VANZACAFTOR, TEZACAFTOR, AND DEUTIVACAFTOR- vanzacaftor, tezacaftor, and deutivacaftor_tablet, film coated

Vanzacaftor 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- The combined effect of vanzacaftor, tezacaftor and deutivacaftor 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 vanzacaftor/tezacaftor/deutivacaftor on chloride transport for mutant CFTR protein was determined in Ussing chamber electrophysiology studies using a panel of Fischer Rat Thyroid (FRT) cell lines stably expressing CFTR protein from individual mutations. Vanzacaftor/tezacaftor/deutivacaftor increased chloride transport in FRT cells expressing select 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 6 years of age and older for treatment of CF with ALYFTREK based on the presence of at least one F508del CFTR Table 5 [see Indications and Usage (1) Table 5 lists CFTR [see Clinical Studies (14) Table 5: List of CFTR Gene Mutations Responsive to ALYFTREK Based on Clinical Data Clinical data is obtained from Trials 1 and 2. A455E G551D L1077P This mutation is also predicted to be responsive by FRT assay with ALYFTREK. R352Q S549N V754M D1152H G85E L206W R75Q S549R W1098C F508del H1054D M1101K S1159F S945L W1282R G1244E I336K R1066H S1251N V562I Y563N Based on in vitro Data The N1303K 1507_1515del9 E116Q G424S I556V P140S R334L T1053I 2183AarrowG E193K G463V I601F P205S R334Q T1086I 3141del9 E292K G480C I618T P499A R347H T1246I 3195del6 E403D G480S I807M P5L R347L T1299I 3199del6 E474K G551A I980K P574H R347P T338I 546insCTA E56K G551S K1060T P67L R352W T351I A1006E E588V G576A K162E P750L R516G T604I A1067P E60K G576A;R668C Complex/compound mutations where a single allele of the CFTR K464E P99L R516S V1153E A1067T E822K G622D L1011S Q1100P R553Q V1240G A107G E92K G628R L102R Q1291R R555G V1293G A120T F1016S G91R L1065P Q1313K R560S V201M A234D F1052V G970D L1324P Q237E R560T V232D A309D F1074L G970S L1335P Q237H R668C V392G A349V F1099L H1085P L137P Q359R R709Q V456A A46D F1107L H1085R L1480P Q372H R74Q V456F A554E F191V H1375P L15P Q452P R74W V520F A559T F200I H139R L165S Q493R R74W;D1270N V603F A559V F311del H199R L320V Q552P R74W;V201M W361R A561E F311L H199Y L333F Q98R R74W;V201M;D1270N Y1014C A613T F508C H609R L333H R1048G R75L Y1032C A62P F508C;S1251N H620P L346P R1066C R751L Y109N A72D F575Y H620Q L441P R1066L R792G Y161D C491R F587I H939R L453S R1066M R933G Y161S D110E G1047R H939R;H949L L619S R1070Q S1045Y Y301C D110H G1061R I1027T L967S R1070W S108F Y569C D1270N G1069R I105N L997F R1162L S1118F Y913C D1445N G1123R I1139V M1101R R117C S1159P D192G G1247R I1234Vdel6aa M1137V R117C;G576A;R668C S1235R D443Y G1249R I125T M150K R117G S1255P D443Y;G576A;R668C G126D I1269N M152V R117H S13F D513G G1349D I331N M265R R117L S341P D565G G149R I1366N M952I R117P S364P D579G G178E I1398S M952T R1283M S492F D614G G178R I148N N1088D R1283S S549I D836Y G194R I148T N1303I R170H S589N D924N G194V I175V N1303K R258G S737F D979V G27E I502T N186K R297Q S912L D993Y G27R I506L N187K R31C S977F E116K G314E I506T N418S R31L T1036N Based on Extrapolation Efficacy is extrapolated to certain non-canonical splice mutations because clinical trials in all mutations in this subgroup are infeasible and these mutations are not amenable to interrogation by FRT system. 1341GarrowA 2789+2insA 3041-15TarrowG 3849+10kbCarrowT 3850-3TarrowG 5T;TG13 711+3AarrowG 1898+3AarrowG 2789+5GarrowA 3272-26AarrowG 3849+4AarrowG 4005+2TarrowC 621+3AarrowG E831X 2752-26AarrowG 296+28AarrowG 3600GarrowA 3849+40AarrowG 5T;TG12 Effects on Sweat Chloride In patients with CF heterozygous for F508del CFTR P In patients with CF homozygous for the F508del F508del F508del P In an open label trial in patients with CF aged 6 to less than 12 years with at least one mutation that is responsive to ELX/TEZ/IVA (Trial 3) [see Adverse Reactions (6. 1) The clinical relevance of these differences in sweat chloride has not been established in interventional clinical trials. Cardiac Electrophysiology At approximately 6 times the maximum recommended dose of vanzacaftor, clinically significant QTc interval prolongation was not observed. Similarly, in separate studies of tezacaftor and ivacaftor evaluating up to 3 times the respective maximum recommended doses, clinically significant QTc interval prolongation was not observed. The pharmacokinetic parameters for vanzacaftor, tezacaftor, and deutivacaftor in patients with CF aged 12 years and older are provided in Table 6 as mean (SD) unless otherwise specified. No clinically significant differences in the pharmacokinetics of vanzacaftor, tezacaftor, and deutivacaftor were observed between healthy adult subjects and patients with CF. Table 6: Pharmacokinetics Parameters of ALYFTREK Components Vanzacaftor Tezacaftor Deutivacaftor Abbreviations: max max Exposure C max,ss 0. 637) AUC 0-24h,ss ∙ 18. 3) Time to steady state within 20 days within 8 days within 8 days AUC Accumulation Ratio 6. 497) Absorption T max Median (range) 7. 4) Effect of food AUC inf When administered with fat-containing meals relative to fasted conditions. Note: The high-fat meal was approximately 800-1000 calories with 50% fat. The low-fat meal was approximately 400-500 calories with 25% fat. Increase 4- (low-fat meal) to 6- (high-fat meal) fold No clinically significant change Increase 3- (low-fat meal) to 4- (high-fat meal) fold Distribution Vanzacaftor, tezacaftor, deutivacaftor do not partition preferentially into human red blood cells. Apparent (oral) volume of distribution (L) 121 (28. 1) Protein Binding Vanzacaftor and deutivacaftor bind primarily to albumin and alpha 1-acid glycoprotein. Tezacaftor binds primarily to albumin. > 99% Approximately 99% > 99% Elimination Effective Half-life (hours) The mean (SD) terminal half-lives of vanzacaftor, tezacaftor, and deutivacaftor are 54. 1) hours, 92. 1) hours and 17. 67) hours, respectively based on a single dose of vanzacaftor/tezacaftor/deutivacaftor tablets in healthy subjects in the fed state. 71) Apparent (oral) Clearance (L/hours) 1. 68) Metabolism Primary Pathway CYP3A4/5 CYP3A4/5 CYP3A4/5 Active metabolites None M1-TEZ M1-D-IVA Metabolite potency (relative to parent) Not applicable Similar Approximately 20% Excretion Following radiolabeled doses. 6% 72% (unchanged or M2-TEZ) Not available Urine 0. 7% Not available Specific Populations No clinically significant differences in the pharmacokinetics of vanzacaftor, tezacaftor, or deutivacaftor were observed based on age, sex, race, CFTR 2 2 Weight was identified as the key covariate having a clinically meaningful impact on pharmacokinetics of vanzacaftor, tezacaftor, and deutivacaftor. Pediatric Patients Aged 6 to Less Than 18 Years Vanzacaftor, tezacaftor and deutivacaftor exposures observed in clinical trials are presented by age group and dosage administered in Table 7. No clinically significant differences in vanzacaftor, tezacaftor, and deutivacaftor exposures were observed in patients with CF aged 6 to less than 18 years compared to adults following the recommended dosages. Table 7: Mean (SD) Vanzacaftor, Tezacaftor and Deutivacaftor Exposures by Age Group Age group Weight Dosage (once daily) AUC 0-24h Vanzacaftor Tezacaftor Deutivacaftor Abbreviations 0-24h 6 to <12 years <40 kg vanzacaftor 12 mg 13. 6) >=40 kg vanzacaftor 20 mg 18. 49) 101 (33. 7) 12 to <18 years - vanzacaftor 20 mg 15. 3) >=18 years - 19. 3) Patients with Hepatic Impairment Vanzacaftor AUC was approximately 30% lower, tezacaftor AUC was comparable, and deutivacaftor AUC was approximately 20% lower in subjects with moderate hepatic impairment (Child-Pugh Class B) compared to subjects with normal liver function matched for demographics [see Use in Specific Populations (8. 7) The effect of mild hepatic impairment (Child-Pugh Class A) or severe hepatic impairment (Child-Pugh Class C) on vanzacaftor, tezacaftor, or deutivacaftor pharmacokinetics is unknown. Drug Interaction Studies Clinical Studies and Model-Informed Approaches Exposure changes associated with concomitant use of vanzacaftor, tezacaftor, ivacaftor and/or deutivacaftor with other drugs are shown in Table 8. Table 8: Observed or Predicted Exposure Changes Associated with Concomitant Use of Vanzacaftor, Tezacaftor, Ivacaftor and/or Deutivacaftor with Other Drugs Dosage Effected Drug Geometric Mean Ratio (90% CI) AUC C max Abbreviations Itraconazole TEZ 25 mg daily + IVA 50 mg daily Tezacaftor 4. 83 Itraconazole ELX 20 mg + TEZ 50 mg + D-IVA 50 mg single dose Tezacaftor 4. 48 Deutivacaftor 11. 96 Itraconazole The itraconazole dosing (200 mg qd for14 days) did not fully cover the elimination of vanzacaftor. 5-fold increase in vanzacaftor AUC is predicted by physiologically based pharmacokinetic modeling and simulations when itraconazole fully covers the elimination. VNZ 5 mg single dose Vanzacaftor 6. 55 Ciprofloxacin Effect is not clinically significant [see Drug Interactions (7. 3) TEZ 50 mg q12h + IVA 150 mg q12h Tezacaftor 1. 05 Digoxin 0. 5 mg TEZ 25 mg daily + IVA 50 mg daily Digoxin 1. 32 Fluconazole VNZ 20 mg qd + TEZ 100 mg + D-IVA 250 mg qd Vanzacaftor 2. 55 Predicted by physiologically based pharmacokinetic modeling and simulations. Data presented as geometric mean ratio and 5 th th [see Drug Interactions (7. 48 Deutivacaftor 3. 27 Erythromycin VNZ 20 mg qd + TEZ 100 mg + D-IVA 250 mg qd Vanzacaftor 3. 19 Deutivacaftor 4. 89 Verapamil VNZ 20 mg qd + TEZ 100 mg + D-IVA 250 mg qd Vanzacaftor 3. 80 Deutivacaftor 5. 43 Rifampin VNZ 20 mg qd + TEZ 100 mg + D-IVA 250 mg qd Vanzacaftor 0. 22 Deutivacaftor 0. 20 Carbamazepine VNZ 20 mg qd + TEZ 100 mg + D-IVA 250 mg qd Vanzacaftor 0. 46 Deutivacaftor 0. 32 Efavirenz VNZ 20 mg qd + TEZ 100 mg + D-IVA 250 mg qd Vanzacaftor 0. 35 Deutivacaftor 0. 44 Other Drugs: In Vitro Studies CYP450 Enzymes: Transporter Systems:.

ALYFTREK is indicated for the treatment of cystic fibrosis (CF) in patients 6 years of age and older who have at least one F508del CFTR Table 5 [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. ALYFTREK is a combination of deutivacaftor, a CFTR potentiator, tezacaftor, and vanzacaftor indicated for the treatment of cystic fibrosis (CF) in patients aged 6 years and older who have at least one F508del CFTR 1 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.

Prior to initiating ALYFTREK 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 6 Years and Older (with fat-containing food) ( 2. 2 Age Weight Once Daily Oral Dosage 6 to less than 12 years old Less than 40 kg Three tablets of vanzacaftor 4 mg/tezacaftor 20 mg/deutivacaftor 50 mg Greater than or equal to 40 kg Two tablets of vanzacaftor 10 mg/tezacaftor 50 mg/deutivacaftor 125 mg 12 years and older Any Weight Two tablets of vanzacaftor 10 mg/tezacaftor 50 mg/deutivacaftor 125 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. If used, no dose adjustment is recommended. Liver function tests should be closely monitored. 7 See full prescribing information for dosage modifications for concomitant use of ALYFTREK with strong or moderate CYP3A inhibitors. 1 Prior to initiating ALYFTREK, 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, elevated liver function tests at baseline, or a history of elevated liver function tests with drugs containing elexacaftor, tezacaftor, and/or ivacaftor [see Warnings and Precautions (5. 1) Use in Specific Populations (8. 7) The recommended ALYFTREK dosage in adult and pediatric patients aged 6 years and older is provided in Table 1. Administer ALYFTREK orally (swallow the tablets whole) with fat-containing food, once daily, at approximately the same time each day [see Clinical Pharmacology (12. 3) Table 1: Recommended Dosage of ALYFTREK in Adult and Pediatric Patients Aged 6 Years and Older Age Weight Once Daily Oral Dosage 6 to less than 12 years old Less than 40 kg Three tablets of vanzacaftor 4 mg/tezacaftor 20 mg/deutivacaftor 50 mg (total dose of vanzacaftor 12 mg/tezacaftor 60 mg/ deutivacaftor 150 mg) Greater than or equal to 40 kg Two tablets of vanzacaftor 10 mg/tezacaftor 50 mg/deutivacaftor 125 mg (total dose of vanzacaftor 20 mg/tezacaftor 100 mg/ deutivacaftor 250 mg) 12 years and older Any weight Two tablets of vanzacaftor 10 mg/tezacaftor 50 mg/deutivacaftor 125 mg (total dose of vanzacaftor 20 mg/tezacaftor 100 mg/ deutivacaftor 250 mg) Table 2 describes the recommended dosage modification for ALYFTREK when used concomitantly with strong or moderate CYP3A inhibitors [see Warnings and Precautions (5. 5) [see Clinical Pharmacology (12. 3) Table 2: Dosage Modification for Concomitant Use of ALYFTREK with Strong or Moderate CYP3A Inhibitors in Adult and Pediatric Patients Aged 6 Years and Older Age Weight Moderate CYP3A Inhibitors Strong CYP3A Inhibitors 6 to less than 12 years old Less than 40 kg Two tablets of vanzacaftor 4 mg/tezacaftor 20 mg/deutivacaftor 50 mg every other day (total dose of vanzacaftor 8 mg/tezacaftor 40 mg/deutivacaftor 100 mg) Two tablets of vanzacaftor 4 mg/tezacaftor 20 mg/deutivacaftor 50 mg once a week (total dose of vanzacaftor 8 mg/tezacaftor 40 mg/deutivacaftor 100 mg) Greater than or equal to 40 kg One tablet of vanzacaftor 10 mg/tezacaftor 50 mg/deutivacaftor 125 mg every other day One tablet of vanzacaftor 10 mg/tezacaftor 50 mg/deutivacaftor 125 mg once a week 12 years and older Any weight One tablet of vanzacaftor 10 mg/tezacaftor 50 mg/deutivacaftor 125 mg every other day One tablet of vanzacaftor 10 mg/tezacaftor 50 mg/deutivacaftor 125 mg once a week Severe Hepatic Impairment (Child-Pugh Class C) Moderate Hepatic Impairment (Child-Pugh Class B) [see Dosage and Administration (2. 2) Mild Hepatic Impairment (Child-Pugh Class A) [see Dosage and Administration (2. 2) If 6 hours or less have passed since the missed dose, take the missed dose as soon as possible and continue on the original schedule. If more than 6 hours have passed since the missed dose, skip the missed dose, and continue on the original schedule the next day.

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) Patients Who Discontinued or Interrupted Elexacaftor-, Tezacaftor-, or Ivacaftor-Containing Drugs Due to Adverse Reactions [see Warnings and Precautions (5. 3) Cataracts [see Warnings and Precautions (5. 6) Most common adverse reactions to ALYFTREK (>=5% of patients and at a frequency higher than ELX/TEZ/IVA by >=1%) were cough, nasopharyngitis, upper respiratory tract infection, headache, oropharyngeal pain, influenza, fatigue, increased ALT, rash, increased AST, and sinus congestion. 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. The adverse reactions data below are from clinical trials of ALYFTREK in patients 6 years of age and older with CF with at least one responsive CFTR. Adverse Reactions in Patients Aged 12 Years and Older with CF The safety of ALYFTREK is based on 480 patients with CF aged 12 years and older who have at least one F508del CFTR [see Clinical Studies (14) In Trial 1 and Trial 2 combined, the proportion of patients who discontinued treatment prematurely due to adverse reactions were 3. 7% in ALYFTREK and ELX/TEZ/IVA treatment groups, respectively. Serious adverse reactions that occurred more frequently with ALYFTREK treatment than with ELX/TEZ/IVA treatment that occurred in 2 or more patients (>=0. 4%) were influenza (1. 5%), increased AST (0. 4%), increased GGT (0. 4%), depression (0. 4%), and syncope (0. Table 3: Adverse Reactions Occurring in >=5% of ALYFTREK-Treated Patients and >=1% Higher than ELX/TEZ/IVA-Treated Patients Aged 12 Years and Older with CF Who Had at Least One F508del Mutation or Responsive Mutation in the CFTR Gene (Trials 1 and 2) Adverse Reactions ALYFTREK ELX/TEZ/IVA Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; ELX, elexacaftor; IVA, ivacaftor; TEZ, tezacaftor Cough Cough is composed of several similar terms including productive cough 120 (25%) 116 (24%) Nasopharyngitis 102 (21%) 95 (19%) Upper respiratory tract infection Upper respiratory tract infection is composed of several similar terms including viral upper respiratory tract infection 101 (21%) 97 (20%) Headache 76 (16%) 63 (13%) Oropharyngeal pain 69 (14%) 60 (12%) Influenza 52 (11%) 26 (5%) Fatigue 51 (11%) 46 (9%) ALT increased 38 (8%) 29 (6%) Rash 37 (8%) 22 (4%) AST increased 33 (7%) 27 (5%) Sinus congestion 32 (7%) 15 (3%) Adverse events that occurred in >=5% of ELX/TEZ/IVA-treated patients at a similar or higher incidence than the ALYFTREK-treated patients included: infective pulmonary exacerbation of CF, COVID-19, diarrhea, abdominal pain, pyrexia, nasal congestion, increased sputum, increased blood creatinine phosphokinase, rhinorrhea, hemoptysis, nausea, back pain, arthralgia, constipation, sinusitis, dyspnea, and vomiting. Liver Function Test Elevations The incidence of adverse reactions of transaminase elevations was 9% in ALYFTREK-treated patients and 7. 1% in ELX/TEZ/IVA-treated patients in Trials 1 and 2. In these trials, 1. 5% of ALYFTREK-treated patients and 0. 6% of ELX/TEZ/IVA-treated patients discontinued treatment for elevated transaminases. Table 4 shows the incidence of maximum transaminase (ALT or AST) elevations in Trials 1 and 2. Table 4: Number and Incidence of Maximum Transaminase Elevation in Patients Aged 12 Years and Older with CF Who Had at Least One F508del Mutation or Responsive Mutation in the CFTR Gene (Trials 1 and 2) Maximum ALT or AST Elevation ALYFTREK ELX/TEZ/IVA Trials 1 and 2 were not designed to evaluate meaningful comparisons of safety between the ALYFTREK and ELX/TEZ/IVA treatment groups. For additional information regarding ELX/TEZ/IVA transaminase elevations, refer to ELX/TEZ/IVA Prescribing Information. Abbreviations: ALT: alanine aminotransferase; AST, aspartate aminotransferase; ELX, elexacaftor; IVA, ivacaftor; TEZ, tezacaftor. >3× ULN 29 (6%) 15 (3. 1%) >5× ULN 12 (2. 2%) >8× ULN 6 (1. 2%) Rash In Trials 1 and 2, the incidence of rash (e. , rash, rash pruritic) was 11% in ALYFTREK-treated patients and 7. 7% in ELX/TEZ/IVA-treated patients. The rashes were generally mild to moderate in severity. The incidence of rash was 9. 4% in males and 13% in females with ALYFTREK treatment and 7. 6% in males and 7. 9% in females with ELX/TEZ/IVA treatment. A role of hormonal contraceptives in the occurrence of rash cannot be excluded [see Drug Interactions (7. 3) Increased Creatine Phosphokinase In Trials 1 and 2, the incidence of maximum creatine phosphokinase >5× the ULN was 7. 9% with ALYFTREK treatment and 6. 5% with ELX/TEZ/IVA treatment. Discontinuation due to increased creatinine phosphokinase was 0. 2% for ALYFTREK-treated patients and 0. 2% for ELX/TEZ/IVA-treated patients. Cases of rhabdomyolysis without renal involvement have been reported in patients who had recently exercised taking a fixed-dose combination drug containing ELX/TEZ/IVA (the same or similar active ingredients as ALYFTREK). Increased Blood Pressure Elevations in mean systolic and diastolic blood pressure have been reported in patients taking a fixed-dose combination drug containing ELX/TEZ/IVA (the same or similar active ingredients as ALYFTREK). The proportion of patients who had systolic blood pressure >140 mmHg and >10 mmHg increase from baseline on at least two occasions was 3. 5% in ALYFTREK-treated patients and 3. 3% in ELX/TEZ/IVA-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. 7% in ALYFTREK-treated patients and 1. 8% in ELX/TEZ/IVA-treated patients. The mean systolic and diastolic blood pressures remained in the normal range from both ALYFTREK and ELX/TEZ/IVA treatment arms. Adverse Reactions in Pediatric Patients Aged 6 to Less Than 12 Years with CF A 24-week, open-label trial of ALYFTREK was conducted in 78 patients with CF aged 6 to less than 12 years with at least one mutation responsive to ELX/TEZ/IVA (Trial 3). In Trial 3, patients who weighed less than 40 kg received ALYFTREK (vanzacaftor 12 mg/tezacaftor 60 mg/deutivacaftor 150 mg once daily) and patients who weighed 40 kg or more received ALYFTREK (vanzacaftor 20 mg/tezacaftor 100 mg/deutivacaftor 250 mg once daily). Adverse reactions for these patients were generally similar to those reported in Trial 1 and Trial 2. In Trial 3, the incidence of maximum transaminase (ALT or AST) >3×, >5×, and >8× ULN were 3. 3%, and 0%, respectively.

Risk Summary There are no available data on ALYFTREK use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. Although there are no animal reproduction studies with the concomitant administration of vanzacaftor, tezacaftor, and deutivacaftor, separate reproductive and developmental studies were conducted with vanzacaftor and tezacaftor in pregnant rats and rabbits. Deutivacaftor is a deuterated isotopologue of ivacaftor with a toxicity profile similar to ivacaftor. Reproductive and development studies were conducted with ivacaftor in pregnant rats and rabbits. In animal embryo fetal development (EFD) studies, oral administration of vanzacaftor to pregnant rats and rabbits during organogenesis demonstrated no adverse developmental effects at doses that produced maternal exposures up to approximately 30 times the exposure at the maximum recommended human dose (MRHD) in rats and 22 times the MRHD in rabbits. 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 the metabolite 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 8 and 9 times the exposure at the MRHD, respectively (based on AUC of ivacaftor for rats and rabbits). No adverse developmental effects were observed after oral administration of vanzacaftor, tezacaftor, or ivacaftor to pregnant rats from the period of organogenesis through lactation at doses that produced maternal exposures approximately 18 times, 1 time, and 8 times the exposures at the MRHD, respectively (based on AUCs of vanzacaftor, tezacaftor and M1-TEZ, and ivacaftor) ( see Data The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. 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 Vanzacaftor Tezacaftor: Deutivacaftor In an EFD study, pregnant rats were administered ivacaftor at oral doses of 50, 100, and 200 mg/kg/day during the period of organogenesis from gestation Days 7-17. Ivacaftor did not cause adverse effects to the fetus at exposures up to 8 times the MRHD for deutivacaftor (based on AUC of ivacaftor in animal studies up to 200 mg/kg/day). In an EFD study, pregnant rabbits were administered ivacaftor at oral doses of 25, 50, and 100 mg/kg/day during the period of organogenesis from gestation Days 7-19. Ivacaftor did not cause adverse effects to the fetus at exposures up to 9 times the MRHD for deutivacaftor (based on AUC of ivacaftor in animal studies). 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 3 times the MRHD). In a PPND study, pregnant rats were administered ivacaftor at oral doses of 50, 100, and 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 8 times the MRHD (based on AUC for ivacaftor at maternal oral doses up to 100 mg/kg/day). Decreased fetal body weights were observed at a maternally toxic dose (200 mg/kg/day, 13 times the exposure at MHRD). Placental transfer of ivacaftor was observed in pregnant rats and rabbits. Risk Summary There are no data on the presence of vanzacaftor, tezacaftor, or deutivacaftor or their metabolites in human milk, the effects on the breastfed infant, or the effects on milk production. Vanzacaftor and tezacaftor are excreted into the milk of lactating female rats. Deutivacaftor has not been evaluated; however, ivacaftor is excreted into the milk of lactating female rats ( see Data Data The concentration of vanzacaftor, tezacaftor, or deutivacaftor in animal milk does not necessarily predict the concentration of drug in human milk. Vanzacaftor: 14 14 0-72h Tezacaftor: 14 14 0-72h Deutivacaftor: 14 14 0-24h The safety and effectiveness of ALYFTREK for the treatment of CF in pediatric patients aged 6 years and older who have at least one F508del CFTR F508del CFTR F508del CFTR In Trial 1, 26 adolescents aged 12 to less than 18 years who were heterozygous for F508del CFTR [see Adverse Reactions (6. 1) Clinical Studies (14) In Trial 2, 41 adolescents aged 12 to less than 18 years who were homozygous for F508del F508del F508del [see Adverse Reactions (6. 1) Clinical Studies (14) In Trial 3, 78 pediatric patients with CF aged 6 to less than 12 years (mean age 9. 1 years) with at least one mutation that is responsive to ELX/TEZ/IVA [see Adverse Reactions (6. 1) The efficacy of ALYFTREK in patients aged 6 to less than 12 years for this indication was extrapolated from patients aged 12 years and older with support from population pharmacokinetic analyses showing vanzacaftor, tezacaftor, and deutivacaftor exposure levels in patients aged 6 to less than 12 years to be within the range of exposures observed in patients aged 12 years and older [see Clinical Pharmacology (12. 3) Safety of ALYFTREK in patients aged 6 to less than 12 years for this indication was based on Trial 3. The overall safety profile of patients in Trial 3 was generally similar to the safety data in adult and pediatric patients 12 years of age and older observed in Trials 1 and 2 [see Adverse Reactions (6. 1) There is a risk of cataracts in pediatric patients treated with ALYFTREK. Perform baseline and follow-up ophthalmological examination in pediatric patients prior to and during treatment with ALYFTREK [see Warnings and Precautions (5. 6) The safety and effectiveness of ALYFTREK in patients younger than 6 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 time 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. 6) 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 6 to 11 years of age, for whom levels of P-glycoprotein activity are equivalent to levels observed in adults. Clinical studies of ALYFTREK did not include a sufficient number of patients with CF aged 65 years and older (n=2, 0. 4% of patients treated with ALYFTREK in Trials 1 and 2) to determine whether they respond differently from younger adult patients with CF. The recommended ALYFTREK dosage in patients with CF with mild to moderate renal impairment (RI) (eGFR 30 to < 90 mL/min/1. 73 m 2 2 No clinically significant differences in the pharmacokinetics of vanzacaftor, tezacaftor, or deutivacaftor were observed in patients with mild to moderate RI (eGFR 30 to <90 mL/min/1. 73 m 2 [see Clinical Pharmacology (12. 3) 2 [see Clinical Pharmacology (12. 3) Severe Hepatic Impairment ALYFTREK should not be used in patients with severe hepatic impairment (HI) (Child-Pugh Class C). ALYFTREK has not been studied in patients with CF with severe HI [see Warnings and Precautions (5. 1) Adverse Reactions (6. 1) Moderate Hepatic Impairment The use of ALYFTREK is not recommended in patients with moderate HI (Child-Pugh Class B). Use of ALYFTREK should only be considered in patients with HI when there is a clear medical need, and the benefit outweighs the risk. If used, the recommended dosage in patients with moderate HI is the same as for patients with normal hepatic function. Liver function tests should be closely monitored [see Dosage and Administration (2. 2) Warnings and Precautions (5. 1) Mild Hepatic Impairment The recommended dosage of ALYFTREK in patients with mild HI (Child-Pugh Class A) is the same as in patients with normal hepatic function. Liver function tests should be closely monitored [see Warnings and Precautions (5.

Strong or moderate CYP3A inducers 5. 1 Strong or moderate CYP3A inhibitors 2. 1 Strong or Moderate CYP3A Inducers Concomitant use of ALYFTREK with strong or moderate CYP3A inducers is not recommended. Vanzacaftor, tezacaftor, and deutivacaftor are substrates of CYP3A. Concomitant use of ALYFTREK with a strong or moderate CYP3A inducer decreases vanzacaftor, tezacaftor, and deutivacaftor exposure [see Clinical Pharmacology (12. 3) [see Warnings and Precautions (5. 4) Strong or Moderate CYP3A Inhibitors Reduce the ALYFTREK dosage when used concomitantly with a strong or moderate CYP3A inhibitor [see Dosage and Administration (2. 3) Vanzacaftor, tezacaftor, and deutivacaftor are CYP3A substrates. Concomitant use with a strong CYP3A inhibitor increases vanzacaftor, tezacaftor, and deutivacaftor exposure [see Clinical Pharmacology (12. 5) [see Clinical Pharmacology (12. 5) Grapefruit Food or drink containing grapefruit should be avoided during treatment with ALYFTREK. Concomitant use of ALYFTREK with grapefruit juice which contains one or more components that moderately inhibit CYP3A may increase exposure of vanzacaftor, tezacaftor and deutivacaftor. P-glycoprotein (P-gp) Substrates Unless otherwise recommended in the P-gp substrate Prescribing Information, monitor more frequently for adverse reactions with concomitant use of ALYFTREK with P-gp substrates where minimal concentration changes may lead to serious adverse reactions related to P-gp substrates. Tezacaftor and deutivacaftor (components of ALYFTREK) are P-gp inhibitors. Administration of tezacaftor/ivacaftor increases exposure of P-gp substrates [see Clinical Pharmacology (12. 3) Breast Cancer Resistance Protein (BCRP) Substrates Unless otherwise recommended in BCRP substrate Prescribing Information, monitor more frequently for adverse reactions with concomitant use of ALYFTREK with BCRP substrate where minimal concentrations may lead to serious adverse reactions related to BCRP substrates. Vanzacaftor (VNZ) and deutivacaftor (D-IVA) (components of ALYFTREK) are inhibitors of BCRP in vitro. Concomitant use of ALYFTREK with BCRP substrates may increase exposure of these substrates; however, this has not been studied clinically [see Clinical Pharmacology (12. 3) CYP2C9 Substrates Use caution when ALYFTREK is used concomitantly with CYP2C9 substrates. Monitor the international normalized ratio (INR) more frequently with concomitant use of ALYFTREK with warfarin. This recommendation is based upon a mechanistic understanding of deutivacaftor pharmacokinetics (it is an inhibitor of CYP2C9 in vitro) [see Clinical Pharmacology (12. 3) Ciprofloxacin No clinically relevant effect on the exposure of tezacaftor was observed when tezacaftor/ivacaftor was used concomitantly with ciprofloxacin [see Clinical Pharmacology (12. 3) Hormonal Contraceptives No clinically significant differences in the pharmacokinetics of ethinyl estradiol/norethindrone containing hormonal contraceptives were observed when used concomitantly with tezacaftor in combination with ivacaftor and ivacaftor alone [see Clinical Pharmacology (12. 3) [see Clinical Pharmacology (12. 3) A role for hormonal contraceptives contributing to rash 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.
NONCLINICAL TOXICOLOGY
No studies of carcinogenicity, mutagenicity, or impairment of fertility were conducted with the combination of vanzacaftor, tezacaftor, and deutivacaftor; however, separate studies of vanzacaftor, tezacaftor, deutivacaftor, and ivacaftor are described below. Vanzacaftor A 6-month study in Tg. rasH2 mice showed no evidence of tumorigenicity at 30 mg/kg/day dose, the highest dose tested. Vanzacaftor was negative for genotoxicity in the following assays: Ames test for bacterial gene mutation, in vitro micronucleus assay in TK6 cells, and in vivo rat micronucleus assay. Administration of oral vanzacaftor had no effects on fertility and early embryonic development in male and female rats at up to 12. 5 and 10 mg/kg/day, respectively (approximately 19 times for males and 30 times for females the exposure at the MRHD based on AUCs of vanzacaftor). 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 2 and 4 times the MRHD based on summed AUCs of tezacaftor and M1-TEZ 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). Deutivacaftor Deutivacaftor is a deuterated isotopologue of ivacaftor with an established toxicity profile similar to ivacaftor based on a 13-week single-agent repeat dose toxicity study; therefore, reproductive and developmental toxicity data and carcinogenicity data from ivacaftor are expected to be equivalent to deutivacaftor. 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 3 and 11 times MRHD, respectively, based on summed AUCs of ivacaftor). 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 15 and 13 times, respectively, the MRHD based on AUCs of ivacaftor). 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 when dams were dosed prior to and during early pregnancy. Slight decreases of the seminal vesicle weights were observed in males at 200 mg/kg/day dose (approximately 15 times the MRHD based on summed AUCs of IVA). 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 ALYFTREK in patients aged 12 years and older with cystic fibrosis (CF) who have at least one F508del CFTR F508del CFTR Trial 1 enrolled patients with CF heterozygous for F508del CFTR 1 Trial 2 enrolled patients with CF who had one of the following genotypes: homozygous for the F508del F508del F508del 1 Efficacy Endpoints In both trials, the primary endpoint evaluated non-inferiority in mean absolute change in ppFEV 1 Trials 1 and 2 also assessed other secondary endpoints including pulmonary exacerbation rate and change in Cystic Fibrosis Questionnaire-Revised respiratory domain (CFQ-R RD) score from baseline. Efficacy Results In Trial 1, treatment with ALYFTREK resulted in an LS mean difference of 0. 2 percentage points (95% CI: -0. 1) in absolute change in ppFEV 1 In Trial 2, treatment with ALYFTREK resulted in an LS mean difference of 0. 9) in absolute change in ppFEV 1 As the lower bounds of the 95% CI of the LS mean difference in absolute change from baseline in ppFEV 1 Table 9 provides the primary and key secondary efficacy endpoints results for Trials 1 and 2. Table 9: Efficacy Results in Patients Aged 12 Years and Older with CF Who Had at Least One F508del Mutation or Responsive Mutation in the CFTR Gene (Trials 1 and 2) Analysis A 4-week ELX/TEZ/IVA run-in-period was performed to establish an on-treatment baseline. Statistic Trial 1 Trial 2 ALYFTREK ELX/TEZ/IVA ALYFTREK ELX/TEZ/IVA ppFEV 1 Note: Analyses were based on the full analysis set (FAS). FAS was defined as all randomized subjects who carry the intended CFTR allele mutation and received at least 1 dose of study drug. Primary Endpoint Absolute change from baseline in ppFEV 1 n 187 193 268 276 LS mean (SE) 0. 2) LS mean difference, 95% CI The pre-specified non-inferiority margin was -3. 0 percentage points. 9) Key Secondary Endpoint Absolute change from baseline in SwCl through Week 24 (mmol/L) n 185 194 270 276 LS mean (SE) -7. 7) LS mean difference, 95% CI -8. 9) P-value (2-sided) < 0. 0034 The trials were not designed to demonstrate a difference between the treatment groups or to support non-inferiority of the other secondary endpoints. In Trial 1 and Trial 2, mean absolute change from baseline ppFEV 1.

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VANZACAFTOR, TEZACAFTOR, AND DEUTIVACAFTOR- vanzacaftor, tezacaftor, and deutivacaftor_tablet, film coated Product manual source documgent