TRIKAFTA- elexacaftor, tezacaftor, and ivacaftor

Elexacaftor and tezacaftor bind to different sites on the CFTR protein and have an additive effect in facilitating the cellular processing and trafficking of select mutant forms of CFTR (including F508del-CFTR) to increase the amount of CFTR protein delivered to the cell surface compared to either molecule alone. Ivacaftor potentiates the channel open probability (or gating) of the CFTR protein at the cell surface. The combined effect of elexacaftor, tezacaftor and ivacaftor is increased quantity and function of CFTR at the cell surface, resulting in increased CFTR activity as measured both by CFTR mediated chloride transport in vitro and by sweat chloride in patients with CF. CFTR Chloride Transport Assay in Fischer Rat Thyroid Cells Expressing Mutant CFTR Protein Effects of elexacaftor/tezacaftor/ivacaftor on chloride transport for mutant CFTR proteins was determined in Ussing chamber electrophysiology studies using a panel of Fischer Rat Thyroid (FRT) cell lines stably expressing individual mutant CFTR CFTR The threshold that the treatment-induced increase in chloride transport must exceed for the mutant CFTR protein to be considered responsive is >=10% of normal over baseline. This threshold was used because it is expected to predict clinical benefit. For individual 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. CFTR Chloride Transport Assay in Human Bronchial Epithelial Cells Expressing Mutant CFTR Protein Homozygous and heterozygous N1303K F508del/F508del F508del) Patient Selection Select patients 2 years of age and older for treatment of CF with TRIKAFTA based on the presence of at least one F508del CFTR Table 6 [see Indications and Usage (1) Table 6 lists CFTR Table 6: List of CFTR Gene Mutations Responsive to TRIKAFTA Mutations responsive to TRIKAFTA based on clinical data Clinical data obtained from Trials 1, 2, and 5. 2789+5GarrowA D1152H This mutation is also predicted to be responsive by FRT assay. L206W R1066H S945L 3272-26AarrowG F508del L997F R117C T338I 3849+10kbCarrowT G85E M1101K R347H V232D A455E L1077P P5L R347P Mutations responsive to TRIKAFTA based on in vitro data The N1303K mutation is predicted to be responsive by HBE assay. All other mutations predicted to be responsive with in vitro data are supported by FRT assay. N1303K F200I I1139V P574H S1045Y 1507_1515del9 F311del I125T P67L S108F 2183AarrowG F311L I1269N P750L S1118F 3141del9 F508C I1366N Q1291R S1159F 546insCTA F508C;S1251N I148N Q1313K S1159P A1006E F575Y I148T Q237E S1235R A1067P F587I I175V Q237H S1251N A1067T G1047R I331N Q359R S1255P A107G G1061R I336K Q372H S13F A120T G1069R I502T Q493R S341P A234D G1123R I506L Q552P S364P A309D G1244E I556V Q98R S492F A349V G1247R I601F R1048G S549I A46D G1249R I618T R1070Q S549N A554E G126D I807M R1070W S549R A62P G1349D I980K R1162L S589N C491R G178E K1060T R117C;G576A;R668C S737F D110E G178R K162E R117G S912L D110H G194R K464E R117H S977F D1270N G194V L1011S R117L T1036N D1445N G27E L1324P R117P T1053I D192G G27R L1335P R1283M T1086I D443Y G314E L137P R1283S T1246I D443Y;G576A;R668C G424S L1480P R170H T1299I D565G G463V L15P R258G T351I D579G G480C L165S R297Q V1153E D614G G480S L320V R31C V1240G D836Y G551A L333F R31L V1293G D924N G551D L333H R334L V201M D979V G551S L346P R334Q V392G D993Y G576A L441P R347L V456A E116K G576A;R668C L453S R352Q V456F E116Q G622D L619S R352W V562I E193K G628R L967S R516S V603F E292K G970D M1137V R553Q V754M E403D G970S M150K R555G W1098C E474K H1054D M152V R668C W1282R E56K H1085P M265R R709Q W361R E588V H1085R M952I R74Q Y1014C E60K H1375P M952T R74W Y1032C E822K H139R N1088D R74W;D1270N Y109N E92K H199Y N1303I R74W;V201M Y161D F1016S H620P N186K R74W;V201M;D1270N Y161S F1052V H620Q N187K R751L Y301C F1074L H939R N418S R75L Y563N F1099L H939R;H949L P140S R75Q F1107L I1027T P205S R792G F191V I105N P499A R933G Mutations responsive to TRIKAFTA based on extrapolation from Trial 5 Efficacy is extrapolated from Trial 5 to non-canonical splice mutations because clinical trials in all mutations of this subgroup are infeasible and these mutations are not amenable to interrogation by FRT system. 4005+2TarrowC 2789+2insA 3849+40AarrowG 5T;TG13 1341GarrowA 296+28AarrowG 3849+4AarrowG 621+3AarrowG 1898+3AarrowG 3041-15TarrowG 3850-3TarrowG 711+3AarrowG 2752-26AarrowG 3600GarrowA 5T;TG12 E831X Sweat Chloride Evaluation In Trial 1 (patients with an F508del [see Clinical Studies (14. 1) F508del [see Clinical Studies (14. 2) F508del F508del F508del F508del CFTR 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. The pharmacokinetics of elexacaftor, tezacaftor and ivacaftor are similar between healthy adult subjects and patients with CF. The pharmacokinetic parameters for elexacaftor, tezacaftor and ivacaftor in patients with CF aged 12 years and older are shown in Table 7. Table 7: Pharmacokinetic Parameters of TRIKAFTA Components Elexacaftor Tezacaftor Ivacaftor AUC ss max max General Information AUC ss Based 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. 5) AUC 0-24h 89. 01) AUC 0-12h C max 9. 3) Time to Steady State, days Within 7 days Within 8 days Within 3-5 days Accumulation Ratio 2. 4 Absorption Absolute Bioavailability 80% Not determined Not determined Median T max 6 (4 to 12) 3 (2 to 4) 4 (3 to 6) Effect of Food AUC increases 1. 5-fold No clinically significant effect Exposure increases 2. 5- to 4-fold Distribution Mean (SD) Apparent Volume of Distribution, L Elexacaftor, tezacaftor and ivacaftor do not partition preferentially into human red blood cells. 8) Protein Binding Elexacaftor 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, hours Mean (SD) terminal half-lives of elexacaftor, tezacaftor and ivacaftor are approximately 24. 87) hours, 60. 7) hours and 13. 98) hours, respectively. 92) Mean (SD) Apparent Clearance, L/hours 1. 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 Excretion Following 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 8. Elexacaftor, tezacaftor and ivacaftor exposures in this patient population are within the range observed in patients aged 12 years and older. Table 8: Mean (SD) Elexacaftor, Tezacaftor and Ivacaftor Exposures Observed at Steady State by Age Group and Dose Administered Age Group Dose Elexacaftor AUC 0-24h,ss Tezacaftor AUC 0-24h,ss Ivacaftor AUC 0-12h,ss SD: Standard Deviation; AUC ss Patients aged 2 to less than 6 years weighing less than 14 kg elexacaftor 80 mg qd/tezacaftor 40 mg qd/ivacaftor 60 mg qAM and ivacaftor 59. 5 mg qPM 128 (24. 86) Patients aged 2 to less than 6 years weighing 14 kg or more elexacaftor 100 mg qd/tezacaftor 50 mg qd/ivacaftor 75 mg q12h 138 (47. 11) Patients aged 6 to less than 12 years weighing less than 30 kg elexacaftor 100 mg qd/tezacaftor 50 mg qd/ivacaftor 75 mg q12h 116 (39. 50) Patients aged 6 to less than 12 years weighing 30 kg or more elexacaftor 200 mg qd/ tezacaftor 100 mg qd/ ivacaftor 150 mg q12h 195 (59. 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 ss 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 m 2 2 2 [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 max max max max [see Dosage and Administration (2. 3) Warnings and Precautions (5. 1) Adverse Reactions (6) Use in Specific Populations (8. 7) Tezacaftor and Ivacaftor Following multiple doses of tezacaftor and ivacaftor for 10 days, subjects with moderately impaired hepatic function had an approximately 36% higher AUC and a 10% higher in C max max Ivacaftor In a study with ivacaftor alone, subjects with moderately impaired hepatic function had similar ivacaftor C max 0-infinity Male and Female Patients Based on population PK analysis, the exposures of elexacaftor, tezacaftor and ivacaftor are similar in males and females. Drug Interaction Studies Drug interaction studies were performed with elexacaftor, tezacaftor and/or ivacaftor and other drugs likely to be co-administered or drugs commonly used as probes for pharmacokinetic interaction studies [see Drug Interactions (7) Potential for Elexacaftor, Tezacaftor and/or Ivacaftor to Affect Other Drugs Based on in vitro results, elexacaftor and tezacaftor have a low potential to inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A4, whereas ivacaftor has the potential to inhibit CYP2C8, CYP2C9 and CYP3A. However, clinical studies showed that the combination regimen of tezacaftor/ivacaftor is not an inhibitor of CYP3A and ivacaftor is not an inhibitor of CYP2C8 or CYP2D6. Based on in vitro results, elexacaftor, tezacaftor and ivacaftor are not likely to induce CYP3A, CYP1A2 and CYP2B6. Based on in vitro results, elexacaftor and tezacaftor have a low potential to inhibit the transporter P-gp, while ivacaftor has the potential to inhibit P-gp. Co-administration of tezacaftor/ivacaftor with digoxin, a sensitive P-gp substrate, increased digoxin exposure by 1. 3-fold in a clinical study. Based on in vitro results, elexacaftor and M23-ELX may inhibit OATP1B1 and OATP1B3 uptake. Tezacaftor has a low potential to inhibit BCRP, OCT2, OAT1, or OAT3. Ivacaftor is not an inhibitor of the transporters OCT1, OCT2, OAT1, or OAT3. The effects of elexacaftor, tezacaftor and/or ivacaftor on the exposure of co-administered drugs are shown in Table 9 [see Drug Interactions (7) Table 9: Impact of Elexacaftor, Tezacaftor and/or Ivacaftor on Other Drugs Dose and Schedule Effect on Other Drug PK Geometric Mean Ratio (90% CI) of Other Drug AUC C max up arrow = increase, down arrow = decrease, left-right arrow = no change. AUC: area under the concentration versus time curve; CI: Confidence Interval; ELX: elexacaftor; C max Midazolam TEZ 100 mg qd/IVA 150 mg q12h left-right arrow Midazolam 1. 13 Digoxin TEZ 100 mg qd/IVA 150 mg q12h up arrow Digoxin 1. 32 Oral Contraceptive ELX 200 mg qd/TEZ 100 mg qd/IVA 150 mg q12h up arrow Ethinyl estradiol Effect is not clinically significant [see Drug Interactions (7. 26 up arrow Levonorgestrel 1. 10 Rosiglitazone IVA 150 mg q12h left-right arrow Rosiglitazone 0. 928 Desipramine IVA 150 mg q12h left-right arrow Desipramine 1. 00 Potential for Other Drugs to Affect Elexacaftor, Tezacaftor and/or Ivacaftor In vitro studies showed that elexacaftor, tezacaftor and ivacaftor are all metabolized by CYP3A. Exposure to elexacaftor, tezacaftor and ivacaftor may be reduced by concomitant CYP3A inducers and increased by concomitant CYP3A inhibitors. In vitro studies showed that elexacaftor and tezacaftor are substrates for the efflux transporter P-gp, but ivacaftor is not. Elexacaftor and ivacaftor are not substrates for OATP1B1 or OATP1B3; tezacaftor is a substrate for OATP1B1, but not OATP1B3. Tezacaftor is a substrate for BCRP. The effects of co-administered drugs on the exposure of elexacaftor, tezacaftor and/or ivacaftor are shown in Table 10 [see Dosage and Administration (2. 4) Drug Interactions (7) Table 10: Impact of Other Drugs on Elexacaftor, Tezacaftor and/or Ivacaftor Dose and Schedule Effect on ELX, TEZ and/or IVA PK Geometric Mean Ratio (90% CI) of Elexacaftor, Tezacaftor and Ivacaftor AUC C max up arrow = increase, down arrow = decrease, left-right arrow = no change. AUC: area under the concentration versus time curve; CI: Confidence Interval; C max Itraconazole TEZ 25 mg qd + IVA 50 mg qd up arrow Tezacaftor 4. 83 up arrow Ivacaftor 15. 60 Itraconazole ELX 20 mg + TEZ 50 mg single dose up arrow Elexacaftor 2. 05 up arrow Tezacaftor 4. 48 Ketoconazole IVA 150 mg single dose up arrow Ivacaftor 8. 65 Ciprofloxacin TEZ 50 mg q12h + IVA 150 mg q12h left-right arrow Tezacaftor 1. 05 up arrow Ivacaftor Effect is not clinically significant [see Drug Interactions (7. 18 Rifampin IVA 150 mg single dose down arrow Ivacaftor 0. 200 Fluconazole IVA 150 mg q12h up arrow Ivacaftor 2.

TRIKAFTA is indicated for the treatment of cystic fibrosis (CF) in patients aged 2 years and older who have at least one F508del CFTR CFTR Table 6 [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 indicated mutation [see Clinical Pharmacology (12. 1) 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 CFTR CFTR If the patient's genotype is unknown, an FDA-cleared CF mutation test should be used to confirm the presence of at least one indicated mutation.

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. 1 Recommended Dosage for Adult and Pediatric Patients Aged 2 Years and Older (with fat-containing food ( 2. 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. 3 See full prescribing information for dosage modifications due to drug interactions with TRIKAFTA. 3 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) Use in Specific Populations (8. 7) Recommended dosage for adult and pediatric patients aged 2 years and older is provided in Table 1. Administer TRIKAFTA tablets (swallow the tablets whole) or oral granules orally with fat-containing food, in the morning and in the evening approximately 12 hours apart. Examples of meals or snacks that contain fat are those prepared with butter or oils or those containing eggs, peanut butter, cheeses, nuts, whole milk, or meats [see Clinical Pharmacology (12. 3) Administer each dose of TRIKAFTA oral granules immediately before or after ingestion of fat-containing food. Mix entire contents of each packet of oral granules with one teaspoon (5 mL) of age-appropriate soft food or liquid that is at or below room temperature. Some examples of soft food or liquids include pureed fruits or vegetables, yogurt, applesauce, water, milk, or juice. Once mixed, the product should be consumed completely within one hour. 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 em dash 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 Severe Hepatic Impairment (Child-Pugh Class C): [see Warnings and Precautions (5. 1) Adverse Reactions (6) Use in Specific Populations (8. 7) Clinical Pharmacology (12. 3) Moderate Hepatic Impairment (Child-Pugh Class B) Table 2 [see Use in Specific Populations (8. 3) [see Dosage and Administration (2. 1) Warnings and Precautions (5. 1) 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 elexacaftor 100 mg/tezacaftor 50 mg/ivacaftor 75 mg No evening ivacaftor tablet dose. 12 years and older em dash 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 elexacaftor 100 mg/tezacaftor 50 mg/ivacaftor 75 mg No evening ivacaftor tablet dose. Mild Hepatic Impairment (Child-Pugh Class A): [see Use in Specific Populations (8. 3) Table 1 [see Dosage and Administration (2. 1) Table 3 describes the recommended dosage modification for TRIKAFTA when used concomitantly with strong (e. , ketoconazole, itraconazole, posaconazole, voriconazole, telithromycin, and clarithromycin) or moderate (e. , fluconazole, erythromycin) CYP3A inhibitors. Administer TRIKAFTA orally with fat-containing food [see Dosage and Administration (2. 2) [see Warnings and Precautions (5. 4) Drug Interactions (7. 1) 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 One packet (containing elexacaftor 80 mg/tezacaftor 40 mg/ivacaftor 60 mg) in the morning twice a week, approximately 3 to 4 days apart. 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 One packet (containing elexacaftor 100 mg/tezacaftor 50 mg/ivacaftor 75 mg) in the morning twice a week, approximately 3 to 4 days apart. 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 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. 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/tezacaftor100 mg/ivacaftor 150 mg) in the morning Day 2: One tablet of ivacaftor 150 mg in the morning 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. 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 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. 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. Morning and evening doses should not be taken at the same time.

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) 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, blood bilirubin increased and constipation. 1 To report SUSPECTED ADVERSE REACTIONS, contact Vertex Pharmaceuticals Incorporated at 1-877-634-8789 or FDA at 1-800-FDA-1088 or www. gov/medwatch. 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 The safety profile of TRIKAFTA in patients with CF with at least one F508del 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 Placebo 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) 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 F508del 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 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 The safety of TRIKAFTA in patients with CF with at least one non- F508del F508del 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 Placebo 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. 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. 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. 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. 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 In Trial 5, the overall incidence of rash was 23% in TRIKAFTA-treated and 2% in placebo-treated patients (see Table 5 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 1 The following adverse reactions have been identified during postapproval 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 Immune System Disorders.

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. 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. , death, decreased food consumption, decreased mean body weight and body weight gain, decreased clinical condition, abortions) was observed at doses greater than or equal to 50 mg/kg/day (approximately 5 times the MRHD). In a PPND study, pregnant rats were administered ivacaftor at oral doses of 50, 100, or 200 mg/kg/day from gestation Day 7 through lactation Day 20. Ivacaftor had no effects on delivery or growth and development of offspring at exposures up to 3 times the MRHD (based on summed AUCs for ivacaftor and its metabolites at maternal oral doses up to 100 mg/kg/day). Decreased fetal body weights were observed at a maternally toxic dose that produced exposures 5 times the MRHD (based on summed AUCs of ivacaftor and its metabolites). Placental transfer of ivacaftor was observed in pregnant rats and rabbits. Risk Summary There is no information regarding the presence of elexacaftor, tezacaftor, or ivacaftor in human milk, the effects on the breastfed infant, or the effects on milk production. Elexacaftor, tezacaftor, and ivacaftor are excreted into the milk of lactating rats (see Data Data Elexacaftor: 14 14 0-72h Tezacaftor: 14 14 0-72h Ivacaftor: 14 14 0-24h 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 CFTR CFTR [see Adverse Reactions (6. 1) Clinical Studies (14) Use of TRIKAFTA for this indication in pediatric patients 2 to less than 12 years of age is based on the following: Trial 1, 56 pediatric patients aged 12 to less than 18 years who had an F508del [see Adverse Reactions (6) Clinical Studies (14) Trial 2, 16 pediatric patients aged 12 to less than 18 years who were homozygous for the F508del [see Adverse Reactions (6) Clinical Studies (14) Trial 3, 66 pediatric patients aged 6 to less than 12 years who were homozygous for the F508del F508del [see Adverse Reactions (6) Clinical Pharmacology (12. 3) Trial 4, 75 pediatric patients aged 2 to less than 6 years who had at least one F508del [see Adverse Reactions (6) Clinical Pharmacology (12. 3) Trial 5, 64 pediatric patients aged 6 years to less than 18 years who had a least one qualifying non- F508del [see Adverse Reactions (6) Clinical Studies (14. 2) The effectiveness of TRIKAFTA in patients aged 2 to less than 12 years was extrapolated from patients aged 12 years and older with support from population pharmacokinetic analyses showing elexacaftor, tezacaftor, and ivacaftor exposure levels in patients aged 2 to less than 12 years within the range of exposures observed in patients aged 12 years and older [see Clinical Pharmacology (12. 3) [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. Clinical studies of TRIKAFTA did not include any patients aged 65 years and older. TRIKAFTA has not been studied in patients with severe renal impairment or end-stage renal disease. No dosage adjustment is recommended in patients with mild (eGFR 60 to <90 mL/min/1. 73 m 2 2 2 [see Clinical Pharmacology (12. 3) Severe Hepatic Impairment (Child-Pugh Class C): [see Dosage and Administration (2. 3) Warnings and Precautions (5. 1) Adverse Reactions (6) Clinical Pharmacology (12. 3) Moderate Hepatic Impairment (Child-Pugh Class B): [see Dosage and Administration (2. 1) [see Clinical Pharmacology (12. 3) Mild Hepatic Impairment (Child-Pugh Class A): [see Dosage and Administration (2. 1) Warnings and Precautions (5. 1) Trial 1 included a total of 18 patients receiving TRIKAFTA with ppFEV 1.

Strong CYP3A inducers: Avoid concomitant use. 3 Strong or moderate CYP3A inhibitors: Reduce TRIKAFTA dosage when used concomitantly. Avoid food or drink containing grapefruit. 3 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. 3) [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) Warnings and Precautions (5. 4) [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. 3) Examples of moderate CYP3A inhibitors include: fluconazole erythromycin Grapefruit Concomitant use of TRIKAFTA with grapefruit juice, which contains one or more components that moderately inhibit CYP3A, may increase exposure of elexacaftor, tezacaftor and ivacaftor; therefore, food or drink containing grapefruit should be avoided during treatment with TRIKAFTA [see Dosage and Administration (2. 4) CYP2C9 Substrates Ivacaftor may inhibit CYP2C9; therefore, monitoring of the international normalized ratio (INR) during concomitant use of TRIKAFTA with warfarin is recommended. Other medicinal products for which exposure may be increased by TRIKAFTA include glimepiride and glipizide; these medicinal products should be used with caution [see Clinical Pharmacology (12. 3) Transporters Concomitant use of ivacaftor or tezacaftor/ivacaftor with digoxin, a sensitive P-gp substrate, increased digoxin AUC by 1. 3-fold, consistent with weak inhibition of P-gp by ivacaftor. Administration of TRIKAFTA may increase systemic exposure of medicinal products that are sensitive substrates of P-gp, which may increase or prolong their therapeutic effect and adverse reactions. When used concomitantly with digoxin or other substrates of P-gp with a narrow therapeutic index such as cyclosporine, everolimus, sirolimus and tacrolimus, caution and appropriate monitoring should be used [see Clinical Pharmacology (12. 3) Elexacaftor and M23-ELX inhibit uptake by OATP1B1 and OATP1B3 in vitro. Concomitant use of TRIKAFTA may increase exposures of medicinal products that are substrates of these transporters, such as statins, glyburide, nateglinide and repaglinide. When used concomitantly with substrates of OATP1B1 or OATP1B3, caution and appropriate monitoring should be used [see Clinical Pharmacology (12. 3) 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.

OVERDOSAGE
Treatment of overdosage consists of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient.
NONCLINICAL TOXICOLOGY
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.
CLINICAL STUDIES
The efficacy of TRIKAFTA in patients aged 12 years and older with cystic fibrosis (CF) with at least one F508del Trial 1 (NCT03525444) was a 24-week, randomized, double-blind, placebo-controlled study in patients who had an F508del Trial 2 (NCT03525548) was a 4-week, randomized, double-blind, active-controlled study in patients who are homozygous for the F508del Patients in Trials 1 and 2 had a confirmed diagnosis of CF and at least one F508del 1 Burkholderia cenocepacia Burkholderia dolosa Mycobacterium abscessus Trial 1 Trial 1 evaluated 403 patients (200 TRIKAFTA, 203 placebo) with CF aged 12 years and older (mean age 26. The mean ppFEV 1 1 1 Of the 403 patients included in the interim analysis, the treatment difference between TRIKAFTA and placebo for the mean absolute change from baseline in ppFEV 1 P The treatment difference between TRIKAFTA and placebo for mean absolute change in ppFEV 1 P 1 Figure 1 1 1 Table 11 Table 11: Primary and Key Secondary Efficacy Analyses (Trial 1) Analysis Statistic Treatment Difference Treatment difference provided as the outcome measure for changes in ppFEV 1 ppFEV 1 Primary (Interim Full Analysis Set) Primary endpoint was based on interim analysis in 403 patients. Absolute change in ppFEV 1 Treatment difference (95% CI) P 13. 4) P Key Secondary (Full Analysis Set) Key secondary endpoints were tested at the final analysis in 403 patients. Absolute change in ppFEV 1 Treatment difference (95% CI) P 14. 8) P Number of pulmonary exacerbations from baseline through Week 24 A pulmonary exacerbation was defined as a change in antibiotic therapy (IV, inhaled, or oral) as a result of 4 or more of 12 pre-specified sino-pulmonary signs/symptoms. Number of pulmonary exacerbation events (event rate per year calculated based on 48 weeks per year) in the TRIKAFTA group were 41 (0. 37) and 113 (0. 98) in the placebo group. Rate ratio (95% CI) P 0. 55) P Absolute change in sweat chloride from baseline through Week 24 (mmol/L) Treatment difference (95% CI) P -41. 3) P Absolute change in CFQ-R respiratory domain score from baseline through Week 24 (points) Treatment difference (95% CI) P 20. 0) P Absolute change in BMI from baseline at Week 24 (kg/m 2 Treatment difference (95% CI) P 1. 23) P Absolute change in sweat chloride from baseline at Week 4 (mmol/L) Treatment difference (95% CI) P -41. 5) P Absolute change in CFQ-R respiratory domain score from baseline at Week 4 (points) Treatment difference (95% CI) P 20. 2) P Figure 1: Absolute Change from Baseline in Percent Predicted FEV 1 Figure 1 Trial 2 Trial 2 evaluated 107 patients with CF aged 12 years and older (mean age 28. The mean ppFEV 1 1 1 P 1 1 1 Table 12 Table 12: Primary and Key Secondary Efficacy Analyses, Full Analysis Set (Trial 2) Analysis Baseline for primary and key secondary endpoints is defined as the end of the 4-week tezacaftor/ivacaftor run-in period. Statistic Treatment Difference for TRIKAFTA (N=55) vs Tezacaftor/Ivacaftor Regimen of tezacaftor 100 mg qd/ivacaftor 150 mg q12h. ppFEV 1 Primary Absolute change in ppFEV 1 Treatment difference (95% CI) P 10. 6) P Key Secondary Absolute change in sweat chloride from baseline at Week 4 (mmol/L) Treatment difference (95% CI) P -45. 1) P Absolute change in CFQ-R respiratory domain score from baseline at Week 4 (points) Treatment difference (95% CI) P 17. 0) P The efficacy of TRIKAFTA in patients with cystic fibrosis (CF) without an F508del Trial 5 (NCT05274269) was a 24-week, randomized, placebo-controlled, double-blind, parallel-group trial in 307 patients aged 6 years and older with CF (mean age 33. The mean baseline ppFEV1 was 67. 7% (range: 34. The trial included patients who had at least one qualifying non- F508del Patients aged 6 to less than 12 years, weighing less than 30 kg: total morning dose of elexacaftor 100 mg/ tezacaftor 50 mg/ ivacaftor 75 mg and evening dose of ivacaftor 75 mg Patients aged 6 to less than 12 years, weighing greater than or equal to 30 kg: total morning dose of elexacaftor 200 mg/ tezacaftor 100 mg/ ivacaftor 150 mg and evening dose of ivacaftor 150 mg Patients aged 12 years and older: total morning dose of elexacaftor 200 mg/ tezacaftor 100 mg/ ivacaftor 150 mg and evening dose of ivacaftor 150 mg Patients discontinued any previous CFTR modulator therapies but continued on their other standard-of-care CF therapies (e. , bronchodilators, inhaled antibiotics, dornase alfa and hypertonic saline). Patients had a ppFEV 1 1 Burkholderia cenocepacia Burkholderia dolosa Mycobacterium abscessus In Trial 5, the primary efficacy endpoint was absolute change in ppFEV 1 Table 13: Primary and Secondary Efficacy Analyses, Full Analysis Set (Trial 5) Analysis Statistic Treatment Difference Treatment difference was provided as the outcome measure for changes in ppFEV 1 BMI: body mass index; CFQ-R: Cystic Fibrosis Questionnaire-Revised; CI: confidence interval; N: total sample size; P 1 Primary Absolute change in ppFEV 1 Treatment difference (95% CI) P 9. 3) P Secondary Absolute change in sweat chloride from baseline through Week 24 (mmol/L) Treatment difference (95% CI) P -28. 5) P Absolute change in CFQ-R respiratory domain score from baseline through Week 24 (points) Treatment difference (95% CI) P 19. 5) P Absolute change from baseline in BMI at Week 24 (kg/m 2 Treatment difference (95% CI) P 0. 69) P Absolute change from baseline in weight at Week 24 (kg) Treatment difference (95% CI) P 1. 9) P Number of pulmonary exacerbations through Week 24 Number of pulmonary exacerbation events (event rate per year calculated based on 48 weeks per year) in the TRIKAFTA group were 21 (0. 17) and in the placebo group were 40 (0.

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TRIKAFTA- elexacaftor, tezacaftor, and ivacaftor Product manual source documgent