Trikafta

Q: Who makes Trikafta?

Trikafta is listed by 1 labeler in the FDA NDC directory, including Vertex Pharmaceuticals Incorporated.

Elexacaftor, Tezacaftor, and Ivacaftor · Kit

Prescription (Rx)

Boxed warning. WARNING: 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…

Uses

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

Dosage and administration

Prior to initiating TRIKAFTA obtain liver function tests (ALT, AST, alkaline phosphatase, and bilirubin) in all patients. Monitor liver function tests every month during the first 6 months of treatment, then every 3 months during the next 12 months, then at least annually thereafter. ( 2.1 , 5.1) Recommended Dosage for Adult and Pediatric Patients Aged 2 Years and Older (with fat-containing food ( 2.2 , 12.3 )) Age Weight Morning Dose Evening Dose 2 to less than 6 years Less than 14 kg One packet containing elexacaftor 80 mg/tezacaftor 40 mg/ivacaftor 60 mg oral granules One packet containing ivacaftor 59.5 mg oral granules 14 kg or more One packet containing elexacaftor 100 mg/tezacaftor 50 mg/ivacaftor 75 mg oral granules One packet containing ivacaftor 75 mg oral granules 6 to less than 12 years Less than 30 kg Two tablets, each containing elexacaftor 50 mg/tezacaftor 25 mg/ivacaftor 37.5 mg One tablet of ivacaftor 75 mg 30 kg or more Two tablets, each containing elexacaftor 100 mg/tezacaftor 50 mg/ivacaftor 75 mg One tablet of ivacaftor 150 mg 12 years and older - Two tablets, each containing elexacaftor 100 mg/tezacaftor 50 mg/ivacaftor 75 mg One tablet of ivacaftor 150 mg Should not be used in patients with severe hepatic impairment. Use not recommended in patients with moderate hepatic impairment unless the benefit outweighs the risk. Reduce dose if used in patients with moderate hepatic impairment. Liver function tests should be closely monitored. ( 2.3 , 5.1 , 6 , 8.7 , 12.3 ) See full prescribing information for dosage modifications due to drug interactions with TRIKAFTA. ( 2.4 , 5.6 , 7.1 , 12.3 ) 2.1 Recommended Laboratory Testing Prior to TRIKAFTA Initiation and During Treatment 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) ] . 2.2 Recommended Dosage in Adults and Pediatric Patients Aged 2 Years and Older Recommended dosage for adult and pediatric patients aged 2 years and older is provided in Table 1. 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. Table 1: Recommended Dosage of TRIKAFTA for Adult and Pediatric Patients Aged 2 Years and Older Age Weight Oral Morning Dose Oral Evening Dose 2 to less than 6 years Less than 14 kg One packet (containing elexacaftor 80 mg/tezacaftor 40 mg/ivacaftor 60 mg) oral granules One packet (containing ivacaftor 59.5 mg) oral granules 14 kg or more One packet (containing elexacaftor 100 mg/tezacaftor 50 mg/ivacaftor 75 mg) oral granules One packet (containing ivacaftor 75 mg) oral granules 6 to less than 12 years Less than 30 kg 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) One tablet of ivacaftor 75 mg 30 kg or more Two tablets of elexacaftor 100 mg/tezacaftor 50 mg/ivacaftor 75 mg (total dose of elexacaftor 200 mg/tezacaftor 100 mg/ivacaftor 150 mg) One tablet of ivacaftor 150 mg 12 years and older — Two tablets of elexacaftor 100 mg/tezacaftor 50 mg/ivacaftor 75 mg (total dose of elexacaftor 200 mg/tezacaftor 100 mg/ivacaftor 150 mg) One tablet of ivacaftor 150 mg 2.3 Recommended Dosage for Patients with Hepatic Impairment 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.

Dosage forms and strengths

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

Contraindications

None. None. ( 4 )

Warnings and precautions

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) ] .

Side effects

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).

Drug interactions

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.

Use in specific populations

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).

Pregnancy

Pediatric use

8.4 Pediatric Use 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. 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.

Geriatric use

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

Overdosage

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

Description

11 DESCRIPTION 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 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 C 26 H 34 N 7 O 4 SF 3 and its molecular weight is 597.66. Elexacaftor has the following structural formula: Chemical Structure 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 C 26 H 27 N 2 F 3 O 6 and its molecular weight is 520.50. Tezacaftor has the following structural formula: Chemical Structure 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 C 24 H 28 N 2 O 3 and its molecular weight is 392.49. Ivacaftor has the following structural formula: Chemical Structure

Mechanism of action

12.1 Mechanism of Action Elexacaftor and tezacaftor bind to different sites on the CFTR protein and have an additive effect in facilitating the cellular processing and trafficking of select mutant forms of CFTR (including F508del-CFTR) to increase the amount of CFTR protein delivered to the cell surface compared to either molecule alone. Ivacaftor potentiates the channel open probability (or gating) of the CFTR protein at the cell surface. The combined effect of elexacaftor, tezacaftor and ivacaftor is increased quantity and function of CFTR at the cell surface, resulting in increased CFTR activity as measured 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…

How supplied

16 HOW SUPPLIED/STORAGE AND HANDLING 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: Table 14: TRIKAFTA Tablets and Package Configuration Strengths Tablet Description Package Configuration NDC Elexacaftor 50 mg, tezacaftor 25 mg, and ivacaftor 37.5 mg tablets light orange, oblong-shaped, debossed with "T50" on one side and plain on the other 84-count carton containing 4 wallets, each wallet containing 14 tablets of elexacaftor, tezacaftor and ivacaftor, and 7 tablets of ivacaftor NDC 51167-106-02 Ivacaftor 75 mg light blue, film-coated, oblong-shaped, printed with the characters "V 75" in black ink on one side and plain on the other Elexacaftor 100 mg, tezacaftor 50 mg, and ivacaftor 75 mg orange, oblong-shaped, debossed with "T100" on one side and plain on the other 84-count carton containing 4 wallets, each wallet containing 14 tablets of elexacaftor, tezacaftor and ivacaftor, and 7 tablets of ivacaftor NDC 51167-331-01 Ivacaftor 150 mg light blue, film-coated, oblong-shaped, printed with the characters "V 150" in black ink on one side and plain on the other 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: Table 15: TRIKAFTA Oral Granules and Package Configuration Strengths Granule Description Package Configuration NDC Elexacaftor 80 mg, tezacaftor 40 mg, and ivacaftor 60 mg white to off-white, sweetened, unflavored granules approximately 2 mm in diameter enclosed in white and blue unit-dose packets 56-count carton containing 4 wallets, each wallet containing 7 white and blue packets of elexacaftor, tezacaftor and ivacaftor, and 7 white and green packets of ivacaftor NDC 51167-445-01 Ivacaftor 59.5 mg white to off-white, sweetened, unflavored granules approximately 2 mm in diameter enclosed in white and green unit-dose packets Elexacaftor 100 mg, tezacaftor 50 mg, and ivacaftor 75 mg white to off-white, sweetened, unflavored granules approximately 2 mm in diameter enclosed in white and orange unit-dose packets 56-count carton containing 4 wallets, each wallet containing 7 white and orange packets of elexacaftor, tezacaftor and ivacaftor, and 7 white and pink packets of ivacaftor NDC 51167-446-01 Ivacaftor 75 mg white to off-white, sweetened, unflavored granules approximately 2 mm in diameter enclosed in white and pink unit-dose packets Store at 20 ºC – 25 ºC (68 ºF – 77 ºF); excursions permitted to 15 ºC – 30 ºC (59 ºF – 86 ºF) [see USP Controlled Room Temperature].

Storage

Store at 20 ºC – 25 ºC (68 ºF – 77 ºF); excursions permitted to 15 ºC – 30 ºC (59 ºF – 86 ºF) [see USP Controlled Room Temperature].

Patient information

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

Label text from the FDA structured product label by Vertex Pharmaceuticals Incorporated (revised Jun 22, 2026). Long sections are shortened; the complete label is on DailyMed.

Trikafta NDC products (4)

NDC	Strength & form	Labeler	Type
51167-106	Kit	Vertex Pharmaceuticals Incorporated	NDA
51167-331	Kit	Vertex Pharmaceuticals Incorporated	NDA
51167-445	Kit	Vertex Pharmaceuticals Incorporated	NDA
51167-446	Kit	Vertex Pharmaceuticals Incorporated	NDA

Frequently asked questions

What is Trikafta used for?

What are the side effects of Trikafta?

Who makes Trikafta?

Trikafta is listed by 1 labeler in the FDA NDC directory, including Vertex Pharmaceuticals Incorporated.