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Vanzacaftor, tezacaftor, and deutivacaftor: Pediatric drug information

Vanzacaftor, tezacaftor, and deutivacaftor: Pediatric drug information
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ALERT: US Boxed Warning
Drug-induced liver injury and liver failure:

Elevated transaminases have been observed in patients treated with vanzacaftor/tezacaftor/deutivacaftor. 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 vanzacaftor/tezacaftor/deutivacaftor. Liver injury has been reported within the first month of therapy and up to 15 months following initiation of elexacaftor/tezacaftor/ivacaftor.

Assess liver function tests (ALT, AST, alkaline phosphatase, and bilirubin) in all patients prior to initiating vanzacaftor/tezacaftor/deutivacaftor, 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.

Interrupt vanzacaftor/tezacaftor/deutivacaftor 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 vanzacaftor/tezacaftor/deutivacaftor.

Vanzacaftor/tezacaftor/deutivacaftor should not be used in patients with severe hepatic impairment (Child-Pugh Class C). Vanzacaftor/tezacaftor/deutivacaftor 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.

Brand Names: US
  • Alyftrek
Dosing: Pediatric

Dosage guidance:

Dosage form information: Multiple strengths are available; use caution when selecting dosage form.

Cystic fibrosis

Cystic fibrosis:

Children 6 to <12 years:

<40 kg: Vanzacaftor 4 mg/tezacaftor 20 mg/deutivacaftor 50 mg per tablet:

Oral: 3 tablets once daily (vanzacaftor 12 mg/tezacaftor 60 mg/deutivacaftor 150 mg per dose).

≥40 kg: Vanzacaftor 10 mg/tezacaftor 50 mg/deutivacaftor 125 mg per tablet:

Oral: 2 tablets once daily (vanzacaftor 20 mg/tezacaftor 100 mg/deutivacaftor 250 mg per dose).

Children ≥12 years and Adolescents: Vanzacaftor 10 mg/tezacaftor 50 mg/deutivacaftor 125 mg per tablet:

Oral: 2 tablets once daily (vanzacaftor 20 mg/tezacaftor 100 mg/deutivacaftor 250 mg per dose).

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Kidney Impairment: Pediatric

Altered kidney function:

Children ≥6 years and Adolescents: Oral:

eGFR ≥30 mL/minute/1.73 m2: No dosage adjustment necessary.

eGFR <30 mL/minute/1.73 m2: There are no dosage adjustments provided in the manufacturer's labeling; use only if benefits are expected to outweigh risks.

End-stage kidney disease: There are no dosage adjustments provided in the manufacturer's labeling; use only if benefits are expected to outweigh risks.

Dosing: Liver Impairment: Pediatric

Hepatic impairment prior to initiation (baseline):

Children ≥6 years and Adolescents: Oral:

Mild impairment: No dosage adjustment necessary; monitor liver function tests closely.

Moderate impairment: Use is not recommended; may consider use only if medical need is clear and benefit outweighs risk. If used, no dosage adjustment necessary; monitor liver function tests closely.

Severe impairment: Do not use.

Hepatotoxicity during treatment: Children ≥6 years and Adolescents: Oral:

ALT or AST >5 × ULN: Temporarily discontinue vanzacaftor/tezacaftor/deutivacaftor; consider hepatologist referral. May resume if elevated transaminases are resolved and benefit is expected to outweigh risk; monitor closely.

ALT or AST >3 × ULN with concomitant bilirubin >2 × ULN: Temporarily discontinue vanzacaftor/tezacaftor/deutivacaftor; consider hepatologist referral. May resume if laboratory abnormalities are resolved and benefit is expected to outweigh risk; monitor closely.

Clinical signs or symptoms suggestive of liver injury (eg, jaundice, right upper quadrant pain, nausea, vomiting, altered mental status, ascites): Temporarily discontinue vanzacaftor/tezacaftor/deutivacaftor; consider hepatologist referral. May resume if signs or symptoms are resolved and benefit is expected to outweigh risk; monitor closely.

Dosing: Adult

(For additional information see "Vanzacaftor, tezacaftor, and deutivacaftor: Drug information")

Cystic fibrosis

Cystic fibrosis: Oral: Two tablets (each tablet contains vanzacaftor 10 mg/tezacaftor 50 mg/deutivacaftor 125 mg) once daily.

Missed dose: If ≤6 hours since the missed dose, take the missed dose as soon as possible and continue the original schedule. If >6 hours since the missed dose, skip the missed dose and continue on the original schedule the next day.

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Kidney Impairment: Adult

eGFR ≥30 mL/minute/1.73 m2: No dosage adjustment necessary.

eGFR <30 mL/minute/1.73 m2: There are no specific dosage adjustments provided in the manufacturer's labeling (has not been studied); use only if benefits outweigh risks.

End-stage renal disease: There are no specific dosage adjustments provided in the manufacturer's labeling (has not been studied); use only if benefits outweigh risks.

Dosing: Liver Impairment: Adult

Hepatic impairment prior to treatment initiation:

Mild impairment (Child-Turcotte-Pugh class A): No dosage adjustment necessary; monitor LFTs closely.

Moderate impairment (Child-Turcotte-Pugh class B): Use is not recommended; however, if there is a medical need and benefits outweigh risks, no dosage adjustment necessary; use with caution and close monitoring of LFTs.

Severe impairment (Child-Turcotte-Pugh class C): Use not recommended (has not been studied).

Hepatotoxicity during treatment: ALT/AST >5 × ULN or ALT/AST >3 × ULN with bilirubin >2 × ULN and/or symptoms suggestive of liver injury (eg, ascites, jaundice, nausea, altered mental status, right upper quadrant pain, vomiting): Interrupt therapy and monitor closely until resolved; consider referral to hepatologist. Consider the benefits and risks prior to resuming treatment and monitor closely.

Adverse Reactions

The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Adverse reactions reported in adolescents and adults.

>10%:

Dermatologic: Skin rash (8% to 11%)

Infection: Influenza (11%)

Nervous system: Fatigue (11%), headache (16%)

Respiratory: Cough (25%), nasopharyngitis (21%), oropharyngeal pain (14%), upper respiratory tract infection (21%)

1% to 10%:

Cardiovascular: Increased diastolic blood pressure (2%), increased systolic blood pressure (4%)

Hepatic: Increased serum alanine aminotransferase (8%), increased serum aspartate aminotransferase (7%), increased serum transaminases (>3 × ULN: 6%; >5 × ULN: 3%; >8 × ULN: 1%)

Neuromuscular & skeletal: Increased creatine phosphokinase in blood specimen (8%)

Respiratory: Paranasal sinus congestion (7%)

<1%:

Cardiovascular: Syncope

Hepatic: Increased gamma-glutamyl transferase (severe)

Nervous system: Depression (severe)

Frequency not defined:

Gastrointestinal: Abdominal pain, constipation, diarrhea, nausea, vomiting

Hepatic: Hepatic failure, hepatic injury

Neuromuscular & skeletal: Arthralgia, back pain

Respiratory: Dyspnea, hemoptysis, increased bronchial secretions, nasal congestion, rhinorrhea, sinusitis

Miscellaneous: Fever

Contraindications

There are no contraindications listed in the manufacturer's labeling.

Warnings/Precautions

Concerns related to adverse effects:

• Cataracts: Noncongenital lens opacities and cataracts have been reported in pediatric patients treated with ivacaftor; other risk factors were present in some cases (eg, corticosteroid use, exposure to radiation), but a possible risk related to ivacaftor cannot be excluded. Baseline and follow-up ophthalmological examinations are recommended in pediatric patients.

• Hypersensitivity reactions: Hypersensitivity reactions, including anaphylaxis, have been reported with medications containing elexacaftor, tezacaftor, and/or ivacaftor. If signs and symptoms of severe hypersensitivity occur, discontinue use and treat appropriately; consider risk versus benefit prior to resuming therapy.

Disease-related concerns:

• Hepatic impairment: Use with caution in patients with hepatic impairment; dosage adjustment recommended in patients with moderate impairment (Child-Pugh class B); use not recommended in severe impairment (Child-Pugh class C).

• Renal impairment: Use with caution in patients with severe renal impairment (eGFR <30 mL/minute/1.73 m2) or end-stage renal disease.

Other warnings/precautions:

• Appropriate use: If the patient's genotype is unknown, use an FDA-cleared cystic fibrosis mutation test to detect the presence of at least one F508del mutation.

Dosage Forms: US

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Alyftrek: Vanzacaftor calcium 4 mg, tezacaftor 20 mg, and deutivacaftor 50 mg, Vanzacaftor calcium 10 mg, tezacaftor 50 mg, and deutivacaftor 125 mg [contains carmine (cochineal extract), fd&c blue #1 (brill blue) aluminum lake]

Generic Equivalent Available: US

No

Pricing: US

Tablets (Alyftrek Oral)

4-20-50 mg (per each): $405.77

10-50-125 mg (per each): $608.66

Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.

Administration: Pediatric

Oral: Administer with fat-containing food (eg, eggs, cheese, nuts, peanut butter, meat, whole milk, or foods prepared with butter or oils) at approximately the same time each day. Avoid food or drink containing grapefruit. Swallow tablets whole.

Missed doses: If a dose is missed within 6 hours of the usual time it is taken, administer the dose as soon as possible; if >6 hours have passed since the missed dose, skip the missed dose and resume the normal dosing schedule.

Administration: Adult

Oral: Swallow tablets whole. Administer at approximately the same time each day with a fat-containing meal or snack (eg, those prepared with butter or oils or those containing eggs, cheeses, nuts, peanut butter, whole milk, or meats).

Storage/Stability

Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F).

Use

Treatment of cystic fibrosis in patients who have at least one F508del mutation or another responsive mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene (FDA approved in ages ≥6 years of age and adults).

Metabolism/Transport Effects

Substrate of BCRP, CYP3A4 (Major), OATP1B1/1B3, P-glycoprotein (Minor); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential; Inhibits P-glycoprotein;

Drug Interactions

Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the drug interactions program by clicking on the “Launch drug interactions program” link above.

Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the drug interactions program

Afatinib: P-glycoprotein/ABCB1 Inhibitors may increase serum concentration of Afatinib. Management: If combined, administer the P-gp inhibitor simultaneously with, or after, the dose of afatinib. Monitor closely for signs and symptoms of afatinib toxicity and if the combination is not tolerated, reduce the afatinib dose by 10 mg. Risk D: Consider Therapy Modification

Aliskiren: P-glycoprotein/ABCB1 Inhibitors may increase serum concentration of Aliskiren. Risk C: Monitor

BCRP/ABCG2 Substrates (Clinically Relevant with Inhibitors): Vanzacaftor, Tezacaftor, and Deutivacaftor may increase serum concentration of BCRP/ABCG2 Substrates (Clinically Relevant with Inhibitors). Risk C: Monitor

Beta-Acetyldigoxin: P-glycoprotein/ABCB1 Inhibitors may increase serum concentration of Beta-Acetyldigoxin. Risk C: Monitor

Bilastine: P-glycoprotein/ABCB1 Inhibitors may increase serum concentration of Bilastine. Risk X: Avoid

Celiprolol: P-glycoprotein/ABCB1 Inhibitors may increase serum concentration of Celiprolol. Risk C: Monitor

Clofazimine: May increase serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor

Colchicine: P-glycoprotein/ABCB1 Inhibitors may increase serum concentration of Colchicine. Colchicine distribution into certain tissues (e.g., brain) may also be increased. Management: This combination is often contraindicated, but combined use may be permitted with dose adjustment and monitoring. Recommendations vary based on brand, indication, use of CYP3A4 inhibitors, and hepatic/renal function. See interaction monograph for details. Risk D: Consider Therapy Modification

CycloSPORINE (Systemic): P-glycoprotein/ABCB1 Inhibitors may increase serum concentration of CycloSPORINE (Systemic). Risk C: Monitor

CYP2C9 Substrates (High risk with Inhibitors): Vanzacaftor, Tezacaftor, and Deutivacaftor may increase serum concentration of CYP2C9 Substrates (High risk with Inhibitors). Risk C: Monitor

CYP3A4 Inducers (Moderate): May decrease serum concentration of Vanzacaftor, Tezacaftor, and Deutivacaftor. Risk X: Avoid

CYP3A4 Inducers (Strong): May decrease serum concentration of Vanzacaftor, Tezacaftor, and Deutivacaftor. Risk X: Avoid

CYP3A4 Inhibitors (Moderate): May increase serum concentration of Vanzacaftor, Tezacaftor, and Deutivacaftor. Management: Age- and weight-specific dose reductions of vanzacaftor, tezacaftor, and deutivacaftor are recommended. Please see full Interact monograph or labeling for details. Risk D: Consider Therapy Modification

CYP3A4 Inhibitors (Strong): May increase serum concentration of Vanzacaftor, Tezacaftor, and Deutivacaftor. Management: Age- and weight-specific dose reductions of vanzacaftor, tezacaftor, and deutivacaftor are recommended. Please see full Interact monograph or labeling for details. Risk D: Consider Therapy Modification

Dabigatran Etexilate: P-glycoprotein/ABCB1 Inhibitors may increase active metabolite exposure of Dabigatran Etexilate. Risk C: Monitor

Digitoxin: P-glycoprotein/ABCB1 Inhibitors may increase serum concentration of Digitoxin. Risk C: Monitor

Digoxin: P-glycoprotein/ABCB1 Inhibitors may increase serum concentration of Digoxin. Management: Measure digoxin serum concentrations before initiating treatment with these P-glycoprotein (P-gp) inhibitors. Reduce digoxin concentrations by either reducing the digoxin dose by 15% to 30% or by modifying the dosing frequency. Risk D: Consider Therapy Modification

DOXOrubicin (Conventional): P-glycoprotein/ABCB1 Inhibitors may increase serum concentration of DOXOrubicin (Conventional). Risk X: Avoid

DOXOrubicin (Liposomal): P-glycoprotein/ABCB1 Inhibitors may increase serum concentration of DOXOrubicin (Liposomal). Risk C: Monitor

Edoxaban: P-glycoprotein/ABCB1 Inhibitors may increase serum concentration of Edoxaban. Risk C: Monitor

Ensartinib: P-glycoprotein/ABCB1 Inhibitors may increase serum concentration of Ensartinib. Risk X: Avoid

Etoposide Phosphate: P-glycoprotein/ABCB1 Inhibitors may increase serum concentration of Etoposide Phosphate. Risk C: Monitor

Etoposide: P-glycoprotein/ABCB1 Inhibitors may increase serum concentration of Etoposide. Risk C: Monitor

Everolimus: P-glycoprotein/ABCB1 Inhibitors may increase serum concentration of Everolimus. Risk C: Monitor

Fusidic Acid (Systemic): May increase serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Consider avoiding this combination if possible. If required, monitor patients closely for increased adverse effects of the CYP3A4 substrate. Risk D: Consider Therapy Modification

Glecaprevir and Pibrentasvir: P-glycoprotein/ABCB1 Inhibitors may increase serum concentration of Glecaprevir and Pibrentasvir. Risk C: Monitor

Grapefruit Juice: May increase serum concentration of Vanzacaftor, Tezacaftor, and Deutivacaftor. Risk X: Avoid

Lapatinib: P-glycoprotein/ABCB1 Inhibitors may increase serum concentration of Lapatinib. Risk C: Monitor

Larotrectinib: P-glycoprotein/ABCB1 Inhibitors may increase serum concentration of Larotrectinib. Risk C: Monitor

Lefamulin: P-glycoprotein/ABCB1 Inhibitors may increase serum concentration of Lefamulin. Management: Avoid concomitant use of lefamulin tablets with P-glycoprotein/ABCB1 inhibitors. If concomitant use is required, monitor for lefamulin adverse effects. Risk D: Consider Therapy Modification

Mavorixafor: P-glycoprotein/ABCB1 Inhibitors may increase serum concentration of Mavorixafor. Risk C: Monitor

Morphine (Systemic): P-glycoprotein/ABCB1 Inhibitors may increase serum concentration of Morphine (Systemic). Risk C: Monitor

Nadolol: P-glycoprotein/ABCB1 Inhibitors may increase serum concentration of Nadolol. Risk C: Monitor

Naldemedine: P-glycoprotein/ABCB1 Inhibitors may increase serum concentration of Naldemedine. Risk C: Monitor

Naloxegol: P-glycoprotein/ABCB1 Inhibitors may increase serum concentration of Naloxegol. Risk C: Monitor

PAZOPanib: P-glycoprotein/ABCB1 Inhibitors may increase serum concentration of PAZOPanib. Risk X: Avoid

Pralsetinib: P-glycoprotein/ABCB1 Inhibitors may increase serum concentration of Pralsetinib. Management: If this combo cannot be avoided, decrease pralsetinib dose from 400 mg daily to 300 mg daily; from 300 mg daily to 200 mg daily; and from 200 mg daily to 100 mg daily. Risk D: Consider Therapy Modification

Ranolazine: P-glycoprotein/ABCB1 Inhibitors may increase serum concentration of Ranolazine. Risk C: Monitor

Relugolix, Estradiol, and Norethindrone: P-glycoprotein/ABCB1 Inhibitors may increase serum concentration of Relugolix, Estradiol, and Norethindrone. Management: Avoid use of relugolix/estradiol/norethindrone with P-glycoprotein (P-gp) inhibitors. If concomitant use is unavoidable, relugolix/estradiol/norethindrone should be administered at least 6 hours before the P-gp inhibitor. Risk D: Consider Therapy Modification

Relugolix: P-glycoprotein/ABCB1 Inhibitors may increase serum concentration of Relugolix. Management: Avoid coadministration of relugolix with oral P-gp inhibitors whenever possible. If combined, take relugolix at least 6 hours prior to the P-gp inhibitor and monitor patients more frequently for adverse reactions. Risk D: Consider Therapy Modification

Repotrectinib: P-glycoprotein/ABCB1 Inhibitors may increase serum concentration of Repotrectinib. Risk X: Avoid

RifAXIMin: P-glycoprotein/ABCB1 Inhibitors may increase serum concentration of RifAXIMin. Risk C: Monitor

Rimegepant: P-glycoprotein/ABCB1 Inhibitors may increase serum concentration of Rimegepant. Management: Avoid administration of another dose of rimegepant within 48 hours if given concomitantly with a P-glycoprotein (P-gp) inhibitor. Risk D: Consider Therapy Modification

RisperiDONE: P-glycoprotein/ABCB1 Inhibitors may increase serum concentration of RisperiDONE. Risk C: Monitor

RomiDEPsin: P-glycoprotein/ABCB1 Inhibitors may increase serum concentration of RomiDEPsin. Risk C: Monitor

Silodosin: P-glycoprotein/ABCB1 Inhibitors may increase serum concentration of Silodosin. Risk C: Monitor

Sirolimus (Conventional): P-glycoprotein/ABCB1 Inhibitors may increase serum concentration of Sirolimus (Conventional). Management: Avoid concurrent use of sirolimus with P-glycoprotein (P-gp) inhibitors when possible and alternative agents with lesser interaction potential with sirolimus should be considered. Monitor for increased sirolimus concentrations/toxicity if combined. Risk D: Consider Therapy Modification

Sirolimus (Protein Bound): P-glycoprotein/ABCB1 Inhibitors may increase serum concentration of Sirolimus (Protein Bound). Risk X: Avoid

Tacrolimus (Systemic): P-glycoprotein/ABCB1 Inhibitors may increase serum concentration of Tacrolimus (Systemic). Risk C: Monitor

Talazoparib: P-glycoprotein/ABCB1 Inhibitors may increase serum concentration of Talazoparib. Risk C: Monitor

Teniposide: P-glycoprotein/ABCB1 Inhibitors may increase serum concentration of Teniposide. Risk C: Monitor

Tenofovir Disoproxil Fumarate: P-glycoprotein/ABCB1 Inhibitors may increase serum concentration of Tenofovir Disoproxil Fumarate. Risk C: Monitor

Topotecan: P-glycoprotein/ABCB1 Inhibitors may increase serum concentration of Topotecan. Risk X: Avoid

Ubrogepant: P-glycoprotein/ABCB1 Inhibitors may increase serum concentration of Ubrogepant. Management: Use an initial ubrogepant dose of 50 mg and second dose (at least 2 hours later if needed) of 50 mg when used with a P-gp inhibitor. Risk D: Consider Therapy Modification

Venetoclax: P-glycoprotein/ABCB1 Inhibitors may increase serum concentration of Venetoclax. Management: Reduce the venetoclax dose by at least 50% in patients requiring concomitant treatment with P-glycoprotein (P-gp) inhibitors. Resume the previous venetoclax dose 2 to 3 days after discontinuation of a P-gp inhibitor. Risk D: Consider Therapy Modification

VinCRIStine: P-glycoprotein/ABCB1 Inhibitors may increase serum concentration of VinCRIStine. Risk X: Avoid

Warfarin: Vanzacaftor, Tezacaftor, and Deutivacaftor may increase serum concentration of Warfarin. Risk C: Monitor

Food Interactions

Grapefruit juice may increase exposure of elexacaftor, tezacaftor, or ivacaftor. Management: Avoid food or drink containing grapefruit during treatment.

Dietary Considerations

Take with fat-containing food (eg, eggs, butter, peanut butter, whole-milk dairy products [eg, whole milk, cheese, yogurt]). Avoid food or drink containing grapefruit during treatment.

Reproductive Considerations

Fertility and contraception should be reassessed prior to starting variant specific cystic fibrosis transmembrane conductance regulator (CFTR) therapy (Southern 2023).

Fertility may improve with use of CFTR therapy and an increase in unintentional pregnancies has been observed. Contraception advice is recommended for patients who do not wish to become pregnant (Gramegna 2024, Southern 2023).

Pregnancy Considerations

Tezacaftor crosses the placenta (Collins 2022).

Animal reproduction studies have not been conducted with this combination. Data related to the safety of variant specific cystic fibrosis transmembrane conductance regulator (CFTR) therapy during pregnancy are limited (Southern 2023).

Monitoring of newborns exposed to CFTR therapy during pregnancy should include genetic testing, LFTs, and ophthalmic exams (Gramegna 2024). In addition, exposed infants may have a false negative immunoreactive trypsinogen test for cystic fibrosis during the newborn baby screen (Castellani 2023; Southern 2023).

Patients taking variant specific CFTR therapy prior to pregnancy may have an acute deterioration of health if treatment is discontinued once pregnant. Continuing or discontinuing therapy during pregnancy should be based on a shared decision-making process (Gramegna 2024).

Monitoring Parameters

Cystic fibrosis gene mutation test (prior to therapy if genotype is unknown); ophthalmological examinations (baseline and follow-up); ALT, AST, alkaline phosphatase, and bilirubin at baseline, every month during the first 6 months of therapy, then every 3 months for the next 12 months, then at least annually (more frequently in patients with a history of liver disease, elevated liver function tests at baseline, or a history of elevated LFTs with drugs containing elexacaftor, tezacaftor, or ivacaftor); creatine phosphokinase; blood pressure. Monitor for signs and symptoms of hypersensitivity, including anaphylaxis.

Mechanism of Action

Vanzacaftor and tezacaftor facilitate the cellular processing and trafficking of normal and select mutant forms of cystic fibrosis transmembrane conductance regulator (CFTR) (including F508del-CFTR) to increase the amount of mature CFTR protein delivered to the cell surface.

Deutivacaftor is a CFTR potentiator that facilitates increased chloride transport by potentiating the channel-open probability (or gating) of the CFTR protein at the cell surface.

Pharmacokinetics (Adult Data Unless Noted)

Note: The following pharmacokinetic parameters are based on studies in patients with cystic fibrosis ≥12 years of age. Exposures in children ≥6 years are within the range shown in adults.

Absorption:

Vanzacaftor: AUC increased 4-fold (low-fat meal) and 6-fold (high-fat meal).

Tezacaftor: No significant effect from food.

Deutivacaftor: AUC increased 3-fold (low-fat meal) and 4-fold (high-fat meal).

Distribution:

Vanzacaftor: Vd: 121 L.

Tezacaftor: Vd: 73.1 L.

Deutivacaftor: Vd: 159 L.

Protein binding:

Vanzacaftor: >99%.

Tezacaftor: ~99%.

Deutivacaftor: >99%.

Metabolism:

Vanzacaftor: Primarily via CYP3A4/5.

Tezacaftor: Primarily via CYP3A4/5 to active metabolite M1-TEZ (similar potency to parent compound).

Deutivacaftor: Primarily via CYP3A4/5 to active metabolite M1-D-IVA (~20% potency compared to parent compound).

Half-life elimination:

Vanzacaftor: 92.8 hours.

Tezacaftor: 22.5 hours.

Deutivacaftor: 19.2 hours.

Time to peak:

Vanzacaftor: Median: 7.8 hours (range: 3.7 to 11.9 hours).

Tezacaftor: Median: 1.6 hours (range: 1.4 to 1.7 hours).

Deutivacaftor: Median: 3.7 hours (range: 2.7 to 11.4 hours).

Excretion:

Vanzacaftor: Urine (0.5%); feces (91.6% as primarily metabolites).

Tezacaftor: Urine (13.7%); feces (72% as unchanged drug or M2-TEZ metabolite).

Pharmacokinetics: Additional Considerations (Adult Data Unless Noted)

Hepatic function: In patients with moderate impairment (Child-Turcotte-Pugh class B), vanzacaftor AUC decreased ~30%; tezacaftor AUC was similar; and deutivacaftor AUC decreased ~20% compared to healthy subjects.

  1. Alyftrek (vanzacaftor, tezacaftor, deutivacaftor) [prescribing information]. Boston, MA: Vertex Pharmaceuticals Incorporated; December 2024.
  2. Castellani C, Simmonds NJ, Barben J, et al. Standards for the care of people with cystic fibrosis (CF): a timely and accurate diagnosis. J Cyst Fibros. 2023;22(6):963-968. doi:10.1016/j.jcf.2023.09.008 [PubMed 37775442]
  3. Collins B, Fortner C, Cotey A, Esther CRJ, Trimble A. Drug exposure to infants born to mothers taking elexacaftor, tezacaftor, and ivacaftor. J Cyst Fibros. 2022;21(4):725-727. doi:10.1016/j.jcf.2021.12.004 [PubMed 34952795]
  4. Gramegna A, Addy C, Allen L, et al. Standards for the care of people with cystic fibrosis (CF); planning for a longer life. J Cyst Fibros. 2024;23(3):375-387. doi:10.1016/j.jcf.2024.05.007 [PubMed 38789317]
  5. Southern KW, Castellani C, Lammertyn E, et al. Standards of care for CFTR variant-specific therapy (including modulators) for people with cystic fibrosis. J Cyst Fibros. 2023;22(1):17-30. doi:10.1016/j.jcf.2022.10.002 [PubMed 36916675]
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