ALYFTREK- vanzacaftor, tezacaftor, and deutivacaftor tablet, film coated

ALYFTREK by

Drug Labeling and Warnings

ALYFTREK by is a Prescription medication manufactured, distributed, or labeled by Vertex Pharmaceuticals Incorporated. Drug facts, warnings, and ingredients follow.

Drug Details [pdf]

  • BOXED WARNING (What is this?)

    WARNING: DRUG-INDUCED LIVER INJURY AND LIVER FAILURE

    Elevated transaminases have been observed in patients treated with ALYFTREK. Cases of serious and potentially fatal drug-induced liver injury and liver failure were reported in patients who were taking a fixed-dose combination drug containing elexacaftor, tezacaftor, and ivacaftor, which contains the same or similar active ingredients as ALYFTREK. Liver injury has been reported within the first month of therapy and up to 15 months following initiation of elexacaftor/tezacaftor/ivacaftor [see Warnings and Precautions (5.1) and Adverse Reactions (6)].

    Assess liver function tests (ALT, AST, alkaline phosphatase, and bilirubin) in all patients prior to initiating ALYFTREK, 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 elevated liver function tests at baseline [see Dosage and Administration (2.1), Warnings and Precautions (5.1), Adverse Reactions (6), and Use in Specific Populations (8.7)].

    Interrupt ALYFTREK for significant elevations in liver function tests or in the event of signs or symptoms of liver injury. Consider referral to a hepatologist. Follow patients closely with clinical and laboratory monitoring until abnormalities resolve. If abnormalities resolve, resume treatment only if the benefit is expected to outweigh the risk. Closer monitoring is advised after resuming ALYFTREK [see Warnings and Precautions (5.1)].

    ALYFTREK should not be used in patients with severe hepatic impairment (Child-Pugh Class C). ALYFTREK is not recommended in patients with moderate hepatic impairment (Child-Pugh Class B) and should only be considered when there is a clear medical need, and the benefit outweighs the risk. If used, monitor patients closely [see Dosage and Administration (2.4), Warnings and Precautions (5.1), Adverse Reactions (6), Use in Specific Populations (8.7), and Clinical Pharmacology (12.3)].

  • 1 INDICATIONS AND USAGE

    ALYFTREK is indicated for the treatment of cystic fibrosis (CF) in patients 6 years of age and older who have at least one F508del mutation or another responsive mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene (see 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.

  • 2 DOSAGE AND ADMINISTRATION

    2.1 Recommended Laboratory Testing Prior to ALYFTREK Initiation and During Treatment

    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) and Use in Specific Populations (8.7)].

    2.2 Recommended Dosage

    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)]. 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.

    Table 1: Recommended Dosage of ALYFTREK in Adult and Pediatric Patients Aged 6 Years and Older
    AgeWeightOnce Daily Oral Dosage
    6 to less than 12 years oldLess than 40 kgThree 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 kgTwo 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 olderAny weightTwo tablets of vanzacaftor 10 mg/tezacaftor 50 mg/deutivacaftor 125 mg (total dose of vanzacaftor 20 mg/tezacaftor 100 mg/ deutivacaftor 250 mg)

    2.3 Dosage Modification for Strong or Moderate CYP3A Inhibitors

    Table 2 describes the recommended dosage modification for ALYFTREK when used concomitantly with strong or moderate CYP3A inhibitors [see Warnings and Precautions (5.5)]. 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 2: Dosage Modification for Concomitant Use of ALYFTREK with Strong or Moderate CYP3A Inhibitors in Adult and Pediatric Patients Aged 6 Years and Older
    AgeWeightModerate CYP3A InhibitorsStrong CYP3A Inhibitors
    6 to less than 12 years oldLess than 40 kgTwo 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 kgOne tablet of vanzacaftor 10 mg/tezacaftor 50 mg/deutivacaftor 125 mg every other dayOne tablet of vanzacaftor 10 mg/tezacaftor 50 mg/deutivacaftor 125 mg once a week
    12 years and olderAny weightOne tablet of vanzacaftor 10 mg/tezacaftor 50 mg/deutivacaftor 125 mg every other dayOne tablet of vanzacaftor 10 mg/tezacaftor 50 mg/deutivacaftor 125 mg once a week

    2.4 Recommended Dosage for Patients with Hepatic Impairment

    • Severe Hepatic Impairment (Child-Pugh Class C): ALYFTREK should not be used in patients with severe hepatic impairment (HI) (Child-Pugh Class C).
    • Moderate Hepatic Impairment (Child-Pugh Class B): The use of ALYFTREK in patients with moderate HI (Child-Pugh Class B) is not recommended. Use of ALYFTREK should only be considered in patients with moderate 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 (2.1, 2.2)].
    • Mild Hepatic Impairment (Child-Pugh Class A): 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 Dosage and Administration (2.1, 2.2)].

    2.5 Recommendations Regarding Missed Dose(s)

    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.

  • 3 DOSAGE FORMS AND STRENGTHS

    Tablets:

    • Fixed-dose combination containing vanzacaftor 4 mg (equivalent to 4.24 mg of vanzacaftor calcium dihydrate), tezacaftor 20 mg, and deutivacaftor 50 mg. Each tablet is purple, round-shaped, film-coated, debossed with "V4" on one side and plain on the other.
    • Fixed-dose combination containing vanzacaftor 10 mg (equivalent to 10.6 mg of vanzacaftor calcium dihydrate), tezacaftor 50 mg, and deutivacaftor 125 mg. Each tablet is purple, oblong-shaped, film-coated, debossed with "V10" on one side and plain on the other.
  • 4 CONTRAINDICATIONS

    None.

  • 5 WARNINGS AND PRECAUTIONS

    5.1 Drug-Induced Liver Injury and Liver Failure

    Elevated transaminases have been observed in patients treated with ALYFTREK [Adverse Reactions (6.1)]. Cases of serious and potentially fatal drug-induced liver injury and liver failure have been reported in patients with and without a history of liver disease who were taking a fixed-dose combination drug containing elexacaftor, tezacaftor, and ivacaftor (ELX/TEZ/IVA), which contains the same or similar active ingredients as ALYFTREK. Liver injury has been reported within the first month of therapy and up to 15 months following initiation of ELX/TEZ/IVA.

    Assess liver function tests (ALT, AST, alkaline phosphatase, and bilirubin) in all patients prior to initiating ALYFTREK. Assess liver function tests every month during the first 6 months of treatment, then every 3 months for the next 12 months, then at least annually thereafter. Consider more frequent monitoring in patients with a history of liver disease, elevated liver function tests at baseline, or a history of elevated liver function tests with drugs containing ELX, TEZ and/or IVA. [see Dosage and Administration (2.4) and Use in Specific Populations (8.7)].

    Interrupt ALYFTREK in the event of signs or symptoms of liver injury. These may include:

    • Significant elevations in liver function tests (e.g., ALT or AST >5× the upper limit or normal (ULN) or ALT or AST >3× ULN with bilirubin >2× ULN)
    • Clinical signs or symptoms suggestive of liver injury (e.g., jaundice, right upper quadrant pain, nausea, vomiting, altered mental status, ascites)

    Consider referral to a hepatologist and follow patients closely with clinical and laboratory monitoring until abnormalities resolve. If abnormalities resolve and if the benefit is expected to outweigh the risk, resume ALYFTREK treatment with close monitoring.

    ALYFTREK should not be used in patients with severe hepatic impairment (Child-Pugh Class C). ALYFTREK is not recommended in patients with moderate hepatic impairment (Child-Pugh Class B) and should only be considered when there is a clear medical need, and the benefit outweighs the risk. If used, monitor patients closely [see Dosage and Administration (2.4), Use in Specific Populations (8.7), and Clinical Pharmacology (12.3)].

    5.2 Hypersensitivity Reactions, Including Anaphylaxis

    Hypersensitivity reactions, including cases of anaphylaxis, have been reported in the postmarketing setting of drugs containing ELX, TEZ, and/or IVA (the same or similar active ingredients in ALYFTREK). If signs or symptoms of serious hypersensitivity reactions develop during ALYFTREK treatment, discontinue ALYFTREK and institute appropriate therapy. Consider the benefits and risks for the individual patient to determine whether to resume treatment with ALYFTREK.

    5.3 Patients Who Discontinued or Interrupted Elexacaftor-, Tezacaftor-, or Ivacaftor-Containing Drugs Due to Adverse Reactions

    There are no available safety data for ALYFTREK in patients who previously discontinued or interrupted treatment with drugs containing elexacaftor, tezacaftor, or ivacaftor due to adverse reactions. Consider the benefits and risks before using ALYFTREK in these patients. If ALYFTREK is used in these patients, closely monitor for adverse reactions as clinically appropriate.

    5.4 Reduced Effectiveness with Concomitant Use with CYP3A Inducers

    Following concomitant use of strong or moderate CYP3A inducers with ALYFTREK, exposures of vanzacaftor, tezacaftor, and deutivacaftor were decreased, which may reduce ALYFTREK effectiveness. Concomitant use with strong or moderate CYP3A inducers is not recommended [see Drug Interactions (7.1)].

    5.5 Adverse Reactions with Concomitant Use with CYP3A Inhibitors

    Following concomitant use of strong or moderate CYP3A inhibitors with ALYFTREK, exposures of vanzacaftor, tezacaftor, and deutivacaftor were increased, which may increase the risk of ALYFTREK-associated adverse reactions. Reduce the ALYFTREK dosage with concomitant use of strong or moderate CYP3A inhibitors [see Dosage and Administration (2.3) and Drug Interactions (7.1)].

    5.6 Cataracts

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

  • 6 ADVERSE REACTIONS

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

    6.1 Clinical Trials Experience

    Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

    The 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 mutation who were able to tolerate ELX/TEZ/IVA. Adverse reactions data in patients who previously discontinued or interrupted ELX/TEZ/IVA due to adverse reactions are not available.

    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 mutation or another responsive mutation in the CFTR gene in two, 52-week, active-controlled trials (Trials 1 and 2) [see Clinical Studies (14)]. In both trials, patients received a fixed-dose combination drug containing elexacaftor, tezacaftor, and ivacaftor (ELX/TEZ/IVA) in a 4-week run-in period and then were subsequently randomized to continue ELX/TEZ/IVA (elexacaftor 200 mg/tezacaftor 100 mg/ivacaftor 150 mg in the morning and ivacaftor 150 mg in the evening) or receive ALYFTREK (vanzacaftor 20 mg/tezacaftor 100 mg/deutivacaftor 250 mg) once daily. Patients with a history of prior intolerance to ELX/TEZ/IVA (i.e., patients who discontinued or interrupted treatment due to adverse reactions) were excluded. Trials 1 and 2 were not designed to evaluate meaningful comparisons of the incidence of adverse reactions between the ALYFTREK and ELX/TEZ/IVA treatment groups. For additional information regarding ELX/TEZ/IVA adverse reactions, refer to ELX/TEZ/IVA Prescribing Information.

    In Trial 1 and Trial 2 combined, the proportion of patients who discontinued treatment prematurely due to adverse reactions were 3.8% and 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 (0.4%).

    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 ReactionsALYFTREK
    N=480    		ELX/TEZ/IVA
    N=491
    Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; ELX, elexacaftor; IVA, ivacaftor; TEZ, tezacaftor
  • * Cough is composed of several similar terms including productive cough
  • † Upper respiratory tract infection is composed of several similar terms including viral upper respiratory tract infection
    		•
    Cough*120 (25%)116 (24%)
    Nasopharyngitis102 (21%)95 (19%)
    Upper respiratory tract infection†101 (21%)97 (20%)
    Headache76 (16%)63 (13%)
    Oropharyngeal pain69 (14%)60 (12%)
    Influenza52 (11%)26 (5%)
    Fatigue51 (11%)46 (9%)
    ALT increased38 (8%)29 (6%)
    Rash37 (8%)22 (4%)
    AST increased33 (7%)27 (5%)
    Sinus congestion32 (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 ElevationALYFTREK
    N=480    		ELX/TEZ/IVA*
    N=491
    Abbreviations: ALT: alanine aminotransferase; AST, aspartate aminotransferase; ELX, elexacaftor; IVA, ivacaftor; TEZ, tezacaftor.
  • * 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.
    		•
    >3× ULN29 (6%)15 (3.1%)
    >5× ULN12 (2.5%)6 (1.2%)
    >8× ULN6 (1.3%)1 (0.2%)

    Rash

    In Trials 1 and 2, the incidence of rash (e.g., 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 3.8%, 1.3%, and 0%, respectively.

  • 7 DRUG INTERACTIONS

    7.1 Effect of Other Drugs and Grapefruit on ALYFTREK

    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)] which may reduce ALYFTREK effectiveness [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 (12.3)], which may increase the risk of ALYFTREK adverse reactions [see Warnings and Precautions (5.5)]. Concomitant use with a moderate CYP3A inhibitor is predicted to increase vanzacaftor, tezacaftor, and deutivacaftor exposure [see Clinical Pharmacology (12.3)], which may increase the risk of ALYFTREK adverse reactions [see Warnings and Precautions (5.5)].

    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.

    7.2 Effect of ALYFTREK on Other Drugs

    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)], which may increase the risk of adverse reactions related to these substrates.

    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)]. Concomitant use of ALYFTREK with CYP2C9 substrates may increase exposure of these substrates; however, this has not been studied clinically.

    7.3 Drugs with No Clinically Significant Interactions with ALYFTREK

    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)]. No clinically significant differences in the pharmacokinetics of ethinyl estradiol/norethindrone containing hormonal contraceptives are expected when used in combination with ALYFTREK based upon a mechanistic understanding of vanzacaftor, tezacaftor, and deutivacaftor pharmacokinetics [see Clinical Pharmacology (12.3)]; however, this has not been studied clinically.

    A role for hormonal contraceptives contributing to rash cannot be excluded [see Adverse Reactions (6.1)]. For patients with CF taking hormonal contraceptives who develop rash, consider interrupting ALYFTREK and hormonal contraceptives. Following the resolution of rash, consider resuming ALYFTREK without the hormonal contraceptives. If rash does not recur, resumption of hormonal contraceptives can be considered.

  • 8 USE IN SPECIFIC POPULATIONS

    8.1 Pregnancy

    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. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

    Data

    Animal Data

    Vanzacaftor: In an EFD study, pregnant rats were administered vanzacaftor at oral doses of 2.5, 5, and 10 mg/kg/day during the period of organogenesis from gestation Days 6-17. Vanzacaftor did not cause adverse effects to the fetus at exposures up to 30 times the MRHD (based on AUC for vanzacaftor at maternal doses up to 10 mg/kg/day). In an EFD study, pregnant rabbits were administered vanzacaftor at oral doses of 10, 40, and 70 mg/kg/day during the period of organogenesis from gestation Days 7-20. Vanzacaftor did not cause adverse effects to the fetus at exposures up to 22 times the MRHD (based on AUC of vanzacaftor at maternal doses up to 40 mg/kg/day). The high dose of 70 mg/kg/day (71 times the exposure at the MRHD) produced maternal toxicity (i.e., mortality, abortion, decreased mean body weight or body weight gains) and was associated with findings of increased post-implantation loss, decreased live fetuses, decreased fetal body weight, and increased kidney malformations. In a pre- and postnatal development (PPND) study in pregnant rats administered vanzacaftor at oral doses of 2.5, 5, and 10 mg/kg/day from gestation Day 6 through lactation Day 18, vanzacaftor did not cause adverse developmental effects in pups at maternal doses up to 10 mg/kg/day (approximately 18 times the exposure at the MRHD). Placental transfer of vanzacaftor was observed in pregnant rats.

    Tezacaftor: In an EFD study, pregnant rats were administered tezacaftor at oral doses of 25, 50, and 100 mg/kg/day during the period of organogenesis from gestation Days 6-17. Tezacaftor did not cause adverse effects to the fetus at exposures up to 3 times the MRHD (based on summed AUCs of tezacaftor and M1-TEZ). Maternal toxicity in rats was observed at ≥50 mg/kg/day (approximately ≥1 time the MRHD). In an EFD study, pregnant rabbits were administered tezacaftor at oral doses of 10, 25, and 50 mg/kg/day during the period of organogenesis from gestation Days 7-20. Tezacaftor did not cause adverse effects to the fetus 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, and 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.

    Deutivacaftor: Animal reproduction studies have not been conducted with deutivacaftor. However, as a deuterated isotopologue of ivacaftor with a toxicity profile similar to ivacaftor based on a 13-week single-agent repeat dose toxicity study, the reproductive and developmental toxicity data from ivacaftor can inform the developmental and reproductive risks associated with 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.e., death, decreased food consumption, decreased mean body weight and body weight gain, decreased clinical condition, abortions) was observed at doses greater than or equal to 50 mg/kg/day (approximately 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.

    8.2 Lactation

    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). When a drug is present in animal milk, it is likely that the drug will be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for ALYFTREK and any potential adverse effects on the breastfed child from ALYFTREK or from the underlying maternal condition.

    Data

    The concentration of vanzacaftor, tezacaftor, or deutivacaftor in animal milk does not necessarily predict the concentration of drug in human milk.

    Vanzacaftor: Lacteal excretion of vanzacaftor in rats was demonstrated following a single oral dose (10 mg/kg) of 14C-vanzacaftor administered 6 to 10 days postpartum to lactating dams. Exposure of 14C-vanzacaftor in milk was approximately 0.2 times the value observed in plasma (based on AUC0-72h).

    Tezacaftor: Lacteal excretion of tezacaftor in rats was demonstrated following a single oral dose (30 mg/kg) of 14C-tezacaftor administered 6 to 10 days postpartum to lactating dams. Exposure of 14C-tezacaftor in milk was approximately 3.0 times higher than in plasma (based on AUC0-72h).

    Deutivacaftor: Deutivacaftor has not been evaluated; however, ivacaftor is excreted into the milk of lactating female rats. Lacteal excretion of ivacaftor in rats was demonstrated following a single oral dose (100 mg/kg) of 14C-ivacaftor administered 9 to 10 days postpartum to lactating dams. Exposure of 14C-ivacaftor in milk was approximately 1.5 times higher than in plasma (based on AUC0-24h).

    8.4 Pediatric Use

    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 mutation or another responsive mutation in the CFTR gene have been established. Use of ALYFTREK for this indication was supported by evidence from two adequate and well-controlled trials (Trials 1 and 2) in patients with CF aged 12 years and older who had at least one F508del mutation or another responsive mutation in the CFTR gene and additional pharmacokinetic and safety data in pediatric patients with CF aged 6 to less than 12 years who had at least one F508del mutation or another responsive mutation in the CFTR gene (Trial 3). In these trials, a total of 145 patients with CF aged 6 to less than 18 years received ALYFTREK including:

    • In Trial 1, 26 adolescents aged 12 to less than 18 years who were heterozygous for F508del and a CFTR mutation that is not responsive to ivacaftor or tezacaftor/ivacaftor (minimal function mutation) [see Adverse Reactions (6.1) and Clinical Studies (14)].
    • In Trial 2, 41 adolescents aged 12 to less than 18 years who were homozygous for F508del mutation, heterozygous for F508del mutation and either a gating or a residual function mutation, or with at least one mutation responsive to ELX/TEZ/IVA with no F508del mutation [see Adverse Reactions (6.1) and 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)]. In Trial 3, patients who weighed less than 40 kg patients 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).

    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.

    8.5 Geriatric Use

    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.

    8.6 Renal Impairment

    The recommended ALYFTREK dosage in patients with CF with mild to moderate renal impairment (RI) (eGFR 30 to < 90 mL/min/1.73 m2) is the same in patients with CF with normal kidney function. Use of ALYFTREK in patients with CF with severe RI (eGFR <30 mL/min/1.73 m2) or end-stage renal disease is recommended only if the benefits are expected to outweigh the risks.

    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 m2) [see Clinical Pharmacology (12.3)]. The effect of severe RI (eGFR <30 mL/min/1.73 m2) on vanzacaftor, tezacaftor, or deutivacaftor pharmacokinetics is unknown [see Clinical Pharmacology (12.3)].

    8.7 Hepatic Impairment

    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) and 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) and Adverse Reactions (6.1)].

    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 (5.1) and Adverse Reactions (6.1)].

  • 10 OVERDOSAGE

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

  • 11 DESCRIPTION

    ALYFTREK (vanzacaftor, tezacaftor, and deutivacaftor tablets) are fixed-dose combination tablets for oral use available as:

    • 10 mg of vanzacaftor (equivalent to 10.6 mg of vanzacaftor calcium dihydrate), 50 mg of tezacaftor, 125 mg of deutivacaftor or
    • 4 mg of vanzacaftor (equivalent to 4.24 mg of vanzacaftor calcium dihydrate), 20 mg of tezacaftor, 50 mg of deutivacaftor.

    The tablets contain the following inactive ingredients: croscarmellose sodium, hypromellose, hypromellose acetate succinate, magnesium stearate, microcrystalline cellulose, and sodium lauryl sulfate. The tablet film coating contains Brilliant Blue FCF aluminum lake/FD&C Blue #1, carmine, hydroxypropyl cellulose, hypromellose, iron oxide red, talc, and titanium dioxide.

    The active ingredients of ALYFTREK are described below.

    Vanzacaftor

    Vanzacaftor is provided as a calcium salt. Vanzacaftor calcium dihydrate is a white solid that is practically insoluble in water (< 0.1 mg/mL). Its chemical name is calcium bis((14S)-8-[3-(2-{dispiro[2.0.24.13]heptan-7-yl}ethoxy)pyrazol-1-yl]-12,12-dimethyl-2,2,4-trioxo-2λ6-thia-3,9,11,18,23-pentaazatetracyclo[17.3.1.111,14.05,10]tetracosa-1(23),5,7,9,19,21-hexaen-3-ide) dihydrate. Its molecular formula is C32H38N7O4S∙Ca0.5∙H2O and its molecular weight is 654.82. Vanzacaftor calcium dihydrate has the following structural formula:

    Chemical Structure

    Tezacaftor

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

    Chemical Structure

    Deutivacaftor

    Deutivacaftor is a white to off-white solid that is practically insoluble in water (< 0.1 mg/mL). Pharmacologically, it is a CFTR potentiator. Its chemical name is N-(2-(tert-butyl)-5-hydroxy-4-(2-(methyl-d3)propan-2-yl-1,1,1,3,3,3-d6)phenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide. Its molecular formula is C24H19D9N2O3 and its molecular weight is 401.55. Deutivacaftor has the following structural formula:

    Chemical Structure
  • 12 CLINICAL PHARMACOLOGY

    12.1 Mechanism of Action

    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-CFTR) to increase the amount of CFTR protein delivered to the cell surface compared to either molecule alone. Deutivacaftor potentiates the channel open probability (or gating) of the CFTR protein at the cell surface.

    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 mutations, as identified in Table 5.

    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- Human Bronchial Epithelial (HBE) cells showed greater chloride transport in the presence of vanzacaftor/tezacaftor/deutivacaftor than F508del/F508del-HBE cells treated with tezacaftor/ivacaftor which has shown clinical benefit in people homozygous for 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 mutation or another responsive mutation in the CFTR gene (see Table 5) [see Indications and Usage (1)].

    Table 5 lists CFTR mutations responsive to ALYFTREK based on clinical response, and/or in vitro data in FRT or HBE cells, or based on extrapolation of efficacy [see Clinical Studies (14)].

    Table 5: List of CFTR Gene Mutations Responsive to ALYFTREK
  • * Clinical data is obtained from Trials 1 and 2.
  • † This mutation is also predicted to be responsive by FRT assay with ALYFTREK.
  • ‡ The N1303K mutation is predicted to be responsive only by HBE assay. All other mutations predicted to be responsive with in vitro data are supported by FRT assay.
  • § Complex/compound mutations where a single allele of the CFTR gene has multiple mutations; these exist independent of the presence of mutations on the other allele.
  • 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.
    		•
    Based on Clinical Data*
    A455EG551DL1077P†R352QS549NV754M
    D1152HG85E†L206WR75QS549RW1098C†
    F508del†H1054DM1101K†S1159FS945LW1282R
    G1244EI336KR1066HS1251NV562IY563N†
    Based on in vitro Data‡
    1507_1515del9E116QG424SI556VP140SR334LT1053I
    2183A→GE193KG463VI601FP205SR334QT1086I
    3141del9E292KG480CI618TP499AR347HT1246I
    3195del6E403DG480SI807MP5LR347LT1299I
    3199del6E474KG551AI980KP574HR347PT338I
    546insCTAE56KG551SK1060TP67LR352WT351I
    A1006EE588VG576AK162EP750LR516GT604I
    A1067PE60KG576A;R668C§K464EP99LR516SV1153E
    A1067TE822KG622DL1011SQ1100PR553QV1240G
    A107GE92KG628RL102RQ1291RR555GV1293G
    A120TF1016SG91RL1065PQ1313KR560SV201M
    A234DF1052VG970DL1324PQ237ER560TV232D
    A309DF1074LG970SL1335PQ237HR668CV392G
    A349VF1099LH1085PL137PQ359RR709QV456A
    A46DF1107LH1085RL1480PQ372HR74QV456F
    A554EF191VH1375PL15PQ452PR74WV520F
    A559TF200IH139RL165SQ493RR74W;D1270N§V603F
    A559VF311delH199RL320VQ552PR74W;V201M§W361R
    A561EF311LH199YL333FQ98RR74W;V201M;D1270N§Y1014C
    A613TF508CH609RL333HR1048GR75LY1032C
    A62PF508C;S1251N§H620PL346PR1066CR751LY109N
    A72DF575YH620QL441PR1066LR792GY161D
    C491RF587IH939RL453SR1066MR933GY161S
    D110EG1047RH939R;H949LL619SR1070QS1045YY301C
    D110HG1061RI1027TL967SR1070WS108FY569C
    D1270NG1069RI105NL997FR1162LS1118FY913C
    D1445NG1123RI1139VM1101RR117CS1159P
    D192GG1247RI1234Vdel6aaM1137VR117C;G576A;R668CS1235R
    D443YG1249RI125TM150KR117GS1255P
    D443Y;G576A;R668C§G126DI1269NM152VR117HS13F
    D513GG1349DI331NM265RR117LS341P
    D565GG149RI1366NM952IR117PS364P
    D579GG178EI1398SM952TR1283MS492F
    D614GG178RI148NN1088DR1283SS549I
    D836YG194RI148TN1303IR170HS589N
    D924NG194VI175VN1303K§R258GS737F
    D979VG27EI502TN186KR297QS912L
    D993YG27RI506LN187KR31CS977F
    E116KG314EI506TN418SR31LT1036N
    Based on Extrapolation
    1341G→A2789+2insA3041-15T→G3849+10kbC→T3850-3T→G5T;TG13711+3A→G
    1898+3A→G2789+5G→A3272-26A→G3849+4A→G4005+2T→C621+3A→GE831X
    2752-26A→G296+28A→G3600G→A3849+40A→G5T;TG12

    12.2 Pharmacodynamics

    Effects on Sweat Chloride

    • In patients with CF heterozygous for F508del and a CFTR mutation that results in a protein that is not responsive to ivacaftor or tezacaftor/ivacaftor [minimal function mutation] (Trial 1) the treatment difference of ALYFTREK compared to ELX/TEZ/IVA for mean absolute change in sweat chloride from baseline through Week 24 was -8.4 mmol/L (95% CI: -10.5, -6.3; P <0.0001).
    • In patients with CF homozygous for the F508del mutation, heterozygous for the F508del mutation and either a gating or a residual function mutation, or at least one mutation responsive to ELX/TEZ/IVA with no F508del mutation (Trial 2), the treatment difference of ALYFTREK compared to ELX/TEZ/IVA for mean absolute change in sweat chloride from baseline through Week 24 was -2.8 mmol/L (95% CI: -4.7, -0.9; P = 0.0034).
    • 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 mean absolute change in sweat chloride from baseline through Week 24 was -8.6 mmol/L (95% CI: -11.0, -6.3).

    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.

    12.3 Pharmacokinetics

    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
    VanzacaftorTezacaftorDeutivacaftor
    Abbreviations: AUC: area under the concentration versus time curve; SD: Standard Deviation; Cmax: maximum observed concentration; Tmax: time of maximum concentration; ss: steady state
  • * Median (range)
  • † 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.
  • ‡ Vanzacaftor, tezacaftor, deutivacaftor do not partition preferentially into human red blood cells.
  • § Vanzacaftor and deutivacaftor bind primarily to albumin and alpha 1-acid glycoprotein. Tezacaftor binds primarily to albumin.
  • The mean (SD) terminal half-lives of vanzacaftor, tezacaftor, and deutivacaftor are 54.0 (10.1) hours, 92.4 (23.1) hours and 17.3 (2.67) hours, respectively based on a single dose of vanzacaftor/tezacaftor/deutivacaftor tablets in healthy subjects in the fed state.
  • # Following radiolabeled doses.
    		•
    Exposure
    Cmax,ss (mcg/mL)0.812 (0.344)6.77 (1.24)2.33 (0.637)
    AUC0-24h,ss (mcg∙h/mL)18.6 (8.08)89.5 (28.0)39.0 (15.3)
    Time to steady statewithin 20 dayswithin 8 dayswithin 8 days
    AUC Accumulation Ratio6.09 (1.81)1.92 (0.337)1.74 (0.497)
    Absorption
    Tmax* (hours)7.80 (3.70, 11.9)1.60 (1.40, 1.70)3.7 (2.7, 11.4)
    Effect of food
    AUCinf†Increase 4- (low-fat meal) to 6- (high-fat meal) foldNo clinically significant changeIncrease 3- (low-fat meal) to 4- (high-fat meal) fold
    Distribution‡
    Apparent (oral) volume of distribution (L)121 (28.6)73.1 (13.3)159 (26.1)
    Protein Binding§> 99%Approximately 99%> 99%
    Elimination
    Effective Half-life (hours)92.8 (30.2)22.5 (5.85)19.2 (8.71)
    Apparent (oral) Clearance (L/hours)1.34 (0.819)1.22 (0.390)7.29 (2.68)
    Metabolism
    Primary PathwayCYP3A4/5CYP3A4/5CYP3A4/5
    Active metabolitesNoneM1-TEZM1-D-IVA
    Metabolite potency (relative to parent)Not applicableSimilarApproximately 20%
    Excretion #
    Feces91.6%
    (primarily metabolites)    		72% (unchanged or M2-TEZ)
    [0.79% as unchanged drug]    		Not available
    Urine0.50%13.7%Not available

    Specific Populations

    No clinically significant differences in the pharmacokinetics of vanzacaftor, tezacaftor, or deutivacaftor were observed based on age, sex, race, CFTR genotype, or mild to moderate renal impairment (eGFR 30 to <90 mL/min/1.73m2 as estimated by modification of diet in renal disease (MDRD) equation). The effect of severe renal impairment (eGFR less than 30 mL/min/1.73m2) on vanzacaftor, tezacaftor, or deutivacaftor pharmacokinetics is unknown.

    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 groupWeightDosage (once daily)AUC0-24h (mcg∙h/mL)
    VanzacaftorTezacaftorDeutivacaftor
    Abbreviations: SD: Standard Deviation; AUC0-24h: Area Under the Concentration versus time curve at steady state
    6 to <12 years<40 kg
    (N = 70)    		vanzacaftor 12 mg
    tezacaftor 60 mg
    deutivacaftor 150 mg    		13.0 (4.90)69.1 (20.7)30.2 (11.6)
    ≥40 kg
    (N = 8)    		vanzacaftor 20 mg
    tezacaftor 100 mg
    deutivacaftor 250 mg    		18.6 (7.49)101 (33.7)48.5 (18.7)
    12 to <18 years-
    (N = 66)    		vanzacaftor 20 mg
    tezacaftor 100 mg
    deutivacaftor 250 mg    		15.8 (6.52)93.0 (32.5)37.1 (15.3)
    ≥18 years-
    (N = 414)    		19.0 (8.22)89.0 (27.2)39.3 (15.3)

    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
    DosageEffected DrugGeometric Mean Ratio (90% CI)
    No Effect = 1.0
    AUCCmax
    Abbreviations: CI = Confidence Interval; ELX = elexacaftor; VNZ = vanzacaftor; TEZ = tezacaftor; IVA = ivacaftor; D-IVA = deutivacaftor; PK = Pharmacokinetics; qd = once daily
  • * The itraconazole dosing (200 mg qd for14 days) did not fully cover the elimination of vanzacaftor. A 10.5-fold increase in vanzacaftor AUC is predicted by physiologically based pharmacokinetic modeling and simulations when itraconazole fully covers the elimination.
  • † Effect is not clinically significant [see Drug Interactions (7.3)].
  • ‡ Predicted by physiologically based pharmacokinetic modeling and simulations. Data presented as geometric mean ratio and 5th to 95th percentiles of individuals in the simulated population [see Drug Interactions (7.1)].
    • Itraconazole
    200 mg q12h on Day 1, followed by 200 mg daily    		TEZ 25 mg daily + IVA 50 mg dailyTezacaftor4.02
    (3.71, 4.63)    		2.83
    (2.62, 3.07)
    Itraconazole
    200 mg daily    		ELX 20 mg + TEZ 50 mg + D-IVA 50 mg single doseTezacaftor4.51
    (3.85, 5.29)    		1.48
    (1.33, 1.65)
    Deutivacaftor11.1
    (8.72, 14.1)    		1.96
    (1.70, 2.26)
    Itraconazole
    200 mg daily*    		VNZ 5 mg single doseVanzacaftor6.37
    (5.53, 7.35)    		1.55
    (1.41, 1.70)
    Ciprofloxacin†
    750 mg twice daily    		TEZ 50 mg q12h + IVA 150 mg q12hTezacaftor1.08
    (1.03, 1.13)    		1.05
    (0.99, 1.11)
    Digoxin 0.5 mg
    single dose    		TEZ 25 mg daily + IVA 50 mg dailyDigoxin1.3
    (1.17, 1.45)    		1.32
    (1.07, 1.64)
    Fluconazole
    200 mg daily    		VNZ 20 mg qd + TEZ 100 mg + D-IVA 250 mg qdVanzacaftor2.55
    (2.12, 3.12)‡    		2.48
    (2.04, 3.01)‡
    Deutivacaftor3.13
    (2.44, 3.95)‡    		2.27
    (1.82, 2.93)‡
    Erythromycin
    500 mg four times daily    		VNZ 20 mg qd + TEZ 100 mg + D-IVA 250 mg qdVanzacaftor3.29
    (1.62, 7.55)‡    		3.19
    (1.60, 7.29)‡
    Deutivacaftor4.13
    (1.80, 9.73)‡    		2.89
    (1.52, 6.97)‡
    Verapamil
    80 mg three times daily    		VNZ 20 mg qd + TEZ 100 mg + D-IVA 250 mg qdVanzacaftor3.93
    (1.84, 8.75)‡    		3.80
    (1.78, 8.33)‡
    Deutivacaftor5.11
    (2.06, 12.5)‡    		3.43
    (1.64, 7.65)‡
    Rifampin
    600 mg daily    		VNZ 20 mg qd + TEZ 100 mg + D-IVA 250 mg qdVanzacaftor0.18
    (0.10, 0.34)‡    		0.22
    (0.12, 0.38)‡
    Deutivacaftor0.10
    (0.04, 0.26)‡    		0.20
    (0.08, 0.44)‡
    Carbamazepine
    400 mg twice daily    		VNZ 20 mg qd + TEZ 100 mg + D-IVA 250 mg qdVanzacaftor0.44
    (0.28, 0.61)‡    		0.46
    (0.31, 0.64)‡
    Deutivacaftor0.24
    (0.11, 0.47)‡    		0.32
    (0.17, 0.57)‡
    Efavirenz
    600 mg daily    		VNZ 20 mg qd + TEZ 100 mg + D-IVA 250 mg qdVanzacaftor0.31
    (0.16, 0.57)‡    		0.35
    (0.19, 0.59)‡
    Deutivacaftor0.27
    (0.11, 0.50)‡    		0.44
    (0.23, 0.68)‡

    Other Drugs: No clinically significant differences in tezacaftor pharmacokinetics were observed when tezacaftor/ivacaftor was used concomitantly with ciprofloxacin. No clinically significant differences in the pharmacokinetics of the following drugs were observed when used concomitantly with tezacaftor/ivacaftor: midazolam (CYP3A4 substrate) or ethinyl estradiol/norethindrone containing hormonal contraceptives.

    In Vitro Studies

    CYP450 Enzymes: Vanzacaftor, tezacaftor, and deutivacaftor are CYP3A substrates. Deutivacaftor inhibits CYP2C8, CYP2C9, and CYP3A4. Vanzacaftor and tezacaftor do not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Vanzacaftor, tezacaftor, and deutivacaftor do not induce CYP3A4.

    Transporter Systems: Tezacaftor and deutivacaftor are substrates of P-gp, but vanzacaftor is not a substrate of P-gp. Tezacaftor is a substrate of BCRP, OATP1B1, but not OATP1B3. Vanzacaftor and deutivacaftor are not substrates for OATP1B1 or OATP1B3. Vanzacaftor and deutivacaftor are BCRP inhibitors. Vanzacaftor, tezacaftor and deutivacaftor are P-gp inhibitors. Vanzacaftor, tezacaftor, and deutivacaftor do not inhibit OATP1B1 nor OATP1B3.

  • 13 NONCLINICAL TOXICOLOGY

    13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

    No studies of carcinogenicity, mutagenicity, or impairment of fertility were conducted with the combination of 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.

  • 14 CLINICAL STUDIES

    The efficacy of ALYFTREK in patients aged 12 years and older with cystic fibrosis (CF) who have at least one F508del mutation or a responsive mutation in the CFTR gene was evaluated in two 52-week randomized, double-blind, active-controlled trials comparing ALYFTREK and a fixed-dose combination drug containing elexacaftor, tezacaftor, and ivacaftor (ELX/TEZ/IVA) (Trial 1, NCT05033080 and Trial 2, NCT05076149). The two trials enrolled a total of 971 patients aged 12 years and older with CF who have at least one F508del mutation or other ELX/TEZ/IVA-responsive mutations in the CFTR gene. Because patients in Trial 1 and Trial 2 would receive ELX/TEZ/IVA, patients with a history of intolerance to ELX/TEZ/IVA were excluded from these trials.

    • Trial 1 enrolled patients with CF heterozygous for F508del and a CFTR mutation that results in a protein that was not responsive to ivacaftor or tezacaftor/ivacaftor (minimal function mutation). A total of 398 patients with CF aged 12 years and older received a daily oral dosage of ELX/TEZ/IVA (elexacaftor 200 mg/tezacaftor 100 mg/ivacaftor 150 mg in the morning and ivacaftor 150 mg in the evening) during a 4-week run-in period and were then randomized to receive ALYFTREK (total once daily oral dosage of vanzacaftor 20 mg/tezacaftor 100 mg/deutivacaftor 250 mg) or ELX/TEZ/IVA (same dosage as in the run-in period) during the 52-week treatment period. Patients had a mean age of 30.8 years (range: 12.2 to 71.6 years), were 59% male, 97.5% White, 1.3% Black/African American, 0.3% Asian, 0.3% Other race, and 6% Hispanic or Latino ethnicity. After the 4₋week run-in, the mean ppFEV1 at baseline was 67.1 percentage points (range: 28.0, 108.6) and the mean sweat chloride at baseline was 53.9 mmol/L (range: 10.0 mmol/L, 113.5 mmol/L).
    • Trial 2 enrolled patients with CF who had one of the following genotypes: homozygous for the F508del mutation, heterozygous for the F508del mutation and either a gating or a residual function mutation, at least one mutation responsive to ELX/TEZ/IVA with no F508del mutation. A total of 573 patients with CF aged 12 years and older received a daily oral dosage of ELX/TEZ/IVA (elexacaftor 200 mg/tezacaftor 100 mg/ivacaftor 150 mg in the morning and ivacaftor 150 mg in the evening) during a 4-week run-in period and were then randomized to receive ALYFTREK (total once daily oral dosage of vanzacaftor 20 mg/tezacaftor 100 mg/ deutivacaftor 250 mg) or ELX/TEZ/IVA (same dosage as during the run-in period) during the 52-week treatment period. Patients had a mean age of 33.7 years (range: 12.2 to 71.2 years), were 51.1% male, 92.8% White, 0% Black/African American, 0.3% Asian, 0.2% American Indian or Alaska Native, 0.3% Other race, and 1.6% Hispanic or Latino ethnicity. After the 4-week run-in, the mean ppFEV1 at baseline was 66.8 percentage points (range: 36.4, 112.5) and the mean sweat chloride at baseline was 42.8 mmol/L (range: 10.0 mmol/L, 113.3 mmol/L).

    Efficacy Endpoints

    In both trials, the primary endpoint evaluated non-inferiority in mean absolute change in ppFEV1 from baseline through Week 24 and a key secondary endpoint evaluated the mean absolute change from baseline in sweat chloride through Week 24 in the ALYFTREK and ELX/TEZ/IVA treatment groups.

    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: -0.7, 1.1) in absolute change in ppFEV1 from baseline through Week 24 compared to ELX/TEZ/IVA.
    • In Trial 2, treatment with ALYFTREK resulted in an LS mean difference of 0.2 percentage points (95% CI: -0.5, 0.9) in absolute change in ppFEV1 from baseline through Week 24 compared to ELX/TEZ/IVA.

    As the lower bounds of the 95% CI of the LS mean difference in absolute change from baseline in ppFEV1 through Week 24 were greater than -3.0 percentage points (the pre-specified non-inferiority margin) in Trial 1 and Trial 2, these results demonstrate non-inferiority of ALYFTREK to ELX/TEZ/IVA.

    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*StatisticTrial 1Trial 2
    ALYFTREK
    N = 196    		ELX/TEZ/IVA
    N = 202    		ALYFTREK
    N = 284    		ELX/TEZ/IVA
    N = 289
    ppFEV1: percent predicted Forced Expiratory Volume in 1 second; CI: Confidence Interval; SE: Standard Error; SwCl: sweat chloride
    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.
  • * A 4-week ELX/TEZ/IVA run-in-period was performed to establish an on-treatment baseline.
  • † The pre-specified non-inferiority margin was -3.0 percentage points.
    		•
    Primary Endpoint
    Absolute change from baseline in ppFEV1 through Week 24 (percentage points)n187193268276
    LS mean (SE)0.5 (0.3)0.3 (0.3)0.2 (0.3)0.0 (0.2)
    LS mean difference, 95% CI†0.2 (-0.7, 1.1)0.2 (-0.5, 0.9)
    Key Secondary Endpoint
    Absolute change from baseline in SwCl through Week 24 (mmol/L)n185194270276
    LS mean (SE)-7.5 (0.8)0.9 (0.8)-5.1 (0.7)-2.3 (0.7)
    LS mean difference, 95% CI-8.4 (-10.5, -6.3)-2.8 (-4.7, -0.9)
    P-value (2-sided) < 0.00010.0034

    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 ppFEV1 through Week 52, the rate in pulmonary exacerbations through Week 52, and the absolute change from baseline in the CFQ-R RD through Week 24 were similar between the ALYFTREK-treated and the ELX/TEZ/IVA-treated patients. The results were not tested for statistical significance as they were not in the pre-specified multiple testing procedure.

  • 16 HOW SUPPLIED/STORAGE AND HANDLING

    ALYFTREK (vanzacaftor, tezacaftor, and deutivacaftor) tablets are supplied as follows:

    Table 10: ALYFTREK Tablets and Package Configuration
    StrengthsTablet DescriptionPackage ConfigurationNDC
    4 mg of vanzacaftor/ 20 mg of tezacaftor / 50 mg of deutivacaftorpurple, round-shaped, film-coated, debossed with "V4" on one side and plain on the other84-count carton containing 4 wallets, each wallet containing 21 tablets in blister packsNDC: 51167-135-01
    10 mg of vanzacaftor/ 50 mg of tezacaftor / 125 mg of deutivacaftorpurple, oblong-shaped, film-coated, debossed with "V10" on one side and plain on the other56-count carton containing 4 wallets, each wallet containing 14 tablets in blister packsNDC: 51167-121-01

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

  • 17 PATIENT COUNSELING INFORMATION

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

    Drug-Induced Liver Injury and Liver Failure

    Inform patients that elevations of transaminases have occurred in patients with CF treated with ALYFTREK and that cases of drug-induced liver injury and failure have been observed with fixed-dose combination drug containing elexacaftor, tezacaftor, and ivacaftor, which contains the same or similar active ingredients as ALYFTREK.

    Advise all patients that liver function tests should be assessed prior to initiating ALYFTREK, and then assessed every month during the first 6 months of treatment, then every 3 months for the next 12 months, then at least annually thereafter. Inform patients with a history of liver disease or liver function test elevations at baseline that more frequent monitoring may be necessary. Instruct patients to interrupt treatment with ALYFTREK if symptoms of liver injury occur (e.g., jaundice, right upper quadrant pain, nausea, vomiting, altered mental status, ascites) and notify their healthcare provider immediately [see Dosage and Administration (2.1), Warnings and Precautions (5.1), Adverse Reactions (6.1), Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)].

    Hypersensitivity Reactions, Including Anaphylaxis

    Inform patients that hypersensitivity reactions including anaphylaxis have been reported in patients who received drugs containing elexacaftor, tezacaftor, and/or ivacaftor (the same or similar active ingredients as ALYFTREK). Instruct patients to discontinue ALYFTREK and notify their healthcare provider if they experience signs and symptoms of a hypersensitivity reaction, including rash, hives, itching, facial swelling, tightness of the chest and wheezing [see Warnings and Precautions (5.2)].

    Patients Who Discontinued or Interrupted Elexacaftor-, Tezacaftor-, or Ivacaftor-Containing Drugs Due to Adverse Reactions

    Inform patients that there is no available safety data for ALYFTREK in patients who previously discontinued or interrupted treatment with elexacaftor-, tezacaftor-, or ivacaftor-containing drugs due to adverse reactions. These patients who start treatment with ALYFTREK may require closer and more frequent monitoring [see Warnings and Precautions (5.3)].

    Drug Interactions with CYP3A Inducers and Inhibitors

    Inform patients that certain medications, herbal supplements, or vitamins, when used concomitantly with ALYFTREK, may reduce the effectiveness of ALYFTREK or increase the risk of adverse reactions associated with ALYFTREK. Instruct patients to report all concomitant medications, herbal supplements, or vitamins, to their healthcare providers while taking ALYFTREK [see Dosage and Administration (2.3), Warnings and Precautions (5.4, 5.5) and Drug Interactions (7.1)].

    Instruct patients to avoid food or drink containing grapefruit when using ALYFTREK [see Drug Interactions (7.1)].

    Cataracts

    Inform patients that abnormality of the eye lens (cataract) has been noted in some pediatric patients receiving drugs containing ivacaftor (which is similar to an active ingredient in ALYFTREK) and baseline and follow-up ophthalmological examinations are needed in pediatric patients receiving ALYFTREK [see Warnings and Precautions (5.6) and Nonclinical Toxicology (13.1)].

    Administration

    Inform patients that ALYFTREK is best absorbed by the body when taken with food that contains fat. Examples include eggs, butter, peanut butter, whole-milk dairy products (such as whole milk, cheese and yogurt), etc. [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)].

    Inform patients of the following if they miss an ALYFTREK dose [see Dosage and Administration (2.5)]:

    • If 6 hours or less have passed since the missed dose is usually taken, patients with CF should be instructed to take the prescribed dose with fat-containing food as soon as possible.
    • If more than 6 hours have passed since the missed dose, patients with CF should be instructed to skip the missed dose and continue on the original schedule the next day.
  • SPL UNCLASSIFIED SECTION

    Manufactured for
    Vertex Pharmaceuticals Incorporated
    50 Northern Avenue
    Boston, MA 02210

    ALYFTREK, VERTEX and associated logos are registered trademarks of Vertex Pharmaceuticals Incorporated.
    All other trademarks referenced herein are the property of their respective owners.
    ©2024 Vertex Pharmaceuticals Incorporated
    All Rights Reserved

  • MEDICATION GUIDE

    This Medication Guide has been approved by the U.S. Food and Drug Administration.Issued: 12/2024          
    MEDICATION GUIDE
    ALYFTREK® (ah-LIF-trek)
    (vanzacaftor, tezacaftor, and deutivacaftor tablets), tablets for oral use
    What is the most important information I should know about ALYFTREK?
    Elevated liver enzymes have been observed in patients taking ALYFTREK. Cases of serious liver damage and liver failure leading to transplantation and death have been seen in some people with or without a history of liver problems taking elexacaftor/tezacaftor/ivacaftor (TRIKAFTA®), a medicine which has the same or similar active ingredients as ALYFTREK.
    Your healthcare provider will do blood tests to check your liver:
    • before you start ALYFTREK
    • every month during your first 6 months of taking ALYFTREK
    • then every 3 months during the next 12 months of taking ALYFTREK
    • then at least every year while you are taking ALYFTREK
    Your healthcare provider may do blood tests to check the liver more often if you have had high liver enzymes in your blood in the past or are experiencing signs or symptoms of liver injury.
    Stop taking ALYFTREK and call your healthcare provider right away if you have any of the following symptoms of liver problems:
    • pain, swelling, or discomfort in the upper right stomach (abdominal) area
    • yellowing of your skin or the white part of your eyes
    • mental changes
    • nausea or vomiting
    • dark, amber-colored urine
    • loss of appetite
    • have fluid in your stomach area (ascites)
    What is ALYFTREK?
    • ALYFTREK is a prescription medicine used for the treatment of cystic fibrosis (CF) in people aged 6 years and older who have at least one F508del mutation or another responsive mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene.
    • Talk to your healthcare provider to learn if you have an indicated CF gene mutation.
    It is not known if ALYFTREK is safe and effective in children under 6 years of age.
    What should I tell my healthcare provider before taking ALYFTREK?
    Before taking ALYFTREK, tell your healthcare provider about all of your medical conditions, including if you:
    • have or have had liver problems.
    • are allergic to ALYFTREK or any ingredients in ALYFTREK. See the end of this medication guide for a complete list of ingredients in ALYFTREK.
    • have taken another medicine with elexacaftor, tezacaftor, or ivacaftor before and temporarily or permanently stopped because of side effects. Your healthcare provider may want to see you more often.
    • have kidney problems.
    • are pregnant or plan to become pregnant. It is not known if ALYFTREK will harm your unborn baby. You and your healthcare provider should decide if you will take ALYFTREK while you are pregnant.
    • are breastfeeding or planning to breastfeed. It is not known if ALYFTREK passes into your breast milk. You and your healthcare provider should decide if you will take ALYFTREK while you are breastfeeding.
    Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.
    ALYFTREK may affect the way other medicines work and other medicines may affect how ALYFTREK works.
    The dose of ALYFTREK may need to be adjusted when taken with certain medicines. Ask your healthcare provider or pharmacist for a list of these medicines if you are not sure.
    Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine.
    How should I take ALYFTREK?
    • Take ALYFTREK exactly as your healthcare provider tells you to take it.
    • Take ALYFTREK by mouth only.
    • Always take ALYFTREK tablets with food that contains fat. Examples of fat-containing foods include butter, oil, eggs, peanut butter, nuts, meat, and whole-milk dairy products such as whole milk, cheese, and yogurt.
    • ALYFTREK tablets (age 6 to less than 12 years weighing less than 88 pounds (40 kg)):
      • The purple round-shaped tablet is marked with 'V4' and each tablet contains the medicines vanzacaftor, tezacaftor, and deutivacaftor. Take 3 tablets at the same time each day.
    • AYLFTREK tablets (age 6 to less than 12 years weighing 88 pounds (40 kg) or more, or 12 years and older):
      • The purple oblong-shaped tablet is marked with 'V10' and each tablet contains the medicines vanzacaftor, tezacaftor, and deutivacaftor. Take 2 tablets at the same time each day.
    • Take ALYFTREK tablets whole.
    • Take the doses about the same time every day.
    • If you miss a dose of ALYFTREK and:
      • it is 6 hours or less from the time you usually take the dose, take the missed dose with food that contains fat as soon as you can. Then take your next dose at your usual time.
      • it is more than 6 hours from the time you usually take the dose, do not take the missed dose. Take your dose the next day at your usual time.
      • Do not take more than your usual dose of ALYFTREK to make up for a missed dose.
    If you are not sure about your dosing, call your healthcare provider.
    What should I avoid while taking ALYFTREK?
    Avoid food or drink that contains grapefruit while you are taking ALYFTREK.
    What are the possible or reasonably likely side effects of ALYFTREK?
    ALYFTREK can cause serious side effects, including:
    • See "What is the most important information I should know about ALYFTREK?"
    • Serious Allergic Reactions can happen to people who are treated with ALYFTREK. Call your healthcare provider or go to the emergency room right away if you have any symptoms of an allergic reaction. Symptoms of an allergic reaction may include:
      • rash or hives
      • tightness of the chest or throat or difficulty breathing
      • light-headedness or dizziness
    • Abnormality of the eye lens (cataract) has happened in some children and adolescents treated with ALYFTREK. If you are a child or adolescent, your healthcare provider should perform eye examinations before and during treatment with ALYFTREK to look for cataracts.
    The most common side effects of ALYFTREK include:
    • cough
    • pain or swelling of your nose or throat (nasopharyngitis)
    • upper respiratory tract infection (common cold) including stuffy and runny nose
    • headache
    • mouth or throat pain
    • flu (influenza)
    • tiredness
    • increase in liver enzymes
    • rash
    • sinus congestion
    Your healthcare provider should monitor you during treatment with ALYFTREK. You may require additional monitoring if your treatment with a medicine that works like ALYFTREK has been previously stopped or interrupted because of side effects.
    Tell your healthcare provider if you have any side effect that bothers you or that does not go away.
    These are not all of the possible side effects of ALYFTREK. For more information, ask your healthcare provider or pharmacist.
    Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
    How should I store ALYFTREK?
    • Store ALYFTREK at room temperature between 68°F to 77°F (20°C to 25°C).
    Keep ALYFTREK and all medicines out of the reach of children.
    General information about the safe and effective use of ALYFTREK.
    Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use ALYFTREK for a condition for which it was not prescribed. Do not give ALYFTREK to other people, even if they have the same symptoms that you have. It may harm them.
    You can ask your pharmacist or healthcare provider for information about ALYFTREK that is written for health professionals.
    What are the ingredients in ALYFTREK?
    Active ingredients: vanzacaftor, tezacaftor, and deutivacaftor.
    Inactive ingredients: croscarmellose sodium, hypromellose, hypromellose acetate succinate, magnesium stearate, microcrystalline cellulose, and sodium lauryl sulfate. The tablet film coat contains Brilliant Blue FCF aluminum lake/FD&C Blue #1, carmine, hydroxypropyl cellulose, hypromellose, iron oxide red, talc, and titanium dioxide.
    Manufactured for: Vertex Pharmaceuticals Incorporated; 50 Northern Avenue, Boston, MA 02210
    ALYFTREK, VERTEX and associated logos are registered trademarks of Vertex Pharmaceuticals Incorporated.
    All other trademarks referenced herein are the property of their respective owners.
    ©2024 Vertex Pharmaceuticals Incorporated
    For more information, go to www.alyftrek.com or call 1-877-752-5933.
  • PRINCIPAL DISPLAY PANEL - 4 mg/20 mg/50 mg Tablet Wallet Carton

    Rx Only
    NDC: 51167-135-01

    84 tablets
    4-wallets
    (each containing
    21 tablets)

    alyftrek™
    (vanzacaftor/tezacaftor/deutivacaftor)
    tablets

    4 mg/20 mg/50 mg
    per tablet

    ATTENTION PHARMACIST: Dispense enclosed Medication Guide to each patient.

    Lift to open

    PRINCIPAL DISPLAY PANEL - 4 mg/20 mg/50 mg Blister Pack Carton
  • PRINCIPAL DISPLAY PANEL - 10 mg/50 mg/125 mg Tablet Wallet Carton

    Rx Only
    NDC: 51167-121-01

    56 tablets
    4-wallets
    (each containing
    14 tablets)

    alyftrek™
    (vanzacaftor/tezacaftor/deutivacaftor)
    tablets

    10 mg/50 mg/125 mg
    per tablet

    ATTENTION PHARMACIST: Dispense enclosed Medication Guide to each patient.

    Lift to open

    PRINCIPAL DISPLAY PANEL - 10 mg/50 mg/125 mg Blister Pack Carton
  • INGREDIENTS AND APPEARANCE
    ALYFTREK 
    vanzacaftor, tezacaftor, and deutivacaftor tablet, film coated
    Product Information
    Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC: 51167-135
    Route of AdministrationORAL
    Active Ingredient/Active Moiety
    Ingredient NameBasis of StrengthStrength
    vanzacaftor (UNII: COM1POP492) (vanzacaftor - UNII:COM1POP492) vanzacaftor4 mg
    tezacaftor (UNII: 8RW88Y506K) (tezacaftor - UNII:8RW88Y506K) tezacaftor20 mg
    deutivacaftor (UNII: SHA6U5FJZL) (deutivacaftor - UNII:SHA6U5FJZL) deutivacaftor50 mg
    Inactive Ingredients
    Ingredient NameStrength
    HYPROMELLOSE, UNSPECIFIED (UNII: 3NXW29V3WO)  
    HYPROMELLOSE ACETATE SUCCINATE 06081224 (3 MPA.S) (UNII: 6N003M473W)  
    Sodium lauryl sulfate (UNII: 368GB5141J)  
    CROSCARMELLOSE SODIUM (UNII: M28OL1HH48)  
    Microcrystalline cellulose (UNII: OP1R32D61U)  
    Magnesium stearate (UNII: 70097M6I30)  
    HYPROMELLOSE 2910 (15 MPA.S) (UNII: 36SFW2JZ0W)  
    HYDROXYPROPYL CELLULOSE, UNSPECIFIED (UNII: 9XZ8H6N6OH)  
    Titanium dioxide (UNII: 15FIX9V2JP)  
    Talc (UNII: 7SEV7J4R1U)  
    FD&C BLUE NO. 1 (UNII: H3R47K3TBD)  
    FERRIC OXIDE RED (UNII: 1K09F3G675)  
    Product Characteristics
    ColorPURPLEScoreno score
    ShapeROUNDSize7mm
    FlavorImprint Code V4
    Contains    
    Packaging
    #Item CodePackage DescriptionMarketing Start DateMarketing End Date
    1NDC: 51167-135-014 in 1 CARTON12/20/2024
    121 in 1 BLISTER PACK; Type 0: Not a Combination Product
    Marketing Information
    Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
    NDANDA21873012/20/2024
    ALYFTREK 
    vanzacaftor, tezacaftor, and deutivacaftor tablet, film coated
    Product Information
    Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC: 51167-121
    Route of AdministrationORAL
    Active Ingredient/Active Moiety
    Ingredient NameBasis of StrengthStrength
    vanzacaftor (UNII: COM1POP492) (vanzacaftor - UNII:COM1POP492) vanzacaftor10 mg
    tezacaftor (UNII: 8RW88Y506K) (tezacaftor - UNII:8RW88Y506K) tezacaftor50 mg
    deutivacaftor (UNII: SHA6U5FJZL) (deutivacaftor - UNII:SHA6U5FJZL) deutivacaftor125 mg
    Inactive Ingredients
    Ingredient NameStrength
    HYPROMELLOSE, UNSPECIFIED (UNII: 3NXW29V3WO)  
    HYPROMELLOSE ACETATE SUCCINATE 06081224 (3 MPA.S) (UNII: 6N003M473W)  
    Sodium lauryl sulfate (UNII: 368GB5141J)  
    CROSCARMELLOSE SODIUM (UNII: M28OL1HH48)  
    Microcrystalline cellulose (UNII: OP1R32D61U)  
    Magnesium stearate (UNII: 70097M6I30)  
    HYPROMELLOSE 2910 (15 MPA.S) (UNII: 36SFW2JZ0W)  
    HYDROXYPROPYL CELLULOSE, UNSPECIFIED (UNII: 9XZ8H6N6OH)  
    Titanium dioxide (UNII: 15FIX9V2JP)  
    Talc (UNII: 7SEV7J4R1U)  
    FD&C BLUE NO. 1 (UNII: H3R47K3TBD)  
    FERRIC OXIDE RED (UNII: 1K09F3G675)  
    Product Characteristics
    ColorPURPLEScoreno score
    ShapeOVAL (Oblong) Size15mm
    FlavorImprint Code V10
    Contains    
    Packaging
    #Item CodePackage DescriptionMarketing Start DateMarketing End Date
    1NDC: 51167-121-014 in 1 CARTON12/20/2024
    114 in 1 BLISTER PACK; Type 0: Not a Combination Product
    Marketing Information
    Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
    NDANDA21873012/20/2024
    Labeler - Vertex Pharmaceuticals Incorporated (602478257)

    • Trademark Results [ALYFTREK]

    Mark Image

    Registration | Serial
    Company
    Trademark
    Application Date
    ALYFTREK
    ALYFTREK
    98760764 not registered Live/Pending
    Vertex Pharmaceuticals Incorporated
    2024-09-20
    ALYFTREK
    ALYFTREK
    98321063 not registered Live/Pending
    Vertex Pharmaceuticals Incorporated
    2023-12-19
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