Trikafta (elexacaftor 100 mg tezacaftor 50 mg ivacaftor 75 mg) Dailymed

Generic: elexacaftor, tezacaftor, and ivacaftor is used for the treatment of Cystic Fibrosis

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Recent Major Changes Section

Indications and Usage (1) 04/2023

Dosage and Administration (2) 04/2023

Warnings and Precautions, Hypersensitivity Reactions, Including Anaphylaxis (5.2) 08/2023

1 Indications And Usage

TRIKAFTA is indicated for the treatment of cystic fibrosis (CF) in patients aged 2 years and older who have at least one F508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene or a mutation in the CFTR gene that is responsive based on in vitro data [see Clinical Pharmacology (12.1)].

If the patient's genotype is unknown, an FDA-cleared CF mutation test should be used to confirm the presence of at least one F508del mutation or a mutation that is responsive based on in vitro data.

TRIKAFTA is a combination of ivacaftor, a CFTR potentiator, tezacaftor, and elexacaftor indicated for the treatment of cystic fibrosis (CF) in patients aged 2 years and older who have at least one F508del mutation in the CFTR gene or a mutation in the CFTR gene that is responsive based on in vitro data. If the patient's genotype is unknown, an FDA-cleared CF mutation test should be used to confirm the presence of at least one F508del mutation or a mutation that is responsive based on in vitro data. (1)

2 Dosage And Administration

Recommended Dosage for Adult and Pediatric Patients Aged 2 Years and Older

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

TRIKAFTA should be taken with fat-containing food. (2.5, 12.3)

Should not be used in patients with severe hepatic impairment. Use not recommended in patients with moderate hepatic impairment unless the benefit exceeds the risk. Reduce dose if used in patients with moderate hepatic impairment. Liver function tests should be closely monitored. (2.2, 5.1, 6, 8.7, 12.3)

See full prescribing information for dosage modifications due to drug interactions with TRIKAFTA. (2.3, 5.4, 7.2, 12.3)

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

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

Table 1: Recommended Dosage of TRIKAFTA for Adult and Pediatric Patients Aged 2 Years and Older

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 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

2.2Recommended Dosage for Patients with Hepatic Impairment

Mild Hepatic Impairment (Child-Pugh Class A): No dose adjustment is recommended [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)]. See Table 1 for recommended dosage of TRIKAFTA. Liver function tests should be closely monitored [see Warnings and Precautions (5.1) and Adverse Reactions (6)].

Moderate Hepatic Impairment (Child-Pugh Class B): Treatment is not recommended. Use of TRIKAFTA in patients with moderate hepatic impairment should only be considered when there is a clear medical need, and the benefit exceeds the risk. If used, TRIKAFTA should be used with caution at a reduced dose (see Table 2) [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)]. Liver function tests should be closely monitored [see Warnings and Precautions (5.1) and Adverse Reactions (6)]. Recommended dosage for patients with moderate hepatic impairment (Child-Pugh Class B) is provided in Table 2.

Table 2: Recommended Dosage of TRIKAFTA, if used, in Patients with Moderate Hepatic Impairment (Child-Pugh Class B)

Age Weight Morning Dose Evening Dose

2 to less than 6 years Less than 14 kg Weekly dosing schedule as follows:

Days 1-3: One packet (containing elexacaftor 80 mg/tezacaftor 40 mg/ivacaftor 60 mg) oral granules each day

Day 4: no dose

Days 5-6: One packet (containing elexacaftor 80 mg/tezacaftor 40 mg/ivacaftor 60 mg) oral granules each day

Day 7: no dose

No evening dose of ivacaftor oral granules.

14 kg or more Weekly dosing schedule as follows:

Days 1-3: One packet (containing elexacaftor 100 mg/tezacaftor 50 mg/ivacaftor 75 mg) oral granules each day

Day 4: no dose

Days 5-6: One packet (containing elexacaftor 100 mg/tezacaftor 50 mg/ivacaftor 75 mg) oral granules each day

Day 7: no dose

No evening dose of ivacaftor oral granules.

6 years to less than 12 years Less than 30 kg Alternating daily dosing schedule as follows:

Day 1: Two tablets of elexacaftor 50 mg/tezacaftor 25 mg/ivacaftor 37.5 mg (total dose of elexacaftor 100 mg/tezacaftor 50 mg/ivacaftor 75 mg)

Day 2: One tablet of elexacaftor 50 mg/tezacaftor 25 mg/ivacaftor 37.5 mg

No evening ivacaftor tablet dose.

30 kg or more Alternating daily dosing schedule as follows:

Day 1: Two tablets of elexacaftor 100 mg/tezacaftor 50 mg/ivacaftor 75 mg (total dose of elexacaftor 200 mg/tezacaftor 100 mg/ivacaftor 150 mg)

Day 2: One tablet elexacaftor 100 mg/tezacaftor 50 mg/ivacaftor 75 mg

No evening ivacaftor tablet dose.

12 years and older Alternating daily dosing schedule as follows:

Day 1: Two tablets of elexacaftor 100 mg/tezacaftor 50 mg/ivacaftor 75 mg (total dose of elexacaftor 200 mg/tezacaftor 100 mg/ivacaftor 150 mg)

Day 2: One tablet elexacaftor 100 mg/tezacaftor 50 mg/ivacaftor 75 mg

No evening ivacaftor tablet dose.

Severe Hepatic Impairment (Child-Pugh Class C): Should not be used. TRIKAFTA has not been studied in patients with severe hepatic impairment (Child-Pugh Class C), but the exposure is expected to be higher than in patients with moderate hepatic impairment. [see Warnings and Precautions (5.1), Adverse Reactions (6), Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)].

2.3Dosage Modification for Patients Taking Drugs that are CYP3A Inhibitors

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

Table 3: Dosage Modification for Concomitant Use of TRIKAFTA with Moderate and Strong CYP3A Inhibitors

Age Weight Moderate CYP3A Inhibitors Strong CYP3A Inhibitors

2 to less than 6 years Less than 14 kg Alternating daily dosing schedule is as follows:

Day 1: One packet (containing elexacaftor 80 mg/tezacaftor 40 mg/ivacaftor 60 mg) in the morning

Day 2: One packet (containing ivacaftor 59.5 mg) oral granules in the morning

No evening packet of ivacaftor oral granules. One packet (containing elexacaftor 80 mg/tezacaftor 40 mg/ivacaftor 60 mg) in the morning twice a week, approximately 3 to 4 days apart. No evening packet of ivacaftor oral granules.

14 kg or more Alternating daily dosing schedule is as follows:

Day 1: One packet (containing elexacaftor 100 mg/tezacaftor 50 mg/ivacaftor 75 mg) in the morning

Day 2: One packet (containing ivacaftor 75 mg) oral granules in the morning

No evening packet of ivacaftor oral granules. One packet (containing elexacaftor 100 mg/tezacaftor 50 mg/ivacaftor 75 mg) in the morning twice a week, approximately 3 to 4 days apart. No evening packet of ivacaftor oral granules.

6 years and older Less than 30 kg Alternating daily dosing schedule is as follows:

Day 1: Two tablets of elexacaftor 50 mg/tezacaftor 25 mg/ivacaftor 37.5 mg (total dose of elexacaftor 100 mg/tezacaftor 50 mg/ivacaftor 75 mg) in the morning

Day 2: One tablet of ivacaftor 75 mg in the morning

No evening ivacaftor tablet dose. 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) in the morning twice a week, approximately 3 to 4 days apart.No evening ivacaftor tablet dose.

30 kg or more Alternating daily dosing schedule is as follows:

Day 1: Two tablets elexacaftor 100 mg/tezacaftor 50 mg/ivacaftor 75 mg (total dose of elexacaftor 200 mg/tezacaftor 100 mg/ivacaftor 150 mg) in the morning

Day 2: One tablet of ivacaftor 150 mg in the morning

No evening ivacaftor tablet dose. Two tablets elexacaftor 100 mg/tezacaftor 50 mg/ivacaftor 75 mg (total dose of elexacaftor 200 mg/tezacaftor 100 mg/ivacaftor 150 mg) in the morning twice a week, approximately 3 to 4 days apart. No evening ivacaftor tablet dose.

12 years and older Alternating daily dosing schedule is as follows:

Day 1: Two tablets elexacaftor 100 mg/tezacaftor 50 mg/ivacaftor 75 mg (total dose of elexacaftor 200 mg/tezacaftor 100 mg/ivacaftor 150 mg) in the morning

Day 2: One tablet of ivacaftor 150 mg in the morning

No evening ivacaftor tablet dose. Two tablets elexacaftor 100 mg/tezacaftor 50 mg/ivacaftor 75 mg (total dose of elexacaftor 200 mg/tezacaftor 100 mg/ivacaftor 150 mg) in the morning twice a week, approximately 3 to 4 days apart. No evening ivacaftor tablet dose.

2.4Recommendations Regarding Missed Dose(s)

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

If more than 6 hours have passed since:

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

the missed evening dose, the patient should not take the missed dose. The next scheduled morning dose should be taken at the usual time.

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

2.5Administration Information

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

Instructions for Administration of Tablets

For oral use and swallow TRIKAFTA tablets whole.

Instructions for Administration of Oral Granules

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.

Recommended Dosage for Adult and Pediatric Patients Aged 2 Years and Older
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

Table 1: Recommended Dosage of TRIKAFTA for Adult and Pediatric Patients Aged 2 Years and Older
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 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

Table 2: Recommended Dosage of TRIKAFTA, if used, in Patients with Moderate Hepatic Impairment (Child-Pugh Class B)
Age	Weight	Morning Dose	Evening Dose
2 to less than 6 years	Less than 14 kg	Weekly dosing schedule as follows: Days 1-3: One packet (containing elexacaftor 80 mg/tezacaftor 40 mg/ivacaftor 60 mg) oral granules each day Day 4: no dose Days 5-6: One packet (containing elexacaftor 80 mg/tezacaftor 40 mg/ivacaftor 60 mg) oral granules each day Day 7: no dose	No evening dose of ivacaftor oral granules.
14 kg or more	Weekly dosing schedule as follows: Days 1-3: One packet (containing elexacaftor 100 mg/tezacaftor 50 mg/ivacaftor 75 mg) oral granules each day Day 4: no dose Days 5-6: One packet (containing elexacaftor 100 mg/tezacaftor 50 mg/ivacaftor 75 mg) oral granules each day Day 7: no dose	No evening dose of ivacaftor oral granules.
6 years to less than 12 years	Less than 30 kg	Alternating daily dosing schedule as follows: Day 1: Two tablets of elexacaftor 50 mg/tezacaftor 25 mg/ivacaftor 37.5 mg (total dose of elexacaftor 100 mg/tezacaftor 50 mg/ivacaftor 75 mg) Day 2: One tablet of elexacaftor 50 mg/tezacaftor 25 mg/ivacaftor 37.5 mg	No evening ivacaftor tablet dose.
30 kg or more	Alternating daily dosing schedule as follows: Day 1: Two tablets of elexacaftor 100 mg/tezacaftor 50 mg/ivacaftor 75 mg (total dose of elexacaftor 200 mg/tezacaftor 100 mg/ivacaftor 150 mg) Day 2: One tablet elexacaftor 100 mg/tezacaftor 50 mg/ivacaftor 75 mg	No evening ivacaftor tablet dose.
12 years and older		Alternating daily dosing schedule as follows: Day 1: Two tablets of elexacaftor 100 mg/tezacaftor 50 mg/ivacaftor 75 mg (total dose of elexacaftor 200 mg/tezacaftor 100 mg/ivacaftor 150 mg) Day 2: One tablet elexacaftor 100 mg/tezacaftor 50 mg/ivacaftor 75 mg	No evening ivacaftor tablet dose.

Table 3: Dosage Modification for Concomitant Use of TRIKAFTA with Moderate and Strong CYP3A Inhibitors
Age	Weight	Moderate CYP3A Inhibitors	Strong CYP3A Inhibitors
2 to less than 6 years	Less than 14 kg	Alternating daily dosing schedule is as follows: Day 1: One packet (containing elexacaftor 80 mg/tezacaftor 40 mg/ivacaftor 60 mg) in the morning Day 2: One packet (containing ivacaftor 59.5 mg) oral granules in the morning No evening packet of ivacaftor oral granules.	One packet (containing elexacaftor 80 mg/tezacaftor 40 mg/ivacaftor 60 mg) in the morning twice a week, approximately 3 to 4 days apart. No evening packet of ivacaftor oral granules.
14 kg or more	Alternating daily dosing schedule is as follows: Day 1: One packet (containing elexacaftor 100 mg/tezacaftor 50 mg/ivacaftor 75 mg) in the morning Day 2: One packet (containing ivacaftor 75 mg) oral granules in the morning No evening packet of ivacaftor oral granules.	One packet (containing elexacaftor 100 mg/tezacaftor 50 mg/ivacaftor 75 mg) in the morning twice a week, approximately 3 to 4 days apart. No evening packet of ivacaftor oral granules.
6 years and older	Less than 30 kg	Alternating daily dosing schedule is as follows: Day 1: Two tablets of elexacaftor 50 mg/tezacaftor 25 mg/ivacaftor 37.5 mg (total dose of elexacaftor 100 mg/tezacaftor 50 mg/ivacaftor 75 mg) in the morning Day 2: One tablet of ivacaftor 75 mg in the morning No evening ivacaftor tablet dose.	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) in the morning twice a week, approximately 3 to 4 days apart.No evening ivacaftor tablet dose.
30 kg or more	Alternating daily dosing schedule is as follows: Day 1: Two tablets elexacaftor 100 mg/tezacaftor 50 mg/ivacaftor 75 mg (total dose of elexacaftor 200 mg/tezacaftor 100 mg/ivacaftor 150 mg) in the morning Day 2: One tablet of ivacaftor 150 mg in the morning No evening ivacaftor tablet dose.	Two tablets elexacaftor 100 mg/tezacaftor 50 mg/ivacaftor 75 mg (total dose of elexacaftor 200 mg/tezacaftor 100 mg/ivacaftor 150 mg) in the morning twice a week, approximately 3 to 4 days apart. No evening ivacaftor tablet dose.
12 years and older		Alternating daily dosing schedule is as follows: Day 1: Two tablets elexacaftor 100 mg/tezacaftor 50 mg/ivacaftor 75 mg (total dose of elexacaftor 200 mg/tezacaftor 100 mg/ivacaftor 150 mg) in the morning Day 2: One tablet of ivacaftor 150 mg in the morning No evening ivacaftor tablet dose.	Two tablets elexacaftor 100 mg/tezacaftor 50 mg/ivacaftor 75 mg (total dose of elexacaftor 200 mg/tezacaftor 100 mg/ivacaftor 150 mg) in the morning twice a week, approximately 3 to 4 days apart. No evening ivacaftor tablet dose.

3 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, capsule-shaped and debossed with "T50" on one side and plain on the other

Ivacaftor tablets are light blue, capsule-shaped, and printed with "V 75" in black ink on one side and plain on the other

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

Elexacaftor, tezacaftor and ivacaftor tablets are orange, capsule-shaped and debossed with "T100" on one side and plain on the other

Ivacaftor tablets are light blue, capsule-shaped, and printed with "V 150" in black ink on one side and plain on the other

Oral Granules:

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

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

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

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

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

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

4 Contraindications

None.

None. (4)

5 Warnings And Precautions

Elevated transaminases and hepatic injury: Liver failure leading to transplantation has been reported in a patient with cirrhosis and portal hypertension while receiving TRIKAFTA. Avoid use of TRIKAFTA in patients with pre-existing advanced liver disease, (e.g., as evidenced by cirrhosis, portal hypertension, ascites, hepatic encephalopathy) unless the benefits are expected to outweigh the risks. If used in these patients, they should be closely monitored after the initiation of treatment. Isolated elevations of transaminases or bilirubin have been observed in CF patients treated with TRIKAFTA. In some instances, transaminase elevations have been associated with concomitant elevations in total bilirubin and/or international normalized ratio (INR) and have resulted in patients being hospitalized for intervention, including patients without a history of pre-existing liver disease. Monitor liver function tests (ALT, AST, and bilirubin). Interrupt dosing in the event of significant elevations. In patients with a history of hepatobiliary disease or liver function test elevations, monitor more frequently. (2.2, 5.1, 8.7)

Hypersensitivity reactions: Angioedema and anaphylaxis been reported with TRIKAFTA in the postmarketing setting. Initiate appropriate therapy in the event of a hypersensitivity reaction. (5.2)

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, co-administration is not recommended. (5.3, 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. (5.5, 8.4)

5.1Elevated Transaminases and Hepatic Injury

Liver failure leading to transplantation has been reported in a patient with cirrhosis and portal hypertension while receiving TRIKAFTA. Avoid use of TRIKAFTA in patients with pre-existing advanced liver disease (e.g., as evidenced by cirrhosis, portal hypertension, ascites, hepatic encephalopathy) unless the benefits are expected to outweigh the risks. If used in these patients, they should be closely monitored after the initiation of treatment [see Dosage and Administration (2.2), Adverse Reactions (6), Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)].

Isolated elevations of transaminases or bilirubin have been observed in patients with CF treated with TRIKAFTA. In some instances, transaminase elevations have been associated with concomitant elevations in total bilirubin and/or international normalized ratio (INR) and have resulted in patients being hospitalized for intervention, including in patients without a history of pre-existing liver disease.

Assessments of liver function tests (ALT, AST, and bilirubin) are recommended for all patients prior to initiating TRIKAFTA, every 3 months during the first year of treatment, and annually thereafter. In the event of significant elevations in liver function tests, e.g., ALT or AST >5 × the upper limit of normal (ULN) or ALT or AST >3 × ULN with bilirubin >2 × ULN, dosing should be interrupted, and laboratory tests closely followed until the abnormalities resolve. Following the resolution of liver function test elevations, consider the benefits and risks of resuming treatment. For patients with a history of hepatobiliary disease or liver function test elevations, more frequent monitoring should be considered [see Dosage and Administration (2.2), Adverse Reactions (6), Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)].

5.2Hypersensitivity 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.

5.3Concomitant Use with CYP3A Inducers

Exposure to ivacaftor is significantly decreased and exposure to elexacaftor and tezacaftor are expected to decrease by the concomitant use of strong CYP3A inducers, which may reduce the therapeutic effectiveness of TRIKAFTA. Therefore, co-administration with strong CYP3A inducers is not recommended [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)].

5.4Concomitant Use with CYP3A Inhibitors

Exposure to elexacaftor, tezacaftor and ivacaftor are increased when co-administered with strong or moderate CYP3A inhibitors. Therefore, the dose of TRIKAFTA should be reduced when used concomitantly with moderate or strong CYP3A inhibitors [see Dosage and Administration (2.3), Drug Interactions (7.2) and Clinical Pharmacology (12.3)].

5.5Cataracts

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

6 Adverse Reactions

The following clinically significant adverse reactions are discussed in greater detail in other sections of the labeling:

Elevated Transaminases and Hepatic Injury [see Warnings and Precautions (5.1)]

Hypersensitivity Reactions, Including Anaphylaxis [see Warnings and Precautions (5.2)]

Cataracts [see Warnings and Precautions (5.5)]

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 and blood bilirubin increased. (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.

The safety profile of TRIKAFTA is based on data from 510 CF patients aged 12 years and older in two double-blind, controlled trials of 24 weeks and 4 weeks treatment duration (Trials 1 and 2). Eligible patients were also able to participate in an open-label extension safety study (up to 96 weeks of TRIKAFTA). In the two controlled trials, a total of 257 patients aged 12 years and older received at least one dose of TRIKAFTA.

In addition, the following clinical trials have also been conducted [see Use in Specific Populations (8.4) and Clinical Pharmacology (12.3)]:

a 24-week, open-label trial in 66 patients with CF aged 6 to less than 12 years who were either homozygous for the F508del mutation or heterozygous for the F508del mutation and a mutation on the second allele that results in either no CFTR protein or a CFTR protein that is not responsive to ivacaftor and tezacaftor/ivacaftor (Trial 3).

a 24-week, open-label trial in 75 patients with CF aged 2 to less than 6 years. Patients who had at least one F508del mutation or a mutation known to be responsive to TRIKAFTA were eligible for the study (Trial 4).

In Trial 1, the proportion of patients who discontinued study drug prematurely due to adverse events was 1% for TRIKAFTA-treated patients and 0% for placebo-treated patients.

In Trial 1, serious adverse reactions that occurred more frequently in TRIKAFTA-treated patients compared to placebo were rash (1% vs <1%) and influenza (1% vs 0%). There were no deaths in Trials 1, 2, 3 and 4.

Table 4 shows adverse reactions occurring in ≥5% of TRIKAFTA-treated patients and higher than placebo by ≥1% in the 24-week, placebo-controlled, parallel-group trial (Trial 1).

Table 4: Adverse Drug Reactions in ≥5% of TRIKAFTA-Treated Patients and Higher than Placebo by ≥1% in Trial 1

Adverse Drug Reactions (Preferred Term) TRIKAFTAN=202n (%) PlaceboN=201n (%)

Headache 35 (17) 30 (15)

Upper respiratory tract infectionIncludes upper respiratory tract infection and viral upper respiratory tract infection 32 (16) 25 (12)

Abdominal painIncludes abdominal pain, abdominal pain upper, abdominal pain lower 29 (14) 18 (9)

Diarrhea 26 (13) 14 (7)

RashIncludes 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.

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

Rash Events

In Trial 1, the overall incidence of rash events was 10% in TRIKAFTA-treated and 5% in placebo-treated patients (see Table 4). The incidence of rash events was higher in female TRIKAFTA-treated patients (16%) than in male TRIKAFTA-treated patients (5%).

Hormonal contraceptives may play a role in the occurrence of rash. For patients 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.

Laboratory and Vital Sign Abnormalities

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.

Increased Creatine Phosphokinase

In Trial 1, the incidence of maximum creatine phosphokinase elevation >5 × ULN was 10% in TRIKAFTA-treated and 5% in placebo-treated patients. Among the TRIKAFTA-treated patients with creatine phosphokinase elevation >5 × ULN, 14% (3/21) required treatment interruption and none discontinued treatment.

Increased Blood Pressure

In Trial 1, the maximum increase from baseline in mean systolic and diastolic blood pressure was 3.5 mmHg and 1.9 mmHg, respectively for TRIKAFTA-treated patients (baseline: 113 mmHg systolic and 69 mmHg diastolic) and 0.9 mmHg and 0.5 mmHg, respectively for placebo-treated patients (baseline: 114 mmHg systolic and 70 mmHg diastolic).

The proportion of patients who had systolic blood pressure >140 mmHg and 10 mmHg increase from baseline on at least two occasions was 4% in TRIKAFTA-treated patients and 1% in placebo-treated patients. The proportion of patients who had diastolic blood pressure >90 mmHg and 5 mmHg increase from baseline on at least two occasions was 1% in TRIKAFTA-treated patients and 2% in placebo-treated patients.

With the exception of sex differences in rash, the safety profile of TRIKAFTA was generally similar across all subgroups of patients, including analysis by age, sex, baseline percent predicted FEV₁ (ppFEV₁) and geographic regions.

6.2 Postmarketing Experience

The following adverse reactions have been identified during post approval use of TRIKAFTA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Hepatobiliary: Liver failure leading to transplantation in a patient with pre-existing cirrhosis and portal hypertension. Liver injury characterized by concomitant transaminase (ALT and AST) and total bilirubin elevations [see Warnings and Precautions (5.1)].

Immune System Disorders: anaphylaxis, angioedema

7 Drug Interactions

Potential for other drugs to affect elexacaftor/tezacaftor/ivacaftor

Strong CYP3A inducers: Avoid co-administration. (5.3, 7.1, 12.3)

Strong or moderate CYP3A inhibitors: Reduce TRIKAFTA dosage when co-administered. Avoid food or drink containing grapefruit. (2.3, 5.4, 7.2, 12.3)

7.1Inducers of CYP3A

Elexacaftor, tezacaftor and ivacaftor are substrates of CYP3A (ivacaftor is a sensitive substrate of CYP3A). Concomitant use of CYP3A inducers may result in reduced exposures and thus reduced TRIKAFTA efficacy. Co-administration of ivacaftor with rifampin, a strong CYP3A inducer, significantly decreased ivacaftor area under the curve (AUC) by 89%. Elexacaftor and tezacaftor exposures are expected to decrease during co-administration with strong CYP3A inducers. Therefore, co-administration of TRIKAFTA with strong CYP3A inducers is not recommended [see Warnings and Precautions (5.3) and Clinical Pharmacology (12.3)].

Examples of strong CYP3A inducers include:

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

7.2Inhibitors of CYP3A

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

Examples of strong CYP3A inhibitors include:

ketoconazole, itraconazole, posaconazole and voriconazole

telithromycin and clarithromycin

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

Examples of moderate CYP3A inhibitors include:

fluconazole

erythromycin

Co-administration of TRIKAFTA with grapefruit juice, which contains one or more components that moderately inhibit CYP3A, may increase exposure of elexacaftor, tezacaftor and ivacaftor; therefore, food or drink containing grapefruit should be avoided during treatment with TRIKAFTA [see Dosage and Administration (2.3)].

7.3Ciprofloxacin

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

Potential for elexacaftor/tezacaftor/ivacaftor to affect other drugs

7.4CYP2C9 Substrates

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

7.5Transporters

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

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

7.6Hormonal Contraceptives

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

8 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 teratogenicity or 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 teratogenicity or 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 teratogenicity or 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

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 ¹⁴C-elexacaftor administered 6 to 10 days postpartum to lactating dams. Exposure of ¹⁴C-elexacaftor in milk was approximately 0.4 times the value observed in plasma (based on AUC_0-72h).

Tezacaftor

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

Ivacaftor

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

8.4 Pediatric Use

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

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

Trial 1, 56 pediatric patients aged 12 to less than 18 years who had an F508del mutation on one allele and a mutation on the second allele that results in either no CFTR protein or a CFTR protein that is not responsive to ivacaftor and tezacaftor/ivacaftor [see Adverse Reactions (6) and Clinical Studies (14)].

Trial 2, 16 pediatric patients aged 12 to less than 18 years who were homozygous for the F508del mutation [see Adverse Reactions (6) and Clinical Studies (14)].

Trial 3, 66 pediatric patients aged 6 to less than 12 years who were homozygous for the F508del mutation or heterozygous for the F508del mutation with a mutation on the second allele that results in either no CFTR protein or a CFTR protein that is not responsive to ivacaftor and tezacaftor/ivacaftor [see Adverse Reactions (6) and Clinical Pharmacology (12.3)].

Trial 4, 75 pediatric patients aged 2 to less than 6 years who had at least one F508del mutation or a mutation known to be responsive to TRIKAFTA [see Adverse Reactions (6) and Clinical Pharmacology (12.3)].

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

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

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 (5.5)].

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.

8.5 Geriatric Use

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

8.6 Renal Impairment

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

8.7 Hepatic Impairment

Mild Hepatic Impairment (Child-Pugh Class A): No dose modification is recommended. Liver function tests should be closely monitored.

Moderate Hepatic Impairment (Child-Pugh Class B): Treatment is not recommended. Use of TRIKAFTA in patients with moderate hepatic impairment should only be considered when there is a clear medical need, and the benefit exceeds the risk. If used in patients with moderate hepatic impairment, TRIKAFTA should be used at a reduced dose [see Dosage and Administration (2.2)]. Liver function tests should be closely monitored. In a clinical study of 11 subjects with moderate hepatic impairment, one subject developed total and direct bilirubin elevations >2 × ULN, and a second subject developed direct bilirubin elevation >4.5 × ULN [see Clinical Pharmacology (12.3)].

Severe Hepatic Impairment (Child-Pugh Class C): Should not be used. TRIKAFTA has not been studied in patients with severe hepatic impairment (Child-Pugh Class C), but the exposure is expected to be higher than in patients with moderate hepatic impairment [see Dosage and Administration (2.2), Warnings and Precautions (5.1), Adverse Reactions (6) and Clinical Pharmacology (12.3)].

8.8Patients with Severe Lung Dysfunction

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

10 Overdosage

No specific antidote is available for overdosage with TRIKAFTA. Treatment of overdosage consists of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient.

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, capsule-shaped, film-coated tablet containing 100 mg of elexacaftor, 50 mg of tezacaftor, 75 mg of ivacaftor, or light-orange, capsule-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, capsule-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 C₂₆H₃₄N₇O₄SF₃ and its molecular weight is 597.66. Elexacaftor has the following structural formula:

Tezacaftor

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

Ivacaftor

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

12 Clinical Pharmacology

12.1 Mechanism of Action

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

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

CFTR Chloride Transport Assay in Fischer Rat Thyroid (FRT) Cells Expressing Mutant CFTR

The chloride transport response of mutant CFTR protein to elexacaftor/tezacaftor/ivacaftor was determined in Ussing chamber electrophysiology studies using a panel of FRT cell lines transfected with individual CFTR mutations. Elexacaftor/tezacaftor/ivacaftor increased chloride transport in FRT cells expressing CFTR mutations that result in CFTR protein being delivered to the cell surface.

The in vitro CFTR chloride transport response threshold was designated as a net increase of at least 10% of normal over baseline because it is predictive or reasonably expected to predict clinical benefit. For individual mutations, the magnitude of the net change over baseline in CFTR-mediated chloride transport in vitro is not correlated with the magnitude of clinical response.

Table 5 uls responsive CFTR mutations based on in vitro data in FRT cells indicating that elexacaftor/tezacaftor/ivacaftor increases chloride transport to at least 10% of normal over baseline.

Table 5: List of CFTR Gene Mutations that are Responsive to TRIKAFTA

3141del9 E822K G1069R L967S R117L S912L

546insCTA F191V G1244E L997F R117P S945L

A46D F311del G1249R L1077P R170H S977F

A120T F311L G1349D L1324P R258G S1159F

A234D F508C H139R L1335P R334L S1159P

A349V F508C;S1251N Complex/compound mutations where a single allele of the CFTR gene has multiple mutations; these exist independent of the presence of mutations on the other allele. H199Y L1480P R334Q S1251N

A455E F508del F508del is a responsive CFTR mutation based on both clinical and in vitro data [see Clinical Studies (14)]. H939R M152V R347H S1255P

A554E F575Y H1054D M265R R347L T338I

A1006E F1016S H1085P M952I R347P T1036N

A1067T F1052V H1085R M952T R352Q T1053I

D110E F1074L H1375P M1101K R352W V201M

D110H F1099L I148T P5L R553Q V232D

D192G G27R I175V P67L R668C V456A

D443Y G85E I336K P205S R751L V456F

D443Y;G576A;R668C G126D I502T P574H R792G V562I

D579G G178E I601F Q98R R933G V754M

D614G G178R I618T Q237E R1066H V1153E

D836Y G194R I807M Q237H R1070Q V1240G

D924N G194V I980K Q359R R1070W V1293G

D979V G314E I1027T Q1291R R1162L W361R

D1152H G463V I1139V R31L R1283M W1098C

D1270N G480C I1269N R74Q R1283S W1282R

E56K G551D I1366N R74W S13F Y109N

E60K G551S K1060T R74W;D1270N S341P Y161D

E92K G576A L15P R74W;V201M S364P Y161S

E116K G576A;R668C L165S R74W;V201M;D1270N S492F Y563N

E193K G622D L206W R75Q S549N Y1014C

E403D G628R L320V R117C S549R Y1032C

E474K G970D L346P R117G S589N

E588V G1061R L453S R117H S737F

12.2 Pharmacodynamics

Sweat Chloride Evaluation

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

Cardiac Electrophysiology

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

12.3 Pharmacokinetics

The pharmacokinetics of elexacaftor, tezacaftor and ivacaftor are similar between healthy adult subjects and patients with CF. The pharmacokinetic parameters for elexacaftor, tezacaftor and ivacaftor in patients with CF aged 12 years and older are shown in Table 6.

Table 6: Pharmacokinetic Parameters of TRIKAFTA Components

Elexacaftor Tezacaftor Ivacaftor

AUC_ss: area under the concentration versus time curve at steady state; SD: Standard Deviation; C_max: maximum observed concentration; T_max: time of maximum concentration; AUC: area under the concentration versus time curve.

General Information

  AUC_ss (SD), mcg∙h/mLBased on elexacaftor 200 mg and tezacaftor 100 mg once daily/ivacaftor 150 mg every 12 hours at steady state in patients with CF aged 12 years and older. 162 (47.5)AUC_0-24h. 89.3 (23.2) 11.7 (4.01)AUC_0-12h.

  C_max (SD), mcg/mL 9.2 (2.1) 7.7 (1.7) 1.2 (0.3)

  Time to Steady State, days Within 7 days Within 8 days Within 3-5 days

  Accumulation Ratio 2.2 2.07 2.4

Absorption

  Absolute Bioavailability 80% Not determined Not determined

  Median T_max (range), hours 6 (4 to 12) 3 (2 to 4) 4 (3 to 6)

  Effect of Food AUC increases 1.9- to 2.5-fold(moderate-fat meal) No clinically significant effect Exposure increases 2.5- to 4-fold

Distribution

  Mean (SD) Apparent Volume of Distribution, LElexacaftor, tezacaftor and ivacaftor do not partition preferentially into human red blood cells. 53.7 (17.7) 82.0 (22.3) 293 (89.8)

  Protein BindingElexacaftor and tezacaftor bind primarily to albumin. Ivacaftor primarily bind to albumin, alpha 1-acid glycoprotein and human gamma-globulin. >99% approximately 99% approximately 99%

Elimination

  Mean (SD) Effective Half-Life, hoursMean (SD) terminal half-lives of elexacaftor, tezacaftor and ivacaftor are approximately 24.7 (4.87) hours, 60.3 (15.7) hours and 13.1 (2.98) hours, respectively. 27.4 (9.31) 25.1 (4.93) 15.0 (3.92)

  Mean (SD) Apparent Clearance, L/hours 1.18 (0.29) 0.79 (0.10) 10.2 (3.13)

Metabolism

  Primary Pathway CYP3A4/5 CYP3A4/5 CYP3A4/5

  Active Metabolites M23-ELX M1-TEZ M1-IVA

  Metabolite Potency Relative to Parent Similar Similar approximately 1/6^th of parent

ExcretionFollowing radiolabeled doses.

  Primary Pathway

Feces: 87.3% (primarily as metabolites)

Urine: 0.23%

Feces: 72% (unchanged or as M2-TEZ)

Urine: 14% (0.79% unchanged)

Feces: 87.8%

Urine: 6.6%

Specific Populations

Pediatric Patients 2 to Less Than 12 Years of Age

Elexacaftor, tezacaftor and ivacaftor exposures observed in patients aged 2 to less than 12 years as determined using population PK analysis are presented by age group and dose administered in Table 7. Elexacaftor, tezacaftor and ivacaftor exposures in this patient population are within the range observed in patients aged 12 years and older.

Table 7: Mean (SD) Elexacaftor, Tezacaftor and Ivacaftor Exposures Observed at Steady State by Age Group and Dose Administered

Age Group Dose ElexacaftorAUC_0-24h,ss (µg∙h/mL) Tezacaftor AUC_0-24h,ss (µg∙h/mL) Ivacaftor AUC_0-12h,ss (µg∙h/mL)

SD: Standard Deviation; AUC_ss: area under the concentration versus time curve at steady state.

Patients aged 2 to less than 6 years weighing less than 14 kg(N = 16) elexacaftor 80 mg qd/tezacaftor 40 mg qd/ivacaftor 60 mg qAM and ivacaftor 59.5 mg qPM 128 (24.8) 87.3 (17.3) 11.9 (3.86)

Patients aged 2 to less than 6 years weighing 14 kg or more(N = 59) elexacaftor 100 mg qd/tezacaftor 50 mg qd/ivacaftor 75 mg q12h 138 (47.0) 90.2 (27.9) 13.0 (6.11)

Patients aged 6 to less than 12 years weighing less than 30 kg (N = 36) elexacaftor 100 mg qd/tezacaftor 50 mg qd/ivacaftor 75 mg q12h 116 (39.4) 67.0 (22.3) 9.78 (4.50)

Patients aged 6 to less than 12 years weighing 30 kg or more(N = 30) elexacaftor 200 mg qd/ tezacaftor 100 mg qd/ ivacaftor 150 mg q12h 195 (59.4) 103 (23.7) 17.5 (4.97)

Pediatric Patients 12 to Less Than 18 Years of Age

The following conclusions about exposures between adults and the pediatric population are based on population pharmacokinetic (PK) analyses. Following oral administration of TRIKAFTA to patients 12 to less than 18 years of age (elexacaftor 200 mg qd/tezacaftor 100 mg qd/ivacaftor 150 mg q12h), the mean (±SD) AUC_ss was 147 (36.8) mcg∙h/mL, 88.8 (21.8) mcg∙h/mL and 10.6 (3.35) mcg∙h/mL, respectively for elexacaftor, tezacaftor and ivacaftor, similar to the AUC_ss in adult patients.

Patients with Renal Impairment

Renal excretion of elexacaftor, tezacaftor and ivacaftor is minimal. Elexacaftor alone or in combination with tezacaftor and ivacaftor has not been studied in subjects with severe (eGFR <30 mL/min/1.73 m²) renal impairment or end-stage renal disease. Based on population PK analyses, the clearance of elexacaftor and tezacaftor was similar in subjects with mild (eGFR 60 to <90 mL/min/1.73 m²) or moderate (eGFR 30 to <60 mL/min/1.73 m²) renal impairment relative to patients with normal renal function [see Use in Specific Populations (8.6)].

Patients with Hepatic Impairment

Elexacaftor alone or in combination with tezacaftor and ivacaftor has not been studied in subjects with severe hepatic impairment (Child-Pugh Class C, score 10-15). In a clinical study, following multiple doses of elexacaftor, tezacaftor and ivacaftor for 10 days, subjects with moderately impaired hepatic function (Child-Pugh Class B, score 7-9) had 25% higher AUC and 12% higher C_max for elexacaftor, 73% higher AUC and 70% higher C_max for M23-ELX, 36% higher AUC and 24% higher C_max for combined elexacaftor and M23-ELX, 20% higher AUC but similar C_max for tezacaftor and 1.5-fold higher AUC and 10% higher C_max for ivacaftor compared with healthy subjects matched for demographics [see Dosage and Administration (2.2), Warnings and Precautions (5.1), Adverse Reactions (6) and Use in Specific Populations (8.7)].

Male and Female Patients

Based on population PK analysis, the exposures of elexacaftor, tezacaftor and ivacaftor are similar in males and females.

Drug Interaction Studies

Drug interaction studies were performed with elexacaftor, tezacaftor and/or ivacaftor and other drugs likely to be co-administered or drugs commonly used as probes for pharmacokinetic interaction studies [see Drug Interactions (7)].

Potential for Elexacaftor, Tezacaftor and/or Ivacaftor to Affect Other Drugs

Based on in vitro results, elexacaftor and tezacaftor have a low potential to inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A4, whereas ivacaftor has the potential to inhibit CYP2C8, CYP2C9 and CYP3A. However, clinical studies showed that the combination regimen of tezacaftor/ivacaftor is not an inhibitor of CYP3A and ivacaftor is not an inhibitor of CYP2C8 or CYP2D6.

Based on in vitro results, elexacaftor, tezacaftor and ivacaftor are not likely to induce CYP3A, CYP1A2 and CYP2B6.

Based on in vitro results, elexacaftor and tezacaftor have a low potential to inhibit the transporter P-gp, while ivacaftor has the potential to inhibit P-gp. Co-administration of tezacaftor/ivacaftor with digoxin, a sensitive P-gp substrate, increased digoxin exposure by 1.3-fold in a clinical study. Based on in vitro results, elexacaftor and M23-ELX may inhibit OATP1B1 and OATP1B3 uptake. Tezacaftor has a low potential to inhibit BCRP, OCT2, OAT1, or OAT3. Ivacaftor is not an inhibitor of the transporters OCT1, OCT2, OAT1, or OAT3.

The effects of elexacaftor, tezacaftor and/or ivacaftor on the exposure of co-administered drugs are shown in Table 8 [see Drug Interactions (7)].

Table 8: Impact of Elexacaftor, Tezacaftor and/or Ivacaftor on Other Drugs

Dose and Schedule Effect on Other Drug PK Geometric Mean Ratio (90% CI) of Other DrugNo Effect=1.0

AUC C_max

↑ = increase, ↓ = decrease, ↔ = no change. CI = Confidence Interval; ELX= elexacaftor; TEZ = tezacaftor; IVA = ivacaftor; PK = Pharmacokinetics

Midazolam2 mg single oral dose TEZ 100 mg qd/IVA 150 mg q12h ↔ Midazolam 1.12(1.01, 1.25) 1.13(1.01, 1.25)

Digoxin0.5 mg single dose TEZ 100 mg qd/IVA 150 mg q12h ↑ Digoxin 1.30(1.17, 1.45) 1.32(1.07, 1.64)

Oral ContraceptiveEthinyl estradiol 30 µg/Levonorgestrel 150 µg qd ELX 200 mg qd/TEZ 100 mg qd/IVA 150 mg q12h ↑ Ethinyl estradiol Effect not clinically significant [see Drug Interactions (7.6)]. 1.33(1.20, 1.49) 1.26(1.14, 1.39)

↑ Levonorgestrel 1.23(1.10, 1.37) 1.10(0.985, 1.23)

Rosiglitazone4 mg single oral dose IVA 150 mg q12h ↔ Rosiglitazone 0.975(0.897, 1.06) 0.928(0.858, 1.00)

Desipramine50 mg single dose IVA 150 mg q12h ↔ Desipramine 1.04(0.985, 1.10) 1.00(0.939; 1.07)

Potential for Other Drugs to Affect Elexacaftor, Tezacaftor and/or Ivacaftor

In vitro studies showed that elexacaftor, tezacaftor and ivacaftor are all metabolized by CYP3A. Exposure to elexacaftor, tezacaftor and ivacaftor may be reduced by concomitant CYP3A inducers and increased by concomitant CYP3A inhibitors.

In vitro studies showed that elexacaftor and tezacaftor are substrates for the efflux transporter P-gp, but ivacaftor is not. Elexacaftor and ivacaftor are not substrates for OATP1B1 or OATP1B3; tezacaftor is a substrate for OATP1B1, but not OATP1B3. Tezacaftor is a substrate for BCRP.

The effects of co-administered drugs on the exposure of elexacaftor, tezacaftor and/or ivacaftor are shown in Table 9 [see Dosage and Administration (2.3) and Drug Interactions (7)].

Table 9: Impact of Other Drugs on Elexacaftor, Tezacaftor and/or Ivacaftor

Dose and Schedule Effect on ELX, TEZ and/or IVA PK Geometric Mean Ratio (90% CI) of Elexacaftor, Tezacaftor and IvacaftorNo Effect = 1.0

AUC C_max

↑ = increase, ↓ = decrease, ↔ = no change. CI = Confidence Interval; ELX= elexacaftor; TEZ = tezacaftor; IVA = ivacaftor; PK = Pharmacokinetics

Itraconazole200 mg q12h on Day 1, followed by 200 mg qd TEZ 25 mg qd + IVA 50 mg qd ↑ Tezacaftor 4.02(3.71, 4.63) 2.83(2.62, 3.07)

↑ Ivacaftor 15.6(13.4, 18.1) 8.60(7.41, 9.98)

Itraconazole200 mg qd ELX 20 mg + TEZ 50 mg single dose ↑ Elexacaftor 2.83(2.59, 3.10) 1.05(0.977, 1.13)

↑ Tezacaftor 4.51(3.85, 5.29) 1.48(1.33, 1.65)

Ketoconazole400 mg qd IVA 150 mg single dose ↑ Ivacaftor 8.45(7.14, 10.0) 2.65(2.21, 3.18)

Ciprofloxacin750 mg q12h TEZ 50 mg q12h + IVA 150 mg q12h ↔ Tezacaftor 1.08(1.03, 1.13) 1.05(0.99, 1.11)

↑ IvacaftorEffect is not clinically significant [see Drug Interactions (7.3)]. 1.17(1.06, 1.30) 1.18(1.06, 1.31)

Rifampin600 mg qd IVA 150 mg single dose ↓ Ivacaftor 0.114(0.097, 0.136) 0.200(0.168, 0.239)

Fluconazole400 mg single dose on Day 1, followed by 200 mg qd IVA 150 mg q12h ↑ Ivacaftor 2.95(2.27, 3.82) 2.47(1.93, 3.17)

13 Nonclinical Toxicology

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

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

Elexacaftor

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

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

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

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

Tezacaftor

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

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

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

Ivacaftor

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

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

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

14 Clinical Studies

Efficacy:

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

Trial 1 was a 24-week, randomized, double-blind, placebo-controlled study in patients who had an F508del mutation on one allele and a mutation on the second allele that results in either no CFTR protein or a CFTR protein that is not responsive to ivacaftor and tezacaftor/ivacaftor. An interim analysis was planned when at least 140 patients completed Week 4 and at least 100 patients completed Week 12.

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

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

14.1Trial 1

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

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

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

Table 10: Primary and Key Secondary Efficacy Analyses (Trial 1)

Analysis Statistic Treatment DifferenceTreatment difference provided as the outcome measure for changes in ppFEV₁, sweat chloride, CFQ-R and BMI; Rate ratio provided as the outcome measure for the number of pulmonary exacerbations. for TRIKAFTA (N=200) vs Placebo (N=203)

ppFEV₁: percent predicted Forced Expiratory Volume in 1 second; CI: Confidence Interval; CFQ-R: Cystic Fibrosis Questionnaire-Revised; BMI: Body Mass Index.

Primary (Interim Full Analysis Set) Primary endpoint was based on interim analysis in 403 patients.

Absolute change in ppFEV₁ from baseline at Week 4 (percentage points) Treatment difference (95% CI) P value 13.8 (12.1, 15.4) P<0.0001

Key Secondary (Full Analysis Set) Key secondary endpoints were tested at the final analysis in 403 patients.

Absolute change in ppFEV₁ from baseline through Week 24 (percentage points) Treatment difference (95% CI) P value 14.3 (12.7, 15.8) P<0.0001

Number of pulmonary exacerbations from baseline through Week 24A pulmonary exacerbation was defined as a change in antibiotic therapy (IV, inhaled, or oral) as a result of 4 or more of 12 pre-specified sino-pulmonary signs/symptoms. Number of pulmonary exacerbation events (event rate per year calculated based on 48 weeks per year) in the TRIKAFTA group were 41 (0.37) and 113 (0.98) in the placebo group. Rate ratio (95% CI) P value 0.37 (0.25, 0.55) P<0.0001

Absolute change in sweat chloride from baseline through Week 24 (mmol/L) Treatment difference (95% CI) P value -41.8 (-44.4, -39.3) P<0.0001

Absolute change in CFQ-R respiratory domain score from baseline through Week 24 (points) Treatment difference (95% CI) P value 20.2 (17.5, 23.0) P<0.0001

Absolute change in BMI from baseline at Week 24 (kg/m²) Treatment difference (95% CI) P value 1.04 (0.85, 1.23) P<0.0001

Absolute change in sweat chloride from baseline at Week 4 (mmol/L) Treatment difference (95% CI) P value -41.2 (-44.0, -38.5) P<0.0001

Absolute change in CFQ-R respiratory domain score from baseline at Week 4 (points) Treatment difference (95% CI) P value 20.1 (16.9, 23.2) P<0.0001

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

14.2Trial 2

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

Table 11: Primary and Key Secondary Efficacy Analyses, Full Analysis Set (Trial 2)

AnalysisBaseline for primary and key secondary endpoints is defined as the end of the 4-week tezacaftor/ivacaftor run-in period. Statistic Treatment Difference for TRIKAFTA (N=55) vs Tezacaftor/IvacaftorRegimen of tezacaftor 100 mg qd/ivacaftor 150 mg q12h. (N=52)

ppFEV₁: percent predicted Forced Expiratory Volume in 1 second; CI: Confidence Interval; CFQ-R: Cystic Fibrosis Questionnaire-Revised.

Primary

Absolute change in ppFEV₁ from baseline at Week 4 (percentage points) Treatment difference (95% CI) P value 10.0 (7.4, 12.6) P<0.0001

Key Secondary

Absolute change in sweat chloride from baseline at Week 4 (mmol/L) Treatment difference (95% CI) P value -45.1 (-50.1, -40.1) P<0.0001

Absolute change in CFQ-R respiratory domain score from baseline at Week 4 (points) Treatment difference (95% CI) P value 17.4 (11.8, 23.0) P<0.0001

16 How Supplied/storage And Handling

TRIKAFTA tablets are supplied in a co-packaged buler 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.

The elexacaftor 50 mg, tezacaftor 25 mg, and ivacaftor 37.5 mg tablets are supplied as light orange, capsule-shaped tablets; each containing 50 mg of elexacaftor, 25 mg of tezacaftor and 37.5 mg of ivacaftor. Each tablet is debossed with "T50" on one side and plain on the other. Ivacaftor 75 mg tablets are supplied as light blue, film-coated, capsule-shaped tablets; each containing 75 mg of ivacaftor. Each tablet is printed with the characters "V 75" in black ink on one side and plain on the other. TRIKAFTA is supplied as:

84-count tablet carton(4 wallets, each wallet containing 14 tablets of elexacaftor, tezacaftor and ivacaftor and 7 tablets of ivacaftor) NDC 51167-106-02

The elexacaftor 100 mg, tezacaftor 50 mg, and ivacaftor 75 mg tablets are supplied as orange, capsule-shaped tablets; each containing 100 mg of elexacaftor, 50 mg of tezacaftor and 75 mg of ivacaftor. Each tablet is debossed with "T100" on one side and plain on the other. Ivacaftor 150 mg tablets are supplied as light blue, film-coated, capsule-shaped tablets; each containing 150 mg of ivacaftor. Each tablet is printed with the characters "V 150" in black ink on one side and plain on the other. TRIKAFTA is supplied as:

84-count tablet carton(4 wallets, each wallet containing 14 tablets of elexacaftor, tezacaftor and ivacaftor and 7 tablets of ivacaftor) NDC 51167-331-01

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.

The elexacaftor 80 mg, tezacaftor 40 mg and ivacaftor 60 mg oral granules are supplied as white to off-white, sweetened, unflavored granules approximately 2 mm in diameter enclosed in unit-dose packets each containing 80 mg of elexacaftor, 40 mg of tezacaftor and 60 mg of ivacaftor. The packets are white and blue. The ivacaftor 59.5 mg oral granules are supplied as white to off-white, sweetened, unflavored granules approximately 2 mm in diameter enclosed in unit-dose packets each containing 59.5 mg of ivacaftor. The packets are white and green. TRIKAFTA is supplied as:

56-count packet carton(4 wallets, each containing 7 packets of elexacaftor, tezacaftor, and ivacaftor and 7 packets of ivacaftor) NDC 51167-445-01

The elexacaftor 100 mg, tezacaftor 50 mg and ivacaftor 75 mg oral granules are supplied as white to off-white, sweetened, unflavored granules approximately 2 mm in diameter enclosed in unit-dose packets each containing 100 mg of elexacaftor, 50 mg of tezacaftor and 75 mg of ivacaftor. The packets are white and orange. The ivacaftor 75 mg oral granules are supplied as white to off-white, sweetened, unflavored granules approximately 2 mm in diameter enclosed in unit-dose packets each containing 75 mg of ivacaftor. The packets are white and pink. TRIKAFTA is supplied as:

56-count packet carton(4 wallets, each containing 7 packets of elexacaftor, tezacaftor, and ivacaftor and 7 packets of ivacaftor) NDC 51167-446-01

STORAGE AND HANDLING SECTION

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

17 Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (Patient Information).

Elevated Transaminases and Hepatic Injury

Inform the patients that liver failure leading to transplantation has been reported in a patient with cirrhosis with portal hypertension while receiving TRIKAFTA. Avoid use of TRIKAFTA in patients with pre-existing advanced liver disease (e.g., cirrhosis, portal hypertension, ascites, hepatic encephalopathy) unless the benefits are expected to outweigh the risks. If used in these patients, they should be closely monitored after the initiation of treatment [see Dosage and Administration (2.2), Warnings and Precautions (5.1), Adverse Reactions (6), Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)].

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

Drug Interactions with CYP3A Inducers and Inhibitors

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

Use in Patients with Hepatic Impairment

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

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

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

Hypersensitivity Reactions, Including Anaphylaxis

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

Cataracts

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

Administration

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

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

If 6 hours or less have passed since the missed morning or evening dose is usually taken, patients should be instructed to take the prescribed dose with fat-containing food as soon as possible.

If more than 6 hours have passed since:

the time the morning dose is usually taken, patients should be instructed to take the morning dose as soon as possible, and not take the evening dose. Patients should take the next scheduled morning dose at the usual time.

the time the evening dose is usually taken, patients should be instructed to not take the missed evening dose. Patients should take the next scheduled morning dose at the usual time.

Patients should be instructed to not take the morning and evening doses at the same time.

Patients should be advised to contact their health care provider if they have questions.

Manufactured forVertex Pharmaceuticals Incorporated50 Northern AvenueBoston, MA 02210

TRIKAFTA, VERTEX and associated logos are registered trademarks of Vertex Pharmaceuticals Incorporated.All other trademarks referenced herein are the property of their respective owners.©2023 Vertex Pharmaceuticals IncorporatedALL RIGHTS RESERVED

Spl Patient Package Insert Section

This Patient Information has been approved by the U.S. Food and Drug Administration. Revised: 08/2023

Patient Information TRIKAFTA^® (tri-KAF-tuh) (elexacaftor, tezacaftor, and ivacaftor tablets; ivacaftor tablets), co-packaged for oral use (elexacaftor, tezacaftor, and ivacaftor oral granules; ivacaftor oral granules), co-packaged

What is TRIKAFTA?

TRIKAFTA is a prescription medicine used for the treatment of cystic fibrosis (CF) in people aged 2 years and older who have at least one copy of the F508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene or another mutation that is responsive to treatment with TRIKAFTA.

Talk to your doctor to learn if you have an indicated CF gene mutation.

It is not known if TRIKAFTA is safe and effective in children under 2 years of age.

Before taking TRIKAFTA, tell your doctor about all of your medical conditions, including if you:

are allergic to TRIKAFTA or any ingredients in TRIKAFTA. See the end of this patient information leaflet for a complete ul of ingredients in TRIKAFTA.

have kidney problems.

have or have had liver problems.

are pregnant or plan to become pregnant. It is not known if TRIKAFTA will harm your unborn baby. You and your doctor should decide if you will take TRIKAFTA while you are pregnant.

are breastfeeding or planning to breastfeed. It is not known if TRIKAFTA passes into your breast milk. You and your doctor should decide if you will take TRIKAFTA while you are breastfeeding.

Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. TRIKAFTA may affect the way other medicines work and other medicines may affect how TRIKAFTA works. The dose of TRIKAFTA may need to be adjusted when taken with certain medicines. Ask your doctor or pharmacist for a ul of these medicines if you are not sure. Especially tell your doctor if you take:

antibiotics such as rifampin (RIFAMATE^®, RIFATER^®) or rifabutin (MYCOBUTIN^®)

seizure medicines such as phenobarbital, carbamazepine (TEGRETOL^®, CARBATROL^®, EQUETRO^®), or phenytoin (DILANTIN^®, PHENYTEK^®)

St. John's wort

antifungal medicines including ketoconazole, itraconazole (such as SPORANOX^®), posaconazole (such as NOXAFIL^®), voriconazole (such as VFEND^®), or fluconazole (such as DIFLUCAN^®).

antibiotics including telithromycin, clarithromycin (such as BIAXIN^®), or erythromycin (such as ERY-TAB^®).

Know the medicines you take. Keep a ul of them to show your doctor and pharmacist when you get a new medicine.

How should I take TRIKAFTA?

Take TRIKAFTA exactly as your doctor tells you to take it.

Take TRIKAFTA by mouth only.

TRIKAFTA consists of 2 different doses (a morning dose and an evening dose). Each dose has different ingredients.

Always take TRIKAFTA oral granules or tablets with food that contains fat. Examples of fat-containing foods include butter, oil, eggs, peanut butter, nuts, meat, and whole-milk dairy products such as whole milk, cheese, and yogurt.

TRIKAFTA oral granules (age 2 to less than 6 years weighing less than 14 kg):

The white and blue packets each contain the medicines elexacaftor, tezacaftor, and ivacaftor. Take one morning dose packet in the morning.

The white and green color packets each contain the medicine ivacaftor. Take one evening dose packet in the evening.

TRIKAFTA oral granules (age 2 to less than 6 years weighing 14 kg or more):

The white and orange packets each contain the medicines elexacaftor, tezacaftor, and ivacaftor. Take one morning dose packet in the morning.

The white and pink color packets each contain the medicine ivacaftor. Take one evening dose packet in the evening.

To prepare TRIKAFTA oral granules:

Hold the packet with the cut line on top.

Shake the packet gently to settle the TRIKAFTA oral granules.

Tear or cut the packet open along the cut line.

Carefully pour all the TRIKAFTA oral granules in the packet into 1 teaspoon (5 mL) of soft food or liquid in a small container (like an empty bowl). The food or liquid should be at or below room temperature. Some examples of soft foods or liquids include pureed fruits or vegetables, yogurt, applesauce, water, milk, or juice.

Mix the TRIKAFTA granules with food or liquid.

After mixing, give TRIKAFTA within 1 hour. Make sure all the medicine is taken.

TRIKAFTA tablets (age 6 to less than 12 years weighing less than 30 kg):

The light orange tablet is marked with 'T50' and each tablet contains the medicines elexacaftor, tezacaftor and ivacaftor. Take 2 light orange tablets in the morning.

The light blue tablet is marked with 'V 75' and contains the medicine ivacaftor. Take 1 light blue tablet in the evening.

TRIKAFTA tablets (age 6 to less than 12 years weighing 30 kg or more, and age 12 years and older):

The orange tablet is marked with 'T100' and each tablet contains the medicines elexacaftor, tezacaftor and ivacaftor. Take 2 orange tablets in the morning.

The light blue tablet is marked with 'V 150' and contains the medicine ivacaftor. Take 1 light blue tablet in the evening.

Take TRIKAFTA tablets whole.

Take the morning and the evening doses about 12 hours apart.

If you miss a dose of TRIKAFTA and:

it is 6 hours or less from the time you usually take the morning dose or the evening dose, take the missed dose with food that contains fat as soon as you can. Then take your next dose at your usual time.

it is more than 6 hours from the time you usually take the morning dose, take the missed dose with food that contains fat as soon as you can. Do not take the evening dose.

it is more than 6 hours from the time you usually take the evening dose, do not take the missed dose. Take your next morning dose at the usual time with food that contains fat.

Do not take more than your usual dose of TRIKAFTA to make up for a missed dose.

Do not take the morning and evening doses at the same time.

If you are not sure about your dosing, call your doctor.

What should I avoid while taking TRIKAFTA?

Avoid food or drink that contains grapefruit while you are taking TRIKAFTA.

What are the possible side effects of TRIKAFTA? TRIKAFTA can cause serious side effects, including:

Liver damage and worsening liver function in people with severe liver disease that can be serious and may require transplantation. Liver damage has also happened in people without liver disease. High liver enzymes in the blood is a common side effect in people treated with TRIKAFTA. These can be serious and may be a sign of liver injury. Your doctor will do blood tests to check your liver:

before you start TRIKAFTA

every 3 months during your first year of taking TRIKAFTA

then every year while you are taking TRIKAFTA

Your doctor may do blood tests to check the liver more often if you have had high liver enzymes in your blood in the past. Call your doctor right away if you have any of the following symptoms of liver problems:

pain or discomfort in the upper right stomach (abdominal) area

yellowing of your skin or the white part of your eyes

loss of appetite

nausea or vomiting

dark, amber-colored urine

Serious Allergic Reactions can happen to people who are treated with TRIKAFTA. Call your healthcare provider or go to the emergency room right away if you have any symptoms of an allergic reaction. Symptoms of an allergic reaction may include:

rash or hives

tightness of the chest or throat or difficulty breathing

swelling of the face, lips and/or tongue, difficulty swallowing

light-headedness or dizziness

Abnormality of the eye lens (cataract) has happened in some children and adolescents treated with TRIKAFTA. If you are a child or adolescent, your doctor should perform eye examinations before and during treatment with TRIKAFTA to look for cataracts.

The most common side effects of TRIKAFTA include:

headache

upper respiratory tract infection (common cold) including stuffy and runny nose

stomach (abdominal) pain

diarrhea

rash

increase in liver enzymes

increase in a certain blood enzyme called creatine phosphokinase

flu (influenza)

inflamed sinuses

increase in blood bilirubin

Tell your doctor if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of TRIKAFTA. For more information, ask your doctor or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store TRIKAFTA?

Store TRIKAFTA at room temperature between 68ºF to 77ºF (20ºC to 25ºC).

Keep TRIKAFTA and all medicines out of the reach of children.

General information about the safe and effective use of TRIKAFTA. Medicines are sometimes prescribed for purposes other than those uled in a Patient Information leaflet. Do not use TRIKAFTA for a condition for which it was not prescribed. Do not give TRIKAFTA to other people, even if they have the same symptoms you have. It may harm them. You can ask your pharmacist or doctor for information about TRIKAFTA that is written for health professionals.

What are the ingredients in TRIKAFTA? Elexacaftor/tezacaftor/ivacaftor tablets: Active ingredients: elexacaftor, tezacaftor and ivacaftor. Inactive ingredients: croscarmellose sodium, hypromellose, hypromellose acetate succinate, magnesium stearate, microcrystalline cellulose, sodium lauryl sulfate. The tablet film coat contains hydroxypropyl cellulose, hypromellose, iron oxide red, iron oxide yellow, talc, and titanium dioxide. Ivacaftor tablets: Active ingredients: ivacaftor. 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 oxide. The printing ink contains ammonium hydroxide, iron oxide black, propylene glycol, and shellac. Elexacaftor/tezacaftor/ivacaftor oral granules: Active ingredients: elexacaftor, tezacaftor, and ivacaftor. Inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, hypromellose, hypromellose acetate succinate, lactose monohydrate, magnesium stearate, mannitol, sodium lauryl sulfate, and sucralose. Ivacaftor oral granules: Active ingredients: ivacaftor. Inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, hypromellose acetate succinate, lactose monohydrate, magnesium stearate, mannitol, sodium lauryl sulfate, and sucralose. Manufactured for: Vertex Pharmaceuticals Incorporated; 50 Northern Avenue, Boston, MA 02210 TRIKAFTA, VERTEX and associated logos are registered trademarks of Vertex Pharmaceuticals Incorporated. All other trademarks referenced herein are the property of their respective owners. ©2023 Vertex Pharmaceuticals Incorporated For more information, go to www.trikafta.com or call 1-877-752-5933.

Principal Display Panel - Kit Carton

NDC 51167-331-01Rx Only

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

84 Tablets4-wallets (each containing 14 tablets of elexacaftor, tezacaftor, and ivacaftor and 7 tablets of ivacaftor)

LIFT HERE TO OPEN ►

Principal Display Panel - Kit Carton - 51167-106-02

NDC 51167-106-02Rx Only

trikafta^®

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

84 Tablets4-wallets (each containing 14 tablets of elexacaftor, tezacaftor, and ivacaftor and 7 tablets of ivacaftor)

LIFT HERE TO OPEN →

Principal Display Panel - Kit Carton - 51167-445-01

NDC 51167-445-01 Rx only

trikafta^®

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

80 mg 40 mg 60 mg and 59.5 mg

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

Lift here to open

Principal Display Panel - Kit Carton - 51167-446-01

NDC 51167-446-01 Rx only

trikafta^®

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

100 mg 50 mg 75 mg and 75 mg

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

Lift here to open

Table 4: Adverse Drug Reactions in ≥5% of TRIKAFTA-Treated Patients and Higher than Placebo by ≥1% in Trial 1
Adverse Drug Reactions (Preferred Term)	TRIKAFTAN=202n (%)	PlaceboN=201n (%)
Headache	35 (17)	30 (15)
Upper respiratory tract infectionIncludes upper respiratory tract infection and viral upper respiratory tract infection	32 (16)	25 (12)
Abdominal painIncludes abdominal pain, abdominal pain upper, abdominal pain lower	29 (14)	18 (9)
Diarrhea	26 (13)	14 (7)
RashIncludes 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)

Table 5: List of CFTR Gene Mutations that are Responsive to TRIKAFTA
3141del9	E822K	G1069R	L967S	R117L	S912L
546insCTA	F191V	G1244E	L997F	R117P	S945L
A46D	F311del	G1249R	L1077P	R170H	S977F
A120T	F311L	G1349D	L1324P	R258G	S1159F
A234D	F508C	H139R	L1335P	R334L	S1159P
A349V	F508C;S1251N Complex/compound mutations where a single allele of the CFTR gene has multiple mutations; these exist independent of the presence of mutations on the other allele.	H199Y	L1480P	R334Q	S1251N
A455E	F508del F508del is a responsive CFTR mutation based on both clinical and in vitro data [see Clinical Studies (14)].	H939R	M152V	R347H	S1255P
A554E	F575Y	H1054D	M265R	R347L	T338I
A1006E	F1016S	H1085P	M952I	R347P	T1036N
A1067T	F1052V	H1085R	M952T	R352Q	T1053I
D110E	F1074L	H1375P	M1101K	R352W	V201M
D110H	F1099L	I148T	P5L	R553Q	V232D
D192G	G27R	I175V	P67L	R668C	V456A
D443Y	G85E	I336K	P205S	R751L	V456F
D443Y;G576A;R668C	G126D	I502T	P574H	R792G	V562I
D579G	G178E	I601F	Q98R	R933G	V754M
D614G	G178R	I618T	Q237E	R1066H	V1153E
D836Y	G194R	I807M	Q237H	R1070Q	V1240G
D924N	G194V	I980K	Q359R	R1070W	V1293G
D979V	G314E	I1027T	Q1291R	R1162L	W361R
D1152H	G463V	I1139V	R31L	R1283M	W1098C
D1270N	G480C	I1269N	R74Q	R1283S	W1282R
E56K	G551D	I1366N	R74W	S13F	Y109N
E60K	G551S	K1060T	R74W;D1270N	S341P	Y161D
E92K	G576A	L15P	R74W;V201M	S364P	Y161S
E116K	G576A;R668C	L165S	R74W;V201M;D1270N	S492F	Y563N
E193K	G622D	L206W	R75Q	S549N	Y1014C
E403D	G628R	L320V	R117C	S549R	Y1032C
E474K	G970D	L346P	R117G	S589N
E588V	G1061R	L453S	R117H	S737F

Table 6: Pharmacokinetic Parameters of TRIKAFTA Components
	Elexacaftor	Tezacaftor	Ivacaftor
AUC_ss: area under the concentration versus time curve at steady state; SD: Standard Deviation; C_max: maximum observed concentration; T_max: time of maximum concentration; AUC: area under the concentration versus time curve.
General Information
AUC_ss (SD), mcg∙h/mLBased on elexacaftor 200 mg and tezacaftor 100 mg once daily/ivacaftor 150 mg every 12 hours at steady state in patients with CF aged 12 years and older.	162 (47.5)AUC_0-24h.	89.3 (23.2)	11.7 (4.01)AUC_0-12h.
C_max (SD), mcg/mL	9.2 (2.1)	7.7 (1.7)	1.2 (0.3)
Time to Steady State, days	Within 7 days	Within 8 days	Within 3-5 days
Accumulation Ratio	2.2	2.07	2.4
Absorption
Absolute Bioavailability	80%	Not determined	Not determined
Median T_max (range), hours	6 (4 to 12)	3 (2 to 4)	4 (3 to 6)
Effect of Food	AUC increases 1.9- to 2.5-fold(moderate-fat meal)	No clinically significant effect	Exposure increases 2.5- to 4-fold
Distribution
Mean (SD) Apparent Volume of Distribution, LElexacaftor, tezacaftor and ivacaftor do not partition preferentially into human red blood cells.	53.7 (17.7)	82.0 (22.3)	293 (89.8)
Protein BindingElexacaftor and tezacaftor bind primarily to albumin. Ivacaftor primarily bind to albumin, alpha 1-acid glycoprotein and human gamma-globulin.	>99%	approximately 99%	approximately 99%
Elimination
Mean (SD) Effective Half-Life, hoursMean (SD) terminal half-lives of elexacaftor, tezacaftor and ivacaftor are approximately 24.7 (4.87) hours, 60.3 (15.7) hours and 13.1 (2.98) hours, respectively.	27.4 (9.31)	25.1 (4.93)	15.0 (3.92)
Mean (SD) Apparent Clearance, L/hours	1.18 (0.29)	0.79 (0.10)	10.2 (3.13)
Metabolism
Primary Pathway	CYP3A4/5	CYP3A4/5	CYP3A4/5
Active Metabolites	M23-ELX	M1-TEZ	M1-IVA
Metabolite Potency Relative to Parent	Similar	Similar	approximately 1/6^th of parent
ExcretionFollowing radiolabeled doses.
Primary Pathway	Feces: 87.3% (primarily as metabolites) Urine: 0.23%	Feces: 72% (unchanged or as M2-TEZ) Urine: 14% (0.79% unchanged)	Feces: 87.8% Urine: 6.6%

Table 7: Mean (SD) Elexacaftor, Tezacaftor and Ivacaftor Exposures Observed at Steady State by Age Group and Dose Administered
Age Group	Dose	ElexacaftorAUC_0-24h,ss (µg∙h/mL)	Tezacaftor AUC_0-24h,ss (µg∙h/mL)	Ivacaftor AUC_0-12h,ss (µg∙h/mL)
SD: Standard Deviation; AUC_ss: area under the concentration versus time curve at steady state.
Patients aged 2 to less than 6 years weighing less than 14 kg(N = 16)	elexacaftor 80 mg qd/tezacaftor 40 mg qd/ivacaftor 60 mg qAM and ivacaftor 59.5 mg qPM	128 (24.8)	87.3 (17.3)	11.9 (3.86)
Patients aged 2 to less than 6 years weighing 14 kg or more(N = 59)	elexacaftor 100 mg qd/tezacaftor 50 mg qd/ivacaftor 75 mg q12h	138 (47.0)	90.2 (27.9)	13.0 (6.11)
Patients aged 6 to less than 12 years weighing less than 30 kg (N = 36)	elexacaftor 100 mg qd/tezacaftor 50 mg qd/ivacaftor 75 mg q12h	116 (39.4)	67.0 (22.3)	9.78 (4.50)
Patients aged 6 to less than 12 years weighing 30 kg or more(N = 30)	elexacaftor 200 mg qd/ tezacaftor 100 mg qd/ ivacaftor 150 mg q12h	195 (59.4)	103 (23.7)	17.5 (4.97)

Table 8: Impact of Elexacaftor, Tezacaftor and/or Ivacaftor on Other Drugs
Dose and Schedule	Effect on Other Drug PK	Geometric Mean Ratio (90% CI) of Other DrugNo Effect=1.0
↑ = increase, ↓ = decrease, ↔ = no change. CI = Confidence Interval; ELX= elexacaftor; TEZ = tezacaftor; IVA = ivacaftor; PK = Pharmacokinetics
Midazolam2 mg single oral dose	TEZ 100 mg qd/IVA 150 mg q12h	↔ Midazolam	1.12(1.01, 1.25)	1.13(1.01, 1.25)
Digoxin0.5 mg single dose	TEZ 100 mg qd/IVA 150 mg q12h	↑ Digoxin	1.30(1.17, 1.45)	1.32(1.07, 1.64)
Oral ContraceptiveEthinyl estradiol 30 µg/Levonorgestrel 150 µg qd	ELX 200 mg qd/TEZ 100 mg qd/IVA 150 mg q12h	↑ Ethinyl estradiol Effect not clinically significant [see Drug Interactions (7.6)].	1.33(1.20, 1.49)	1.26(1.14, 1.39)
↑ Levonorgestrel	1.23(1.10, 1.37)	1.10(0.985, 1.23)
Rosiglitazone4 mg single oral dose	IVA 150 mg q12h	↔ Rosiglitazone	0.975(0.897, 1.06)	0.928(0.858, 1.00)
Desipramine50 mg single dose	IVA 150 mg q12h	↔ Desipramine	1.04(0.985, 1.10)	1.00(0.939; 1.07)

Table 9: Impact of Other Drugs on Elexacaftor, Tezacaftor and/or Ivacaftor
Dose and Schedule	Effect on ELX, TEZ and/or IVA PK	Geometric Mean Ratio (90% CI) of Elexacaftor, Tezacaftor and IvacaftorNo Effect = 1.0
↑ = increase, ↓ = decrease, ↔ = no change. CI = Confidence Interval; ELX= elexacaftor; TEZ = tezacaftor; IVA = ivacaftor; PK = Pharmacokinetics
Itraconazole200 mg q12h on Day 1, followed by 200 mg qd	TEZ 25 mg qd + IVA 50 mg qd	↑ Tezacaftor	4.02(3.71, 4.63)	2.83(2.62, 3.07)
↑ Ivacaftor	15.6(13.4, 18.1)	8.60(7.41, 9.98)
Itraconazole200 mg qd	ELX 20 mg + TEZ 50 mg single dose	↑ Elexacaftor	2.83(2.59, 3.10)	1.05(0.977, 1.13)
↑ Tezacaftor	4.51(3.85, 5.29)	1.48(1.33, 1.65)
Ketoconazole400 mg qd	IVA 150 mg single dose	↑ Ivacaftor	8.45(7.14, 10.0)	2.65(2.21, 3.18)
Ciprofloxacin750 mg q12h	TEZ 50 mg q12h + IVA 150 mg q12h	↔ Tezacaftor	1.08(1.03, 1.13)	1.05(0.99, 1.11)
↑ IvacaftorEffect is not clinically significant [see Drug Interactions (7.3)].	1.17(1.06, 1.30)	1.18(1.06, 1.31)
Rifampin600 mg qd	IVA 150 mg single dose	↓ Ivacaftor	0.114(0.097, 0.136)	0.200(0.168, 0.239)
Fluconazole400 mg single dose on Day 1, followed by 200 mg qd	IVA 150 mg q12h	↑ Ivacaftor	2.95(2.27, 3.82)	2.47(1.93, 3.17)

Table 10: Primary and Key Secondary Efficacy Analyses (Trial 1)
Analysis	Statistic	Treatment DifferenceTreatment difference provided as the outcome measure for changes in ppFEV₁, sweat chloride, CFQ-R and BMI; Rate ratio provided as the outcome measure for the number of pulmonary exacerbations. for TRIKAFTA (N=200) vs Placebo (N=203)
ppFEV₁: percent predicted Forced Expiratory Volume in 1 second; CI: Confidence Interval; CFQ-R: Cystic Fibrosis Questionnaire-Revised; BMI: Body Mass Index.
Primary (Interim Full Analysis Set) Primary endpoint was based on interim analysis in 403 patients.
Absolute change in ppFEV₁ from baseline at Week 4 (percentage points)	Treatment difference (95% CI) P value	13.8 (12.1, 15.4) P<0.0001
Key Secondary (Full Analysis Set) Key secondary endpoints were tested at the final analysis in 403 patients.
Absolute change in ppFEV₁ from baseline through Week 24 (percentage points)	Treatment difference (95% CI) P value	14.3 (12.7, 15.8) P<0.0001
Number of pulmonary exacerbations from baseline through Week 24A pulmonary exacerbation was defined as a change in antibiotic therapy (IV, inhaled, or oral) as a result of 4 or more of 12 pre-specified sino-pulmonary signs/symptoms. Number of pulmonary exacerbation events (event rate per year calculated based on 48 weeks per year) in the TRIKAFTA group were 41 (0.37) and 113 (0.98) in the placebo group.	Rate ratio (95% CI) P value	0.37 (0.25, 0.55) P<0.0001
Absolute change in sweat chloride from baseline through Week 24 (mmol/L)	Treatment difference (95% CI) P value	-41.8 (-44.4, -39.3) P<0.0001
Absolute change in CFQ-R respiratory domain score from baseline through Week 24 (points)	Treatment difference (95% CI) P value	20.2 (17.5, 23.0) P<0.0001
Absolute change in BMI from baseline at Week 24 (kg/m²)	Treatment difference (95% CI) P value	1.04 (0.85, 1.23) P<0.0001
Absolute change in sweat chloride from baseline at Week 4 (mmol/L)	Treatment difference (95% CI) P value	-41.2 (-44.0, -38.5) P<0.0001
Absolute change in CFQ-R respiratory domain score from baseline at Week 4 (points)	Treatment difference (95% CI) P value	20.1 (16.9, 23.2) P<0.0001

Table 11: Primary and Key Secondary Efficacy Analyses, Full Analysis Set (Trial 2)
AnalysisBaseline for primary and key secondary endpoints is defined as the end of the 4-week tezacaftor/ivacaftor run-in period.	Statistic	Treatment Difference for TRIKAFTA (N=55) vs Tezacaftor/IvacaftorRegimen of tezacaftor 100 mg qd/ivacaftor 150 mg q12h. (N=52)
ppFEV₁: percent predicted Forced Expiratory Volume in 1 second; CI: Confidence Interval; CFQ-R: Cystic Fibrosis Questionnaire-Revised.
Primary
Absolute change in ppFEV₁ from baseline at Week 4 (percentage points)	Treatment difference (95% CI) P value	10.0 (7.4, 12.6) P<0.0001
Key Secondary
Absolute change in sweat chloride from baseline at Week 4 (mmol/L)	Treatment difference (95% CI) P value	-45.1 (-50.1, -40.1) P<0.0001
Absolute change in CFQ-R respiratory domain score from baseline at Week 4 (points)	Treatment difference (95% CI) P value	17.4 (11.8, 23.0) P<0.0001

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Indications and Usage (1)	04/2023
Dosage and Administration (2)	04/2023
Warnings and Precautions, Hypersensitivity Reactions, Including Anaphylaxis (5.2)	08/2023

Dose and Schedule		Effect on Other Drug PK	Geometric Mean Ratio (90% CI) of Other DrugNo Effect=1.0
		Effect on Other Drug PK	AUC	C_max
↑ = increase, ↓ = decrease, ↔ = no change. CI = Confidence Interval; ELX= elexacaftor; TEZ = tezacaftor; IVA = ivacaftor; PK = Pharmacokinetics
Midazolam2 mg single oral dose	TEZ 100 mg qd/IVA 150 mg q12h	↔ Midazolam	1.12(1.01, 1.25)	1.13(1.01, 1.25)
Digoxin0.5 mg single dose	TEZ 100 mg qd/IVA 150 mg q12h	↑ Digoxin	1.30(1.17, 1.45)	1.32(1.07, 1.64)
Oral ContraceptiveEthinyl estradiol 30 µg/Levonorgestrel 150 µg qd	ELX 200 mg qd/TEZ 100 mg qd/IVA 150 mg q12h	↑ Ethinyl estradiol Effect not clinically significant [see Drug Interactions (7.6)].	1.33(1.20, 1.49)	1.26(1.14, 1.39)
	ELX 200 mg qd/TEZ 100 mg qd/IVA 150 mg q12h	↑ Levonorgestrel	1.23(1.10, 1.37)	1.10(0.985, 1.23)
Rosiglitazone4 mg single oral dose	IVA 150 mg q12h	↔ Rosiglitazone	0.975(0.897, 1.06)	0.928(0.858, 1.00)
Desipramine50 mg single dose	IVA 150 mg q12h	↔ Desipramine	1.04(0.985, 1.10)	1.00(0.939; 1.07)

This Patient Information has been approved by the U.S. Food and Drug Administration.			Revised: 08/2023
Patient Information TRIKAFTA^® (tri-KAF-tuh) (elexacaftor, tezacaftor, and ivacaftor tablets; ivacaftor tablets), co-packaged for oral use (elexacaftor, tezacaftor, and ivacaftor oral granules; ivacaftor oral granules), co-packaged
What is TRIKAFTA? TRIKAFTA is a prescription medicine used for the treatment of cystic fibrosis (CF) in people aged 2 years and older who have at least one copy of the F508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene or another mutation that is responsive to treatment with TRIKAFTA. Talk to your doctor to learn if you have an indicated CF gene mutation. It is not known if TRIKAFTA is safe and effective in children under 2 years of age.
Before taking TRIKAFTA, tell your doctor about all of your medical conditions, including if you: are allergic to TRIKAFTA or any ingredients in TRIKAFTA. See the end of this patient information leaflet for a complete ul of ingredients in TRIKAFTA. have kidney problems. have or have had liver problems. are pregnant or plan to become pregnant. It is not known if TRIKAFTA will harm your unborn baby. You and your doctor should decide if you will take TRIKAFTA while you are pregnant. are breastfeeding or planning to breastfeed. It is not known if TRIKAFTA passes into your breast milk. You and your doctor should decide if you will take TRIKAFTA while you are breastfeeding. Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. TRIKAFTA may affect the way other medicines work and other medicines may affect how TRIKAFTA works. The dose of TRIKAFTA may need to be adjusted when taken with certain medicines. Ask your doctor or pharmacist for a ul of these medicines if you are not sure. Especially tell your doctor if you take: antibiotics such as rifampin (RIFAMATE^®, RIFATER^®) or rifabutin (MYCOBUTIN^®) seizure medicines such as phenobarbital, carbamazepine (TEGRETOL^®, CARBATROL^®, EQUETRO^®), or phenytoin (DILANTIN^®, PHENYTEK^®) St. John's wort antifungal medicines including ketoconazole, itraconazole (such as SPORANOX^®), posaconazole (such as NOXAFIL^®), voriconazole (such as VFEND^®), or fluconazole (such as DIFLUCAN^®). antibiotics including telithromycin, clarithromycin (such as BIAXIN^®), or erythromycin (such as ERY-TAB^®). Know the medicines you take. Keep a ul of them to show your doctor and pharmacist when you get a new medicine.
How should I take TRIKAFTA? Take TRIKAFTA exactly as your doctor tells you to take it. Take TRIKAFTA by mouth only. TRIKAFTA consists of 2 different doses (a morning dose and an evening dose). Each dose has different ingredients. Always take TRIKAFTA oral granules or tablets with food that contains fat. Examples of fat-containing foods include butter, oil, eggs, peanut butter, nuts, meat, and whole-milk dairy products such as whole milk, cheese, and yogurt. TRIKAFTA oral granules (age 2 to less than 6 years weighing less than 14 kg): The white and blue packets each contain the medicines elexacaftor, tezacaftor, and ivacaftor. Take one morning dose packet in the morning. The white and green color packets each contain the medicine ivacaftor. Take one evening dose packet in the evening. TRIKAFTA oral granules (age 2 to less than 6 years weighing 14 kg or more): The white and orange packets each contain the medicines elexacaftor, tezacaftor, and ivacaftor. Take one morning dose packet in the morning. The white and pink color packets each contain the medicine ivacaftor. Take one evening dose packet in the evening. To prepare TRIKAFTA oral granules: Hold the packet with the cut line on top. Shake the packet gently to settle the TRIKAFTA oral granules. Tear or cut the packet open along the cut line. Carefully pour all the TRIKAFTA oral granules in the packet into 1 teaspoon (5 mL) of soft food or liquid in a small container (like an empty bowl). The food or liquid should be at or below room temperature. Some examples of soft foods or liquids include pureed fruits or vegetables, yogurt, applesauce, water, milk, or juice. Mix the TRIKAFTA granules with food or liquid. After mixing, give TRIKAFTA within 1 hour. Make sure all the medicine is taken. TRIKAFTA tablets (age 6 to less than 12 years weighing less than 30 kg): The light orange tablet is marked with 'T50' and each tablet contains the medicines elexacaftor, tezacaftor and ivacaftor. Take 2 light orange tablets in the morning. The light blue tablet is marked with 'V 75' and contains the medicine ivacaftor. Take 1 light blue tablet in the evening. TRIKAFTA tablets (age 6 to less than 12 years weighing 30 kg or more, and age 12 years and older): The orange tablet is marked with 'T100' and each tablet contains the medicines elexacaftor, tezacaftor and ivacaftor. Take 2 orange tablets in the morning. The light blue tablet is marked with 'V 150' and contains the medicine ivacaftor. Take 1 light blue tablet in the evening. Take TRIKAFTA tablets whole. Take the morning and the evening doses about 12 hours apart. If you miss a dose of TRIKAFTA and: it is 6 hours or less from the time you usually take the morning dose or the evening dose, take the missed dose with food that contains fat as soon as you can. Then take your next dose at your usual time. it is more than 6 hours from the time you usually take the morning dose, take the missed dose with food that contains fat as soon as you can. Do not take the evening dose. it is more than 6 hours from the time you usually take the evening dose, do not take the missed dose. Take your next morning dose at the usual time with food that contains fat. Do not take more than your usual dose of TRIKAFTA to make up for a missed dose. Do not take the morning and evening doses at the same time. If you are not sure about your dosing, call your doctor.
What should I avoid while taking TRIKAFTA? Avoid food or drink that contains grapefruit while you are taking TRIKAFTA.
What are the possible side effects of TRIKAFTA? TRIKAFTA can cause serious side effects, including: Liver damage and worsening liver function in people with severe liver disease that can be serious and may require transplantation. Liver damage has also happened in people without liver disease. High liver enzymes in the blood is a common side effect in people treated with TRIKAFTA. These can be serious and may be a sign of liver injury. Your doctor will do blood tests to check your liver: before you start TRIKAFTA every 3 months during your first year of taking TRIKAFTA then every year while you are taking TRIKAFTA Your doctor may do blood tests to check the liver more often if you have had high liver enzymes in your blood in the past. Call your doctor right away if you have any of the following symptoms of liver problems:
	pain or discomfort in the upper right stomach (abdominal) area yellowing of your skin or the white part of your eyes loss of appetite		nausea or vomiting dark, amber-colored urine
Serious Allergic Reactions can happen to people who are treated with TRIKAFTA. Call your healthcare provider or go to the emergency room right away if you have any symptoms of an allergic reaction. Symptoms of an allergic reaction may include: rash or hives tightness of the chest or throat or difficulty breathing swelling of the face, lips and/or tongue, difficulty swallowing light-headedness or dizziness Abnormality of the eye lens (cataract) has happened in some children and adolescents treated with TRIKAFTA. If you are a child or adolescent, your doctor should perform eye examinations before and during treatment with TRIKAFTA to look for cataracts. The most common side effects of TRIKAFTA include:
	headache upper respiratory tract infection (common cold) including stuffy and runny nose stomach (abdominal) pain diarrhea rash	increase in liver enzymes increase in a certain blood enzyme called creatine phosphokinase flu (influenza) inflamed sinuses increase in blood bilirubin
Tell your doctor if you have any side effect that bothers you or that does not go away. These are not all the possible side effects of TRIKAFTA. For more information, ask your doctor or pharmacist. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
How should I store TRIKAFTA? Store TRIKAFTA at room temperature between 68ºF to 77ºF (20ºC to 25ºC). Keep TRIKAFTA and all medicines out of the reach of children.
General information about the safe and effective use of TRIKAFTA. Medicines are sometimes prescribed for purposes other than those uled in a Patient Information leaflet. Do not use TRIKAFTA for a condition for which it was not prescribed. Do not give TRIKAFTA to other people, even if they have the same symptoms you have. It may harm them. You can ask your pharmacist or doctor for information about TRIKAFTA that is written for health professionals.
What are the ingredients in TRIKAFTA? Elexacaftor/tezacaftor/ivacaftor tablets: Active ingredients: elexacaftor, tezacaftor and ivacaftor. Inactive ingredients: croscarmellose sodium, hypromellose, hypromellose acetate succinate, magnesium stearate, microcrystalline cellulose, sodium lauryl sulfate. The tablet film coat contains hydroxypropyl cellulose, hypromellose, iron oxide red, iron oxide yellow, talc, and titanium dioxide. Ivacaftor tablets: Active ingredients: ivacaftor. 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 oxide. The printing ink contains ammonium hydroxide, iron oxide black, propylene glycol, and shellac. Elexacaftor/tezacaftor/ivacaftor oral granules: Active ingredients: elexacaftor, tezacaftor, and ivacaftor. Inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, hypromellose, hypromellose acetate succinate, lactose monohydrate, magnesium stearate, mannitol, sodium lauryl sulfate, and sucralose. Ivacaftor oral granules: Active ingredients: ivacaftor. Inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, hypromellose acetate succinate, lactose monohydrate, magnesium stearate, mannitol, sodium lauryl sulfate, and sucralose. Manufactured for: Vertex Pharmaceuticals Incorporated; 50 Northern Avenue, Boston, MA 02210 TRIKAFTA, VERTEX and associated logos are registered trademarks of Vertex Pharmaceuticals Incorporated. All other trademarks referenced herein are the property of their respective owners. ©2023 Vertex Pharmaceuticals Incorporated For more information, go to www.trikafta.com or call 1-877-752-5933.

Trikafta (elexacaftor 100 mg tezacaftor 50 mg ivacaftor 75 mg) Dailymed

Drug Classes

Version History

Generic: elexacaftor, tezacaftor, and ivacaftor is used for the treatment of Cystic Fibrosis

FDA Adverse Reactions

Recent Major Changes Section

1 Indications And Usage

2 Dosage And Administration

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

2.2Recommended Dosage for Patients with Hepatic Impairment

2.3Dosage Modification for Patients Taking Drugs that are CYP3A Inhibitors

2.4Recommendations Regarding Missed Dose(s)

2.5Administration Information

3 Dosage Forms And Strengths

4 Contraindications

5 Warnings And Precautions

5.1Elevated Transaminases and Hepatic Injury

5.2Hypersensitivity Reactions, Including Anaphylaxis

5.3Concomitant Use with CYP3A Inducers

5.4Concomitant Use with CYP3A Inhibitors

5.5Cataracts

6 Adverse Reactions

6.1 Clinical Trials Experience

6.2 Postmarketing Experience

7 Drug Interactions

7.1Inducers of CYP3A

7.2Inhibitors of CYP3A

7.3Ciprofloxacin

7.4CYP2C9 Substrates

7.5Transporters

7.6Hormonal Contraceptives

8 Use In Specific Populations

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

8.5 Geriatric Use

8.6 Renal Impairment

8.7 Hepatic Impairment

8.8Patients with Severe Lung Dysfunction

10 Overdosage

11 Description

12 Clinical Pharmacology

12.1 Mechanism of Action

12.2 Pharmacodynamics

12.3 Pharmacokinetics

13 Nonclinical Toxicology

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14 Clinical Studies

14.1Trial 1

14.2Trial 2

16 How Supplied/storage And Handling

STORAGE AND HANDLING SECTION

17 Patient Counseling Information

Spl Patient Package Insert Section

Principal Display Panel - Kit Carton

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