Trikafta

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

2 DOSAGE AND ADMINISTRATION Prior to initiating TRIKAFTA obtain liver function tests (ALT, AST, alkaline phosphatase, and bilirubin) in all patients. Monitor liver function tests every month during the first 6 months of treatment, then every 3 months during the next 12 months, then at least annually thereafter. ( 2.1 , 5.1) Recommended Dosage for Adult and Pediatric Patients Aged 2 Years and Older (with fat-containing food ( 2.2 , 12.3 )) Age Weight Morning Dose Evening Dose 2 to less than 6 years Less than 14 kg One packet containing elexacaftor 80 mg/tezacaftor 40 mg/ivacaftor 60 mg oral granules One packet containing ivacaftor 59.5 mg oral granules 14 kg or more One packet containing elexacaftor 100 mg/tezacaftor 50 mg/ivacaftor 75 mg oral granules One packet containing ivacaftor 75 mg oral granules 6 to less than 12 years Less than 30 kg Two tablets, each containing elexacaftor 50 mg/tezacaftor 25 mg/ivacaftor 37.5 mg One tablet of ivacaftor 75 mg 30 kg or more Two tablets, each containing elexacaftor 100 mg/tezacaftor 50 mg/ivacaftor 75 mg One tablet of ivacaftor 150 mg 12 years and older - Two tablets, each containing elexacaftor 100 mg/tezacaftor 50 mg/ivacaftor 75 mg One tablet of ivacaftor 150 mg Should not be used in patients with severe hepatic impairment. Use not recommended in patients with moderate hepatic impairment unless the benefit outweighs the risk. Reduce dose if used in patients with moderate hepatic impairment. Liver function tests should be closely monitored. ( 2.3 , 5.1 , 6 , 8.7 , 12.3 ) See full prescribing information for dosage modifications due to drug interactions with TRIKAFTA. ( 2.4 , 5.6 , 7.1 , 12.3 ) 2.1 Recommended Laboratory Testing Prior to TRIKAFTA Initiation and During Treatment Prior to initiating TRIKAFTA, obtain liver function tests (ALT, AST, alkaline phosphatase, and bilirubin) for all patients. Monitor liver function tests every month during the first 6 months of treatment, then every 3 months for the next 12 months, then at least annually thereafter. Consider more frequent monitoring for patients with a history of liver disease or liver function test elevations at baseline [see Warnings and Precautions (5.1) and Use in Specific Populations (8.7) ] . 2.2 Recommended Dosage in Adults and Pediatric Patients Aged 2 Years and Older Recommended dosage for adult and pediatric patients aged 2 years and older is provided in Table 1. Administer TRIKAFTA tablets (swallow the tablets whole) or oral granules orally with fat-containing food, in the morning and in the evening approximately 12 hours apart. Examples of meals or snacks that contain fat are those prepared with butter or oils or those containing eggs, peanut butter, cheeses, nuts, whole milk, or meats [see Clinical Pharmacology (12.3) ] . Administer each dose of TRIKAFTA oral granules immediately before or after ingestion of fat-containing food. Mix entire contents of each packet of oral granules with one teaspoon (5 mL) of age-appropriate soft food or liquid that is at or below room temperature. Some examples of soft food or liquids include pureed fruits or vegetables, yogurt, applesauce, water, milk, or juice. Once mixed, the product should be consumed completely within one hour. Table 1: Recommended Dosage of TRIKAFTA for Adult and Pediatric Patients Aged 2 Years and Older Age Weight Oral Morning Dose Oral Evening Dose 2 to less than 6 years Less than 14 kg One packet (containing elexacaftor 80 mg/tezacaftor 40 mg/ivacaftor 60 mg) oral granules One packet (containing ivacaftor 59.5 mg) oral granules 14 kg or more One packet (containing elexacaftor 100 mg/tezacaftor 50 mg/ivacaftor 75 mg) oral granules One packet (containing ivacaftor 75 mg) oral granules 6 to less than 12 years Less than 30 kg Two tablets of elexacaftor 50 mg/tezacaftor 25 mg/ivacaftor 37.5 mg (total dose of elexacaftor 100 mg/tezacaftor 50 mg/ivacaftor 75 mg) One tablet of ivacaftor 75 mg 30 kg or more Two tablets of elexacaftor 100 mg/tezacaftor 50 mg/ivacaftor 75 mg (total dose of elexacaftor 200 mg/tezacaftor 100 mg/ivacaftor 150 mg) One tablet of ivacaftor 150 mg 12 years and older — Two tablets of elexacaftor 100 mg/tezacaftor 50 mg/ivacaftor 75 mg (total dose of elexacaftor 200 mg/tezacaftor 100 mg/ivacaftor 150 mg) One tablet of ivacaftor 150 mg 2.3 Recommended Dosage for Patients with Hepatic Impairment Severe Hepatic Impairment (Child-Pugh Class C): Should not be used. TRIKAFTA has not been studied in patients with severe hepatic impairment (Child-Pugh Class C), but the exposure is expected to be higher than in patients with moderate hepatic impairment [see Warnings and Precautions (5.1) , Adverse Reactions (6) , Use in Specific Populations (8.7) and Clinical Pharmacology (12.3) ] . Moderate Hepatic Impairment (Child-Pugh Class B) : Treatment is not recommended. Use of TRIKAFTA in patients with moderate hepatic impairment should only be considered when there is a clear medical need, and the benefit outweighs the risk. If used, TRIKAFTA should be used with caution at a reduced dose (see Table 2 ) [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3) ] . Liver function tests should be closely monitored [see Dosage and Administration (2.1) and Warnings and Precautions (5.1) ]. Recommended dosage for patients with moderate hepatic impairment (Child-Pugh Class B) is provided in Table 2. Table 2: Recommended Dosage of TRIKAFTA, if used, in Patients with Moderate Hepatic Impairment (Child-Pugh Class B) Age Weight Oral Morning Dose Oral Evening Dose 2 to less than 6 years Less than 14 kg Weekly dosing schedule is as follows: Days 1-3: One packet (containing elexacaftor 80 mg/tezacaftor 40 mg/ivacaftor 60 mg) oral granules each day Day 4: no dose Days 5-6: One packet (containing elexacaftor 80 mg/tezacaftor 40 mg/ivacaftor 60 mg) oral granules each day Day 7: no dose No evening dose of ivacaftor oral granules. 14 kg or more Weekly dosing schedule is as follows: Days 1-3: One packet (containing elexacaftor 100 mg/tezacaftor 50 mg/ivacaftor 75 mg) oral granules each day Day 4: no dose Days 5-6: One packet (containing elexacaftor 100 mg/tezacaftor 50 mg/ivacaftor 75 mg) oral granules each day Day 7: no dose No evening dose of ivacaftor oral granules. 6 to less than 12 years Less than 30 kg Alternating daily dosing schedule is as follows: Day 1: Two tablets of elexacaftor 50 mg/tezacaftor 25 mg/ivacaftor 37.5 mg (total dose of elexacaftor 100 mg/tezacaftor 50 mg/ivacaftor 75 mg) Day 2: One tablet of elexacaftor 50 mg/tezacaftor 25 mg/ivacaftor 37.5 mg No evening ivacaftor tablet dose. 30 kg or more Alternating daily dosing schedule is as follows: Day 1: Two tablets of elexacaftor 100 mg/tezacaftor 50 mg/ivacaftor 75 mg (total dose of elexacaftor 200 mg/tezacaftor 100 mg/ivacaftor 150 mg) Day 2: One tablet of elexacaftor 100 mg/tezacaftor 50 mg/ivacaftor 75 mg No evening ivacaftor tablet dose. 12 years and older — Alternating daily dosing schedule is as follows: Day 1: Two tablets of elexacaftor 100 mg/tezacaftor 50 mg/ivacaftor 75 mg (total dose of elexacaftor 200 mg/tezacaftor 100 mg/ivacaftor 150 mg) Day 2: One tablet of elexacaftor 100 mg/tezacaftor 50 mg/ivacaftor 75 mg No evening ivacaftor tablet dose. Mild Hepatic Impairment (Child-Pugh Class A): No dose adjustment is recommended [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3) ] . See Table 1 for recommended dosage of TRIKAFTA. Liver function tests should be closely monitored [see Dosage and Administration (2.1) and Warnings and Precautions (5.1) ]. 2.4 Dosage Modification for Patients Taking Drugs that are CYP3A Inhibitors Table 3 describes the recommended dosage modification for TRIKAFTA when used concomitantly with strong (e.g., ketoconazole, itraconazole, posaconazole, voriconazole, telithromycin, and clarithromycin) or moderate (e.g., fluconazole, erythromycin) CYP3A inhibitors. Administer TRIKAFTA orally with fat-containing food [see Dosage and Administration (2.2) ]. Avoid food or drink containing grapefruit during TRIKAFTA treatment [see Warnings and Precautions (5.6) , Drug Interactions (7.1) and Clinical Pharmacology (12.3) ] . 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 to less than 12 years Less than 30 kg Alternating daily dosing schedule is as follows: Day 1: Two tablets of elexacaftor 50 mg/tezacaftor 25 mg/ivacaftor 37.5 mg (total dose of elexacaftor 100 mg/tezacaftor 50 mg/ivacaftor 75 mg) 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 of elexacaftor 100 mg/tezacaftor 50 mg/ivacaftor 75 mg (total dose of elexacaftor 200 mg/tezacaftor100 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 of 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 of 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 of 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. 2.5 Recommendations Regarding Missed Dose(s) If 6 hours or less have passed since the missed morning or evening dose, the patient should take the missed dose as soon as possible and continue on the original schedule. If more than 6 hours have passed since: the missed morning dose, the patient should take the missed dose as soon as possible and should not take the evening dose. The next scheduled morning dose should be taken at the usual time. the missed evening dose, the patient should not take the missed dose. The next scheduled morning dose should be taken at the usual time. Morning and evening doses should not be taken at the same time.

4 CONTRAINDICATIONS None. None. ( 4 )

5 WARNINGS AND PRECAUTIONS Drug-induced liver injury and liver failure : TRIKAFTA can cause serious and potentially fatal drug-induced liver injury. Assess liver function tests (ALT, AST, alkaline phosphatase, bilirubin) in all patients prior to initiating and throughout treatment with TRIKAFTA. Interrupt TRIKAFTA in the event of significant elevations in liver function tests or signs or symptoms of liver injury. TRIKAFTA should not be used in patients with severe hepatic impairment (Child-Pugh Class C). TRIKAFTA is not recommended in patients with moderate hepatic impairment (Child-Pugh Class B). ( 2.1 , 2.3 , 5.1 , 6 , 8.7 , 12.3 ) Hypersensitivity reactions : Angioedema and anaphylaxis have been reported with TRIKAFTA in the postmarketing setting. Initiate appropriate therapy in the event of a hypersensitivity reaction. ( 5.2 ) Intracranial hypertension : Intracranial hypertension (IH) has been reported in the postmarketing setting with the use of TRIKAFTA. If an unusual headache or visual disturbances occur during treatment, and IH is suspected, interrupt TRIKAFTA and refer for prompt medical evaluation. ( 5.3 ) Neuropsychiatric events, including suicidal thoughts and behaviors : Serious neuropsychiatric events, including symptoms of anxiety, depression, suicidal ideation and behavior, and sleep disturbances, have been reported in the postmarketing setting for TRIKAFTA or drugs containing the same or similar active ingredients. Monitor patients closely for new or worsening symptoms. Consider the risks and benefits for the individual patient to determine if therapy with TRIKAFTA should be interrupted at the occurrence of neuropsychiatric symptoms. ( 5.4 ) Use with CYP3A inducers : Concomitant use with strong CYP3A inducers (e.g., rifampin, St. John's wort) significantly decrease ivacaftor exposure and are expected to decrease elexacaftor and tezacaftor exposure, which may reduce TRIKAFTA efficacy. Therefore, concomitant use is not recommended. ( 5.5 , 7.1 , 12.3 ) Cataracts : Non-congenital lens opacities/cataracts have been reported in pediatric patients treated with ivacaftor-containing regimens. Baseline and follow-up examinations are recommended in pediatric patients initiating TRIKAFTA treatment. ( 5.7 , 8.4 ) 5.1 Drug-Induced Liver Injury and Liver Failure TRIKAFTA can cause serious and potentially fatal drug-induced liver injury. Cases of liver failure leading to transplantation and death have been reported in patients with and without a history of liver disease taking TRIKAFTA, in both clinical trials and the postmarketing setting [see Adverse Reactions (6) ] . Liver injury has been reported within the first month of therapy and up to 15 months following initiation of TRIKAFTA. Assess liver function tests (ALT, AST, alkaline phosphatase, and bilirubin) in all patients prior to initiating TRIKAFTA. Assess liver function tests every month during the first 6 months of treatment, then every 3 months for the next 12 months, then at least annually thereafter. Consider more frequent monitoring for patients with a history of liver disease or liver function test elevations at baseline [see Dosage and Administration (2.1) , Adverse Reactions (6) , and Use in Specific Populations (8.7) ] . Interrupt TRIKAFTA in the event of signs or symptoms of liver injury. These may include: Significant elevations in liver function tests (e.g., ALT or AST >5 × the upper limit of normal (ULN) or ALT or AST >3 × ULN with bilirubin >2 × ULN) Clinical symptoms suggestive of liver injury (e.g., jaundice, right upper quadrant pain, nausea, vomiting, altered mental status, ascites). Consider referral to a hepatologist and follow patients closely with clinical and laboratory monitoring until abnormalities resolve. If abnormalities resolve and if the benefit is expected to outweigh the risk, resume TRIKAFTA treatment with close monitoring. TRIKAFTA should not be used in patients with severe hepatic impairment (Child-Pugh Class C). TRIKAFTA is not recommended in patients with moderate hepatic impairment (Child-Pugh Class B) and should only be considered when there is a clear medical need, and the benefit outweighs the risk. If used, use with caution at a reduced dosage and monitor patients closely [see Dosage and Administration (2.3) , Use in Specific Populations (8.7) and Clinical Pharmacology (12.3) ] . 5.2 Hypersensitivity Reactions, Including Anaphylaxis Hypersensitivity reactions, including cases of angioedema and anaphylaxis, have been reported in the postmarketing setting [see Adverse Reactions (6.2) ] . If signs or symptoms of serious hypersensitivity reactions develop during treatment, discontinue TRIKAFTA and institute appropriate therapy. Consider the benefits and risks for the individual patient to determine whether to resume treatment with TRIKAFTA . 5.3 Intracranial Hypertension Cases of intracranial hypertension (IH) have been reported in the postmarketing setting with the use of TRIKAFTA [see Adverse Reactions (6.2) ] . Clinical manifestations of IH include headache, blurred vision, diplopia, and potential vision loss; papilledema can be found on fundoscopy. If an unusual headache or visual disturbances occur during treatment, and IH is suspected, interrupt TRIKAFTA and refer for prompt medical evaluation. Consider the benefits and risks for the individual patient to determine whether to resume treatment with TRIKAFTA. Patients should be monitored until IH resolution and for recurrence. Patients with elevated vitamin A levels may be at increased risk. 5.4 Neuropsychiatric Events, Including Suicidal Thoughts and Behaviors Serious neuropsychiatric events, including symptoms of anxiety, depression, suicidal ideation and behavior, and sleep disturbances, have been reported in the postmarketing setting in patients taking TRIKAFTA or drugs containing the same or similar active ingredients [see Adverse Reactions (6.2) ] . The events were reported in adult and pediatric patients with and without a previous history of neuropsychiatric symptoms. Symptoms may occur within the first three months of treatment initiation. Assess patients for baseline neuropsychiatric symptoms and monitor for new or worsening symptoms of anxiety, depression, suicidal ideation or behavior, or sleep disturbances. Consider the benefits and risks for the individual patient to determine if therapy with TRIKAFTA should be interrupted at the occurrence of neuropsychiatric symptoms and whether to resume therapy with symptom improvement. 5.5 Concomitant Use with CYP3A Inducers Exposure to ivacaftor is significantly decreased and exposure to elexacaftor and tezacaftor are expected to decrease by the concomitant use of strong CYP3A inducers, which may reduce the therapeutic effectiveness of TRIKAFTA. Therefore, concomitant use with strong CYP3A inducers is not recommended [see Drug Interactions (7.1) and Clinical Pharmacology (12.3) ] . 5.6 Concomitant Use with CYP3A Inhibitors Exposure to elexacaftor, tezacaftor and ivacaftor are increased when used concomitantly with strong or moderate CYP3A inhibitors. Therefore, the dose of TRIKAFTA should be reduced when used concomitantly with moderate or strong CYP3A inhibitors [see Dosage and Administration (2.4) , Drug Interactions (7.1) and Clinical Pharmacology (12.3) ] . 5.7 Cataracts Cases of non-congenital lens opacities have been reported in pediatric patients treated with ivacaftor-containing regimens. Although other risk factors were present in some cases (such as corticosteroid use, exposure to radiation), a possible risk attributable to treatment with ivacaftor cannot be excluded. Baseline and follow-up ophthalmological examinations are recommended in pediatric patients initiating treatment with TRIKAFTA [see Use in Specific Populations (8.4) ] .

7 DRUG INTERACTIONS Strong CYP3A inducers: Avoid concomitant use. ( 5.5 , 7.1 , 12.3 ) Strong or moderate CYP3A inhibitors: Reduce TRIKAFTA dosage when used concomitantly. Avoid food or drink containing grapefruit. ( 2.4 , 5.6 , 7.1 , 12.3 ) 7.1 Effect of Other Drugs and Grapefruit on TRIKAFTA Strong CYP3A Inducers Concomitant use of TRIKAFTA with strong CYP3A inducers is not recommended. Elexacaftor, tezacaftor and ivacaftor are substrates of CYP3A (ivacaftor is a sensitive substrate of CYP3A). Concomitant use of CYP3A inducers may result in reduced exposures and thus reduced TRIKAFTA efficacy [see Warnings and Precautions (5.5) ] . Concomitant use of ivacaftor with rifampin, a strong CYP3A inducer, significantly decreased ivacaftor area under the curve (AUC) by 89%. Elexacaftor and tezacaftor exposures are expected to decrease during concomitant use with strong CYP3A inducers [see Clinical Pharmacology (12.3) ] . Examples of strong CYP3A inducers include: rifampin, rifabutin, phenobarbital, carbamazepine, phenytoin and St. John's wort ( Hypericum perforatum ) Strong or Moderate CYP3A Inhibitors The dosage of TRIKAFTA should be reduced when used concomitantly with strong CYP3A inhibitors [see Dosage and Administration (2.4) and Warnings and Precautions (5.6) ] . Concomitant use with itraconazole, a strong CYP3A inhibitor, increased elexacaftor AUC by 2.8-fold and tezacaftor AUC by 4.0- to 4.5-fold. When used concomitantly with itraconazole and ketoconazole, ivacaftor AUC increased by 15.6-fold and 8.5-fold, respectively [see Clinical Pharmacology (12.3) ] . Examples of strong CYP3A inhibitors include: ketoconazole, itraconazole, posaconazole and voriconazole telithromycin and clarithromycin The dosage of TRIKAFTA should be reduced when used concomitantly with moderate CYP3A inhibitors [see Dosage and Administration (2.4) and Warnings and Precautions (5.6) ]. Simulations indicated that concomitant use with moderate CYP3A inhibitors may increase elexacaftor and tezacaftor AUC by approximately 1.9- to 2.3-fold and 2.1-fold, respectively. Concomitant use of fluconazole increased ivacaftor AUC by 2.9-fold [see Clinical Pharmacology (12.3) ] . Examples of moderate CYP3A inhibitors include: fluconazole erythromycin Grapefruit Concomitant use of TRIKAFTA with grapefruit juice, which contains one or more components that moderately inhibit CYP3A, may increase exposure of elexacaftor, tezacaftor and ivacaftor; therefore, food or drink containing grapefruit should be avoided during treatment with TRIKAFTA [see Dosage and Administration (2.4) ] . 7.2 Effect of TRIKAFTA on Other Drugs CYP2C9 Substrates Ivacaftor may inhibit CYP2C9; therefore, monitoring of the international normalized ratio (INR) during concomitant use of TRIKAFTA with warfarin is recommended. Other medicinal products for which exposure may be increased by TRIKAFTA include glimepiride and glipizide; these medicinal products should be used with caution [see Clinical Pharmacology (12.3) ] . Transporters Concomitant use of ivacaftor or tezacaftor/ivacaftor with digoxin, a sensitive P-gp substrate, increased digoxin AUC by 1.3-fold, consistent with weak inhibition of P-gp by ivacaftor. Administration of TRIKAFTA may increase systemic exposure of medicinal products that are sensitive substrates of P-gp, which may increase or prolong their therapeutic effect and adverse reactions. When used concomitantly with digoxin or other substrates of P-gp with a narrow therapeutic index such as cyclosporine, everolimus, sirolimus and tacrolimus, caution and appropriate monitoring should be used [see Clinical Pharmacology (12.3) ] . Elexacaftor and M23-ELX inhibit uptake by OATP1B1 and OATP1B3 in vitro. Concomitant use of TRIKAFTA may increase exposures of medicinal products that are substrates of these transporters, such as statins, glyburide, nateglinide and repaglinide. When used concomitantly with substrates of OATP1B1 or OATP1B3, caution and appropriate monitoring should be used [see Clinical Pharmacology (12.3) ] . Bilirubin is an OATP1B1 and OATP1B3 substrate. 7.3 Drugs with No Clinically Significant Interactions with TRIKAFTA Ciprofloxacin Ciprofloxacin had no clinically relevant effect on the exposure of tezacaftor or ivacaftor and is not expected to affect the exposure of elexacaftor. Therefore, no dose adjustment is necessary during concomitant administration of TRIKAFTA with ciprofloxacin [see Clinical Pharmacology (12.3) ] . Hormonal Contraceptives TRIKAFTA has been studied with ethinyl estradiol/levonorgestrel and was found to have no clinically relevant effect on the exposures of the oral contraceptive. TRIKAFTA is not expected to have an impact on the efficacy of oral contraceptives. Hormonal contraceptives may play a role in the occurrence of rash and cannot be excluded [see Adverse Reactions (6.1) ] . For patients with CF taking hormonal contraceptives who develop rash, consider interrupting TRIKAFTA and hormonal contraceptives. Following the resolution of rash, consider resuming TRIKAFTA without the hormonal contraceptives. If rash does not recur, resumption of hormonal contraceptives can be considered.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are discussed in greater detail in other sections of the labeling: Drug-Induced Liver Injury and Liver Failure [see Warnings and Precautions (5.1) ] Hypersensitivity Reactions, Including Anaphylaxis [see Warnings and Precautions (5.2) ] Intracranial Hypertension [see Warnings and Precautions (5.3) ] Neuropsychiatric Events, Including Suicidal Thoughts and Behaviors [see Warnings and Precautions (5.4) ] Cataracts [see Warnings and Precautions (5.7) ] The most common adverse drug reactions to TRIKAFTA (≥5% of patients and at a frequency higher than placebo by ≥1%) were headache, upper respiratory tract infection, abdominal pain, diarrhea, rash, alanine aminotransferase increased, nasal congestion, blood creatine phosphokinase increased, aspartate aminotransferase increased, rhinorrhea, rhinitis, influenza, sinusitis, blood bilirubin increased and constipation. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Vertex Pharmaceuticals Incorporated at 1-877-634-8789 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Patients with Cystic Fibrosis with at Least One F508del Variant The safety profile of TRIKAFTA in patients with CF with at least one F508del variant is based on data from 510 patients aged 12 years and older in two double-blind, controlled trials of 24 weeks and 4 weeks treatment duration (Trials 1 and 2, respectively). Eligible patients were also able to participate in an open-label extension safety study (up to 96 weeks of TRIKAFTA). In the two controlled trials, a total of 257 patients aged 12 years and older received at least one dose of TRIKAFTA. In Trial 1, the proportion of patients who discontinued study drug prematurely due to adverse events was 1% for TRIKAFTA-treated patients and 0% for placebo-treated patients. In Trial 1, serious adverse reactions that occurred more frequently in TRIKAFTA-treated patients compared to placebo were rash (1% vs <1%) and influenza (1% vs 0%). There were no deaths. Table 4 shows adverse reactions occurring in ≥5% of TRIKAFTA-treated patients and higher than placebo by ≥1% in the 24-week, placebo-controlled, parallel-group trial (Trial 1). Table 4: Adverse Reactions Occurring in ≥5% of TRIKAFTA-Treated Patients and Higher than Placebo by ≥1% in Trial 1 Adverse Reactions TRIKAFTA N=202 n (%) Placebo N=201 n (%) Headache 35 (17) 30 (15) Upper respiratory tract infection Includes upper respiratory tract infection and viral upper respiratory tract infection. 32 (16) 25 (12) Abdominal pain Includes abdominal pain, abdominal pain upper, abdominal pain lower. 29 (14) 18 (9) Diarrhea 26 (13) 14 (7) Rash Includes rash, rash generalized, rash erythematous, rash macular, rash pruritic. 21 (10) 10 (5) Alanine aminotransferase increased 20 (10) 7 (3) Nasal congestion 19 (9) 15 (7) Blood creatine phosphokinase increased 19 (9) 9 (4) Aspartate aminotransferase increased 19 (9) 4 (2) Rhinorrhea 17 (8) 6 (3) Rhinitis 15 (7) 11 (5) Influenza 14 (7) 3 (1) Sinusitis 11 (5) 8 (4) Blood bilirubin increased 10 (5) 2 (1) Additional adverse reactions that occurred in TRIKAFTA-treated patients at a frequency of 2% to <5% and higher than placebo by ≥1% include the following: flatulence, abdominal distension, conjunctivitis, pharyngitis, respiratory tract infection, tonsillitis, urinary tract infection, C-reactive protein increased, hypoglycemia, dizziness, dysmenorrhea, acne, eczema and pruritus. In addition, the following clinical trials have also been conducted [see Use in Specific Populations (8.4) , Clinical Pharmacology (12.3) and Clinical Studies (14) ]: a 24-week, open-label trial in 66 patients with CF aged 6 to less than 12 years who were either homozygous for the F508del variant or heterozygous for the F508del variant, and a variant on the second allele that results in either no CFTR protein or a CFTR protein that is not responsive to ivacaftor and tezacaftor/ivacaftor (Trial 3). a 24-week, open-label trial in 75 patients with CF aged 2 to less than 6 years. Patients who had at least one F508del variant or a variant known to be responsive to TRIKAFTA were eligible for the study (Trial 4). The safety profile for the CF patients enrolled in Trials 2, 3, and 4 was consistent to that observed in Trial 1. Patients with Cystic Fibrosis with at Least One Qualifying Non- F508del Variant The safety of TRIKAFTA in patients with CF with at least one non- F508del variant is based on data from 307 patients aged 6 years and older with at least one qualifying non- F508del CFTR variant that was TRIKAFTA-responsive. Trial 5 was a randomized, double blind, placebo-controlled trial for a 24-week treatment duration in which 205 patients received at least one dose of TRIKAFTA. Eligible patients were also able to participate in an open-label extension safety study. In Trial 5, the proportion of patients who discontinued study drug prematurely due to adverse reactions was 2% for TRIKAFTA-treated patients and 0% for placebo-treated patients. Table 5 shows adverse reactions occurring in ≥5% of TRIKAFTA-treated patients and higher than placebo by ≥1% in the 24-week, placebo-controlled, parallel-group trial (Trial 5). Table 5: Adverse Reactions Occurring in ≥5% of TRIKAFTA-Treated Patients and Higher than Placebo by ≥1% in Trial 5 Adverse Reactions TRIKAFTA N=205 n (%) Placebo N=102 n (%) Rash Includes rash, rash maculo-papular, rash erythematous, rash papular 48 (23) 2 (2) Headache 37 (18) 13 (13) Diarrhea 26 (13) 10 (10) Rhinitis 20 (10) 6 (6) Influenza 18 (9) 2 (2) Constipation 15 (7) 4 (4) Specific Adverse Reactions Liver Function Test Elevations In Trial 1, the incidence of maximum transaminase (ALT or AST) >8, >5, or >3 × ULN was 1%, 2%, and 8% in TRIKAFTA-treated patients and 1%, 1%, and 5% in placebo-treated patients. The incidence of adverse reactions of transaminase elevations (AST and/or ALT) was 11% in TRIKAFTA-treated patients and 4% in placebo-treated patients. In Trial 1, the incidence of maximum total bilirubin elevation >2 × ULN was 4% in TRIKAFTA-treated patients and <1% in placebo-treated patients. Maximum indirect and direct bilirubin elevations >1.5 × ULN occurred in 11% and 3% of TRIKAFTA-treated patients, respectively. No TRIKAFTA-treated patients developed maximum direct bilirubin elevation >2 × ULN. During Trial 3, in patients aged 6 to less than 12 years, the incidence of maximum transaminase (ALT or AST) >8, >5, and >3 × ULN were 0%, 1.5%, and 10.6%, respectively. No TRIKAFTA-treated patients had transaminase elevation >3 × ULN associated with elevated total bilirubin >2 × ULN or discontinued treatment due to transaminase elevations. During Trial 4 in patients aged 2 to less than 6 years, the incidence of maximum transaminase (ALT or AST) >8, >5, and >3 × ULN were 1.3%, 2.7%, and 8.0%, respectively. No TRIKAFTA-treated patients had transaminase elevation >3 × ULN associated with elevated total bilirubin >2 × ULN. One patient required treatment interruption during Trial 4 and later discontinued TRIKAFTA during the open label extension due to transaminase elevations. In Trial 5, the incidence of maximum transaminase (ALT or AST) >8, >5, and >3 × ULN were 2.0%, 2.0%, and 6.3%, respectively, and led to treatment discontinuation in 0.5% and treatment interruptions in 1.5% of TRIKAFTA-treated patients. There were no transaminase elevations >3 × ULN in placebo-treated patients. Rash In Trial 1, the overall incidence of rash was 10% in TRIKAFTA-treated and 5% in placebo-treated patients (see Table 4 ). The incidence of rash was higher in female TRIKAFTA-treated patients (16%) than in male TRIKAFTA-treated patients (5%). In Trial 5, the overall incidence of rash was 23% in TRIKAFTA-treated and 2% in placebo-treated patients (see Table 5 ). The incidence of rash was higher in female TRIKAFTA-treated patients (27%) than in male TRIKAFTA-treated patients (20%). A role of hormonal contraceptives in the occurrence of rash cannot be excluded [see Drug Interactions (7.3) ] . Increased Creatine Phosphokinase In Trial 1, the incidence of maximum creatine phosphokinase elevation >5 × ULN was 10% in TRIKAFTA-treated and 5% in placebo-treated patients. Among the TRIKAFTA-treated patients with creatine phosphokinase elevation >5 × ULN, 14% (3/21) required treatment interruption and none discontinued treatment. In Trial 5, the incidence of maximum creatine phosphokinase elevation >5 × ULN was 5.4% (11/205) in TRIKAFTA-treated patients and 1% (1/102) in placebo-treated patients. The incidence of maximum creatine phosphokinase elevation >10 × ULN was 2.4% (5/205) in TRIKAFTA-treated patients and 1% (1/102) in placebo-treated patients. There were no interruptions or discontinuations among the TRIKAFTA-treated patients with creatine phosphokinase elevation >5 × ULN. Among the TRIKAFTA-treated patients with creatine phosphokinase elevation > 10 × ULN, two patients, who had exercised within the preceding 72 hours, developed rhabdomyolysis without evidence of renal involvement resulting in treatment interruption in 1 patient. Increased Blood Pressure In Trial 1, the maximum increase from baseline in mean systolic and diastolic blood pressure was 3.5 mmHg and 1.9 mmHg, respectively for TRIKAFTA-treated patients (baseline: 113 mmHg systolic and 69 mmHg diastolic) and 0.9 mmHg and 0.5 mmHg, respectively for placebo-treated patients (baseline: 114 mmHg systolic and 70 mmHg diastolic). The proportion of patients who had systolic blood pressure >140 mmHg and 10 mmHg increase from baseline on at least two occasions was 4% in TRIKAFTA-treated patients and 1% in placebo-treated patients. The proportion of patients who had diastolic blood pressure >90 mmHg and 5 mmHg increase from baseline on at least two occasions was 1% in TRIKAFTA-treated patients and 2% in placebo-treated patients. With the exception of sex differences in rash, the safety profile of TRIKAFTA was generally similar across all subgroups of patients, including analysis by age, sex, baseline percent predicted FEV 1 (ppFEV 1 ) and geographic regions. 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of TRIKAFTA or drugs containing the same or similar active ingredients as TRIKAFTA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Hepatobiliary : liver injury, fatal liver failure, liver transplantation Immune System Disorders : anaphylaxis, angioedema Nervous System Disorders : intracranial hypertension Psychiatric Disorders : anxiety, depression, suicidal ideation and behavior, insomnia

8.1 Pregnancy Risk Summary There are limited and incomplete human data from clinical trials on the use of TRIKAFTA or its individual components, elexacaftor, tezacaftor and ivacaftor, in pregnant women to inform a drug-associated risk. Although there are no animal reproduction studies with the concomitant administration of elexacaftor, tezacaftor and ivacaftor, separate reproductive and developmental studies were conducted with each active component of TRIKAFTA in pregnant rats and rabbits. In animal embryo fetal development (EFD) studies oral administration of elexacaftor to pregnant rats and rabbits during organogenesis demonstrated no adverse developmental effects at doses that produced maternal exposures up to approximately 2 times the exposure at the maximum recommended human dose (MRHD) in rats and 4 times the MRHD in rabbits [based on summed AUCs of elexacaftor and its metabolite (for rat) and AUC of elexacaftor (for rabbit)]. Oral administration of tezacaftor to pregnant rats and rabbits during organogenesis demonstrated no adverse developmental effects at doses that produced maternal exposures up to approximately 3 times the exposure at the MRHD in rats and 0.2 times the MRHD in rabbits (based on summed AUCs of tezacaftor and M1-TEZ). Oral administration of ivacaftor to pregnant rats and rabbits during organogenesis demonstrated no adverse developmental effects at doses that produced maternal exposures up to approximately 5 and 14 times the exposure at the MRHD, respectively [based on summed AUCs of ivacaftor and its metabolites (for rat) and AUC of ivacaftor (for rabbit)]. No adverse developmental effects were observed after oral administration of elexacaftor, tezacaftor or ivacaftor to pregnant rats from the period of organogenesis through lactation at doses that produced maternal exposures approximately 1 time, approximately 1 time and 3 times the exposures at the MRHD, respectively [based on summed AUCs of parent and metabolite(s)] (see Data ) . The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data Elexacaftor In an EFD study, pregnant rats were administered oral doses of elexacaftor at 15, 25, and 40 mg/kg/day during the period of organogenesis from gestation Days 6-17. Elexacaftor did not cause adverse developmental outcomes at exposures up to 9 times the MRHD (based on summed AUCs for elexacaftor and its metabolite at maternal doses up to 40 mg/kg/day). Lower mean fetal body weights were observed at doses ≥25 mg/kg/day that produced maternal exposures ≥4 times the MRHD. Maternal toxicity was observed at 40 mg/kg/day (9 times the MRHD). In an EFD study, pregnant rabbits were administered oral doses of elexacaftor at 50, 100, or 125 mg/kg/day during the period of organogenesis from gestation Days 7-20. Elexacaftor was not teratogenic at exposures up to 4 times the MRHD (based on AUC of elexacaftor at maternal doses up to 125 mg/kg/day). Maternal toxicity was observed at 125 mg/kg/day (4 times the MRHD). In a pre- and postnatal development (PPND), pregnant rats were administered elexacaftor at oral doses of 5, 7.5, and 10 mg/kg/day from gestation Day 6 through lactation Day 18. Elexacaftor did not cause adverse developmental outcomes in pups at maternal doses up to 10 mg/kg/day (approximately 1 time the MRHD based on summed AUCs of elexacaftor and its metabolite). Placental transfer of elexacaftor was observed in pregnant rats. Tezacaftor In an EFD study, pregnant rats were administered tezacaftor at oral doses of 25, 50, or 100 mg/kg/day during the period of organogenesis from gestation Days 6-17. Tezacaftor did not cause adverse developmental effects at exposures up to 3 times the MRHD (based on summed AUCs of tezacaftor and M1-TEZ). Maternal toxicity in rats was observed at greater than or equal to 50 mg/kg/day (approximately greater than or equal to 1 time the MRHD). In an EFD study, pregnant rabbits were administered tezacaftor at oral doses of 10, 25, or 50 mg/kg/day during the period of organogenesis from gestation Days 7-20. Tezacaftor did not affect fetal developmental outcomes at exposures up to 0.2 times the MRHD (based on summed AUCs of tezacaftor and M1-TEZ). Lower fetal body weights were observed in rabbits at a maternally toxic dose that produced exposures approximately 1 time the MRHD (based on summed AUCs of tezacaftor and M1-TEZ at a maternal dose of 50 mg/kg/day). In a PPND study, pregnant rats were administered tezacaftor at oral doses of 25, 50, or 100 mg/kg/day from gestation Day 6 through lactation Day 18. Tezacaftor had no adverse developmental effects on pups at an exposure of approximately 1 time the MRHD (based on summed AUCs for tezacaftor and M1-TEZ at a maternal dose of 25 mg/kg/day). Decreased fetal body weights and early developmental delays in pinna detachment, eye opening, and righting reflex occurred at a maternally toxic dose (based on maternal weight loss) that produced exposures approximately 2 times the exposure at the MRHD (based on summed AUCs for tezacaftor and M1-TEZ). Placental transfer of tezacaftor was observed in pregnant rats. Ivacaftor In an EFD study, pregnant rats were administered ivacaftor at oral doses of 50, 100, or 200 mg/kg/day during the period of organogenesis from gestation Days 7-17. Ivacaftor did not affect fetal survival at exposures up to 5 times the MRHD (based on summed AUCs of ivacaftor and its metabolites at maternal oral doses up to 200 mg/kg/day). Maternal toxicity was observed at 100 and 200 mg/kg/day (3 and 5 times the exposure at the MRHD) and was associated with a decrease in fetal body weights at a maternal dose of 200 mg/kg/day (5 times the MRHD). In an EFD study, pregnant rabbits were administered ivacaftor at oral doses of 25, 50, or 100 mg/kg/day during the period of organogenesis from gestation Days 7-19. Ivacaftor did not affect fetal development or survival at exposures up to 14 times the MRHD (on an ivacaftor AUC basis at maternal oral doses up to 100 mg/kg/day). Maternal toxicity (i.e., death, decreased food consumption, decreased mean body weight and body weight gain, decreased clinical condition, abortions) was observed at doses greater than or equal to 50 mg/kg/day (approximately 5 times the MRHD). In a PPND study, pregnant rats were administered ivacaftor at oral doses of 50, 100, or 200 mg/kg/day from gestation Day 7 through lactation Day 20. Ivacaftor had no effects on delivery or growth and development of offspring at exposures up to 3 times the MRHD (based on summed AUCs for ivacaftor and its metabolites at maternal oral doses up to 100 mg/kg/day). Decreased fetal body weights were observed at a maternally toxic dose that produced exposures 5 times the MRHD (based on summed AUCs of ivacaftor and its metabolites). Placental transfer of ivacaftor was observed in pregnant rats and rabbits.