Elexacaftor, Tezacaftor, and Ivacaftor

TRIKAFTA is indicated for the treatment of cystic fibrosis (CF) in adult and pediatric patients aged 2 years and older who have a clinical diagnosis of CF and who have at least one variant in the cystic fibrosis transmembrane conductance regulator ( CFTR ) gene that is either responsive based on clinical and/or in vitro data (see Table 6 ) or results in production of CFTR protein [see Clinical Pharmacology (12.1) ] . If the patient's genotype is unknown, an FDA-cleared CF genetic test should be used to confirm the presence of at least one variant in the CFTR gene that is either responsive based on clinical and/or in vitro data or results in production of CFTR protein. TRIKAFTA is a combination of ivacaftor, a CFTR potentiator, tezacaftor, and elexacaftor indicated for the treatment of cystic fibrosis (CF) in adult and pediatric patients aged 2 years and older who have a clinical diagnosis of CF and who have at least one variant in the CFTR gene that is either responsive based on clinical and/or in vitro data or results in production of CFTR protein. ( 1 , 12.1 ) If the patient's genotype is unknown, an FDA-cleared CF genetic test should be used to confirm the presence of at least one variant in the CFTR gene that is either responsive based on clinical and/or in vitro data or results in production of CFTR protein. ( 1 )

Tablets: Fixed-dose combination containing elexacaftor 50 mg, tezacaftor 25 mg and ivacaftor 37.5 mg co-packaged with ivacaftor 75 mg; Fixed-dose combination containing elexacaftor 100 mg, tezacaftor 50 mg, and ivacaftor 75 mg co-packaged with ivacaftor 150 mg. ( 3 ) Oral granules: Unit-dose packets of elexacaftor 100 mg, tezacaftor 50 mg and ivacaftor 75 mg co-packaged with unit-dose packets of ivacaftor 75 mg; Unit-dose packets of elexacaftor 80 mg, tezacaftor 40 mg and ivacaftor 60 mg co-packaged with unit-dose packets of ivacaftor 59.5 mg. ( 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, 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

None. None. ( 4 )

Drug-induced liver injury and liver failure : TRIKAFTA can cause serious and potentially fatal drug-induced liver injury. Assess liver function tests (ALT, AST, alkaline phosphatase, bilirubin) in all patients prior to initiating and throughout treatment with TRIKAFTA. Interrupt TRIKAFTA in the event of significant elevations in liver function tests or signs or symptoms of liver injury. 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). ( 2.1 , 2.3 , 5.1 , 6 , 8.7 , 12.3 ) Hypersensitivity reactions : Angioedema and anaphylaxis have been reported with TRIKAFTA in the postmarketing setting. Initiate appropriate therapy in the event of a hypersensitivity reaction. ( 5.2 ) Intracranial hypertension : Intracranial hypertension (IH) has been reported in the postmarketing setting with the use of TRIKAFTA. If an unusual headache or visual disturbances occur during treatment, and IH is suspected, interrupt TRIKAFTA and refer for prompt medical evaluation. ( 5.3 ) Neuropsychiatric events, including suicidal thoughts and behaviors : Serious neuropsychiatric events, including symptoms of anxiety, depression, suicidal ideation and behavior, and sleep disturbances, have been reported in the postmarketing setting for TRIKAFTA or drugs containing the same or similar active ingredients. Monitor patients closely for new or worsening symptoms. Consider the risks and benefits for the individual patient to determine if therapy with TRIKAFTA should be interrupted at the occurrence of neuropsychiatric symptoms. ( 5.4 ) Use with CYP3A inducers : Concomitant use with strong CYP3A inducers (e.g., rifampin, St. John's wort) significantly decrease ivacaftor exposure and are expected to decrease elexacaftor and tezacaftor exposure, which may reduce TRIKAFTA efficacy. Therefore, concomitant use is not recommended. ( 5.5 , 7.1 , 12.3 ) Cataracts : Non-congenital lens opacities/cataracts have been reported in pediatric patients treated with ivacaftor-containing regimens. Baseline and follow-up examinations are recommended in pediatric patients initiating TRIKAFTA treatment. ( 5.7 , 8.4 )

5.1 Drug-Induced Liver Injury and Liver Failure TRIKAFTA can cause serious and potentially fatal drug-induced liver injury. Cases of liver failure leading to transplantation and death have been reported in patients with and without a history of liver disease taking TRIKAFTA, in both clinical trials and the postmarketing setting [see Adverse Reactions (6) ] . Liver injury has been reported within the first month of therapy and up to 15 months following initiation of TRIKAFTA. Assess liver function tests (ALT, AST, alkaline phosphatase, and bilirubin) in all patients prior to initiating TRIKAFTA. Assess liver function tests every month during the first 6 months of treatment, then every 3 months for the next 12 months, then at least annually thereafter. Consider more frequent monitoring for patients with a history of liver disease or liver function test elevations at baseline [see Dosage and Administration (2.1) , Adverse Reactions (6) , and Use in Specific Populations (8.7) ] . Interrupt TRIKAFTA in the event of signs or symptoms of liver injury. These may include: Significant elevations in liver function tests (e.g., ALT or AST >5 × the upper limit of normal (ULN) or ALT or AST >3 × ULN with bilirubin >2 × ULN) Clinical symptoms suggestive of liver injury (e.g., jaundice, right upper quadrant pain, nausea, vomiting, altered mental status, ascites). Consider referral to a hepatologist and follow patients closely with clinical and laboratory monitoring until abnormalities resolve. If abnormalities resolve and if the benefit is expected to outweigh the risk, resume TRIKAFTA treatment with close monitoring. TRIKAFTA should not be used in patients with severe hepatic impairment (Child-Pugh Class C). TRIKAFTA is not recommended in patients with moderate hepatic impairment (Child-Pugh Class B) and should only be considered when there is a clear medical need, and the benefit outweighs the risk. If used, use with caution at a reduced dosage and monitor patients closely [see Dosage and Administration (2.3) , Use in Specific Populations (8.7) and Clinical Pharmacology (12.3) ] .

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 Intracranial Hypertension 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.

5.4 Neuropsychiatric Events, Including Suicidal Thoughts and Behaviors 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.

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

5.6 Concomitant Use with CYP3A Inhibitors Exposure to elexacaftor, tezacaftor and ivacaftor are increased when used concomitantly with strong or moderate CYP3A inhibitors. Therefore, the dose of TRIKAFTA should be reduced when used concomitantly with moderate or strong CYP3A inhibitors [see Dosage and Administration (2.4) , Drug Interactions (7.1) and Clinical Pharmacology (12.3) ] .

5.7 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) ] .

The following clinically significant adverse reactions are discussed in greater detail in other sections of the labeling: Drug-Induced Liver Injury and Liver Failure [see Warnings and Precautions (5.1) ] Hypersensitivity Reactions, Including Anaphylaxis [see Warnings and Precautions (5.2) ] Intracranial Hypertension [see Warnings and Precautions (5.3) ] Neuropsychiatric Events, Including Suicidal Thoughts and Behaviors [see Warnings and Precautions (5.4) ] Cataracts [see Warnings and Precautions (5.7) ] The most common adverse drug reactions to TRIKAFTA (≥5% of patients and at a frequency higher than placebo by ≥1%) were headache, upper respiratory tract infection, abdominal pain, diarrhea, rash, alanine aminotransferase increased, nasal congestion, blood creatine phosphokinase increased, aspartate aminotransferase increased, rhinorrhea, rhinitis, influenza, sinusitis, blood bilirubin increased and constipation. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Vertex Pharmaceuticals Incorporated at 1-877-634-8789 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Patients with Cystic Fibrosis with at Least One F508del Variant The safety profile of TRIKAFTA in patients with CF with at least one F508del variant is based on data from 510 patients aged 12 years and older in two double-blind, controlled trials of 24 weeks and 4 weeks treatment duration (Trials 1 and 2, respectively). Eligible patients were also able to participate in an open-label extension safety study (up to 96 weeks of TRIKAFTA). In the two controlled trials, a total of 257 patients aged 12 years and older received at least one dose of TRIKAFTA. In Trial 1, the proportion of patients who discontinued study drug prematurely due to adverse events was 1% for TRIKAFTA-treated patients and 0% for placebo-treated patients. In Trial 1, serious adverse reactions that occurred more frequently in TRIKAFTA-treated patients compared to placebo were rash (1% vs <1%) and influenza (1% vs 0%). There were no deaths. Table 4 shows adverse reactions occurring in ≥5% of TRIKAFTA-treated patients and higher than placebo by ≥1% in the 24-week, placebo-controlled, parallel-group trial (Trial 1). Table 4: Adverse Reactions Occurring in ≥5% of TRIKAFTA-Treated Patients and Higher than Placebo by ≥1% in Trial 1 Adverse Reactions TRIKAFTA N=202 n (%) Placebo N=201 n (%) Headache 35 (17) 30 (15) Upper respiratory tract infection Includes upper respiratory tract infection and viral upper respiratory tract infection. 32 (16) 25 (12) Abdominal pain Includes abdominal pain, abdominal pain upper, abdominal pain lower. 29 (14) 18 (9) Diarrhea 26 (13) 14 (7) Rash Includes rash, rash generalized, rash erythematous, rash macular, rash pruritic. 21 (10) 10 (5) Alanine aminotransferase increased 20 (10) 7 (3) Nasal congestion 19 (9) 15 (7) Blood creatine phosphokinase increased 19 (9) 9 (4) Aspartate aminotransferase increased 19 (9) 4 (2) Rhinorrhea 17 (8) 6 (3) Rhinitis 15 (7) 11 (5) Influenza 14 (7) 3 (1) Sinusitis 11 (5) 8 (4) Blood bilirubin increased 10 (5) 2 (1) Additional adverse reactions that occurred in TRIKAFTA-treated patients at a frequency of 2% to <5% and higher than placebo by ≥1% include the following: flatulence, abdominal distension, conjunctivitis, pharyngitis, respiratory tract infection, tonsillitis, urinary tract infection, C-reactive protein increased, hypoglycemia, dizziness, dysmenorrhea, acne, eczema and pruritus. In addition, the following clinical trials have also been conducted [see Use in Specific Populations (8.4) , Clinical Pharmacology (12.3) and Clinical Studies (14) ]: a 24-week, open-label trial in 66 patients with CF aged 6 to less than 12 years who were either homozygous for the F508del variant or heterozygous for the F508del variant, and a variant on the second allele that results in either no CFTR protein or a CFTR protein that is not responsive to ivacaftor and tezacaftor/ivacaftor (Trial 3). a 24-week, open-label trial in 75 patients with CF aged 2 to less than 6 years. Patients who had at least one F508del variant or a variant known to be responsive to TRIKAFTA were eligible for the study (Trial 4). The safety profile for the CF patients enrolled in Trials 2, 3, and 4 was consistent to that observed in Trial 1. Patients with Cystic Fibrosis with at Least One Qualifying Non- F508del Variant The safety of TRIKAFTA in patients with CF with at least one non- F508del variant is based on data from 307 patients aged 6 years and older with at least one qualifying non- F508del CFTR variant that was TRIKAFTA-responsive. Trial 5 was a randomized, double blind, placebo-controlled trial for a 24-week treatment duration in which 205 patients received at least one dose of TRIKAFTA. Eligible patients were also able to participate in an open-label extension safety study. In Trial 5, the proportion of patients who discontinued study drug prematurely due to adverse reactions was 2% for TRIKAFTA-treated patients and 0% for placebo-treated patients. Table 5 shows adverse reactions occurring in ≥5% of TRIKAFTA-treated patients and higher than placebo by ≥1% in the 24-week, placebo-controlled, parallel-group trial (Trial 5). Table 5: Adverse Reactions Occurring in ≥5% of TRIKAFTA-Treated Patients and Higher than Placebo by ≥1% in Trial 5 Adverse Reactions TRIKAFTA N=205 n (%) Placebo N=102 n (%) Rash Includes rash, rash maculo-papular, rash erythematous, rash papular 48 (23) 2 (2) Headache 37 (18) 13 (13) Diarrhea 26 (13) 10 (10) Rhinitis 20 (10) 6 (6) Influenza 18 (9) 2 (2) Constipation 15 (7) 4 (4) Specific Adverse Reactions Liver Function Test Elevations In Trial 1, the incidence of maximum transaminase (ALT or AST) >8, >5, or >3 × ULN was 1%, 2%, and 8% in TRIKAFTA-treated patients and 1%, 1%, and 5% in placebo-treated patients. The incidence of adverse reactions of transaminase elevations (AST and/or ALT) was 11% in TRIKAFTA-treated patients and 4% in placebo-treated patients. In Trial 1, the incidence of maximum total bilirubin elevation >2 × ULN was 4% in TRIKAFTA-treated patients and <1% in placebo-treated patients. Maximum indirect and direct bilirubin elevations >1.5 × ULN occurred in 11% and 3% of TRIKAFTA-treated patients, respectively. No TRIKAFTA-treated patients developed maximum direct bilirubin elevation >2 × ULN. During Trial 3, in patients aged 6 to less than 12 years, the incidence of maximum transaminase (ALT or AST) >8, >5, and >3 × ULN were 0%, 1.5%, and 10.6%, respectively. No TRIKAFTA-treated patients had transaminase elevation >3 × ULN associated with elevated total bilirubin >2 × ULN or discontinued treatment due to transaminase elevations. During Trial 4 in patients aged 2 to less than 6 years, the incidence of maximum transaminase (ALT or AST) >8, >5, and >3 × ULN were 1.3%, 2.7%, and 8.0%, respectively. No TRIKAFTA-treated patients had transaminase elevation >3 × ULN associated with elevated total bilirubin >2 × ULN. One patient required treatment interruption during Trial 4 and later discontinued TRIKAFTA during the open label extension due to transaminase elevations. In Trial 5, the incidence of maximum transaminase (ALT or AST) >8, >5, and >3 × ULN were 2.0%, 2.0%, and 6.3%, respectively, and led to treatment discontinuation in 0.5% and treatment interruptions in 1.5% of TRIKAFTA-treated patients. There were no transaminase elevations >3 × ULN in placebo-treated patients. Rash In Trial 1, the overall incidence of rash was 10% in TRIKAFTA-treated and 5% in placebo-treated patients (see Table 4 ). The incidence of rash was higher in female TRIKAFTA-treated patients (16%) than in male TRIKAFTA-treated patients (5%). […]

Strong CYP3A inducers: Avoid concomitant use. ( 5.5 , 7.1 , 12.3 ) Strong or moderate CYP3A inhibitors: Reduce TRIKAFTA dosage when used concomitantly. Avoid food or drink containing grapefruit. ( 2.4 , 5.6 , 7.1 , 12.3 )

7.1 Effect of Other Drugs and Grapefruit on TRIKAFTA Strong CYP3A Inducers Concomitant use of TRIKAFTA with strong CYP3A inducers is not recommended. Elexacaftor, tezacaftor and ivacaftor are substrates of CYP3A (ivacaftor is a sensitive substrate of CYP3A). Concomitant use of CYP3A inducers may result in reduced exposures and thus reduced TRIKAFTA efficacy [see Warnings and Precautions (5.5) ] . 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) ] .

7.2 Effect of TRIKAFTA on Other Drugs 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.

7.3 Drugs with No Clinically Significant Interactions with TRIKAFTA 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.

8.1 Pregnancy 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.

8.2 Lactation 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 14 C-elexacaftor administered 6 to 10 days postpartum to lactating dams. Exposure of 14 C-elexacaftor in milk was approximately 0.4 times the value observed in plasma (based on AUC 0-72h ). […]

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. 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