, ivacaftor) oral granules
80 mg/40 mg/60 mg
Co-packaged with
(ivacaftor) oral granules
59.5 mg

80 mg
40 mg
60 mg
and
59.5 mg

56 packets
Carton contains: 4 individual
wallets with 14 packets per wallet

ATTENTION PHARMACIST: Dispense enclosed Medication Guide to each patient.

Lift here to open

Principal Display Panel (Kit Carton)

NDC 51167-446-01
Rx only

trikafta^®
(elexacaftor, tezacaftor, ivacaftor) oral granules
100 mg/50 mg/75 mg
Co-packaged with
(ivacaftor) oral granules
75 mg

100 mg
50 mg
75 mg
and
75 mg

56 packets
Carton contains: 4 individual
wallets with 14 packets per wallet

ATTENTION PHARMACIST: Dispense enclosed Medication Guide to each patient.

Lift here to open

Principal Display Panel (Kit Carton)