Safety data from 971 patients with CF in 2 randomized, double-blind,
active-controlled, Phase 3 trials of 52 weeks treatment duration1,2
Safety data from 971 patients with CF in 2 randomized, double-blind, active-controlled, Phase 3 trials of 52 weeks treatment duration1,2
- A total of 480 patients with CF aged 12 years and older received at least one dose of ALYFTREK
- Except where otherwise noted, the safety data provided below are from Trials 1 and 2, the active-controlled 52-week trials in patients aged 12 years and older. The adverse reactions in Trial 3 were generally similar to those observed in Trials 1 and 2
Trials 1 and 2 were not designed to evaluate meaningful comparisons of the incidence of adverse reactions between the ALYFTREK and ETI treatment groups.
Discontinuations due to adverse reactions1,2
3.7% OF PATIENTS TREATED WITH ETI (n=18)
3.8% OF PATIENTS TREATED WITH ALYFTREK (n=18)
Serious adverse reactions1,3
- In Trials 1 and 2, serious adverse reactions that occurred more frequently in patients treated with ALYFTREK compared to ETI were influenza (1.5% vs. 0.6%), AST increased (0.4% vs. 0.2%), depression (0.4% vs. 0.0%), GGT increased (0.4% vs. 0.2%), and syncope (0.4% vs. 0.0%)
Most common adverse events and reactions in Trial 1 and 21,4
Adverse events and adverse reactions in ≥5% of patients | ETI N=491 | ALYFTREK N=480 |
---|---|---|
Infective pulmonary exacerbation of CF | 158 (32) | 133 (28) |
Cougha | 116 (24) | 120 (25) |
COVID- 19 | 127 (26) | 107 (22) |
Nasopharyngitisa | 95 (19) | 102 (21) |
Upper respiratory tract infectiona | 97 (20) | 101 (21) |
Headachea | 63 (13) | 76 (16) |
Oropharyngeal paina | 60 (12) | 69 (14) |
Diarrhea | 59 (12) | 58 (12) |
Influenzaa | 26 (5) | 52 (11) |
Pyrexia | 50 (10) | 52 (11) |
Fatiguea | 46 (9) | 51 (11) |
Nasal congestion | 47 (10) | 48 (10) |
Sputum increased | 50 (10) | 45 (9) |
Blood creatine phosphokinase increased | 41 (8) | 43 (9) |
ALT increaseda | 29 (6) | 38 (8) |
Rasha | 22 (4) | 37 (8) |
Rhinorrhea | 36 (7) | 35 (7) |
AST increaseda | 27 (5) | 33 (7) |
Sinus congestiona | 15 (3) | 32 (7) |
Hemoptysis | 33 (7) | 30 (6) |
Nausea | 30 (6) | 29 (6) |
Abdominal pain | 37 (8) | 25 (5) |
Back pain | 31 (6) | 25 (5) |
Arthralgia | 36 (7) | 24 (5) |
Constipation | 30 (6) | 22 (5) |
Sinusitis | 36 (7) | 19 (4) |
Dyspnea | 28 (6) | 18 (4) |
Vomiting | 27 (6) | 15 (3) |
Adverse events and adverse reactions in ≥5% of patients | ETI N=491 | ALYFTREK N=480 |
---|---|---|
Infective pulmonary exacerbation of CF | 158 (32) | 133 (28) |
Cougha | 116 (24) | 120 (25) |
COVID- 19 | 127 (26) | 107 (22) |
Nasopharyngitisa | 95 (19) | 102 (21) |
Upper respiratory tract infectiona | 97 (20) | 101 (21) |
Headachea | 63 (13) | 76 (16) |
Oropharyngeal paina | 60 (12) | 69 (14) |
Diarrhea | 59 (12) | 58 (12) |
Influenzaa | 26 (5) | 52 (11) |
Pyrexia | 50 (10) | 52 (11) |
Fatiguea | 46 (9) | 51 (11) |
Nasal congestion | 47 (10) | 48 (10) |
Sputum increased | 50 (10) | 45 (9) |
Blood creatine phosphokinase increased | 41 (8) | 43 (9) |
ALT increaseda | 29 (6) | 38 (8) |
Rasha | 22 (4) | 37 (8) |
Rhinorrhea | 36 (7) | 35 (7) |
AST increaseda | 27 (5) | 33 (7) |
Sinus congestiona | 15 (3) | 32 (7) |
Hemoptysis | 33 (7) | 30 (6) |
Nausea | 30 (6) | 29 (6) |
Abdominal pain | 37 (8) | 25 (5) |
Back pain | 31 (6) | 25 (5) |
Arthralgia | 36 (7) | 24 (5) |
Constipation | 30 (6) | 22 (5) |
Sinusitis | 36 (7) | 19 (4) |
Dyspnea | 28 (6) | 18 (4) |
Vomiting | 27 (6) | 15 (3) |
Liver function test elevations1,3
Incidence of maximum transaminases and maximum total bilirubin elevations in Trials 1 and 2 | ETI (N=491) | ALYFTREK (N=480) | |
---|---|---|---|
Elevated ALT or AST, n(%) | |||
>3x ULN | 15 (3.1) | 29 (6.0) | |
>5x ULN | 6 (1.2) | 12 (2.5) | |
>8x ULN | 1 (0.2) | 6 (1.3) | |
ALT/AST >3x ULN and total bilirubin elevation >2X ULN,d % | 0.4 | 0.2 |
Incidence of maximum transaminases and maximum total bilirubin elevations in Trials 1 and 2 | ETI (N=491) | ALYFTREK (N=480) | |
---|---|---|---|
Elevated ALT or AST, n(%) | |||
>3x ULN | 15 (3.1) | 29 (6.0) | |
>5x ULN | 6 (1.2) | 12 (2.5) | |
>8x ULN | 1 (0.2) | 6 (1.3) | |
ALT/AST >3x ULN and total bilirubin elevation >2X ULN,d % | 0.4 | 0.2 |
- Adverse reactions of transaminase elevations (AST and/or ALT) occurred in 43 patients (9%) in patients treated with ALYFTREK and 35 patients (7.1%) in treated with ETI
- 7 patients (1.5%) treated with ALYFTREK discontinued due to transaminase elevations, compared to 3 (0.6%) ETI-treated patients
Rash events1
- The overall incidence of rash events was 11.0% in patients treated with ALYFTREK and 7.7% in ETI-treated patients
- In the ALYFTREK arm, the incidence of rash events was 9.4% in males and 13.0% in females
- A role for hormonal contraceptives in the occurrence of rash cannot be excluded. For patients 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
Increased creatine phosphokinase5
In Trial 1, the incidence of maximum CPK >5x ULN was 9.2% (18/196) in patients treated with ALYFTREK and 8.5% (17/202) in patients treated with ETI. In Trial 2, the incidence of maximum CPK >5x ULN was 7.0% (20/284) in patients treated with ALYFTREK and 5.2% (15/289) in patients treated with ETI
Increased blood pressure1
- 3.5% of patients treated with ALYFTREK had systolic blood pressure >140 mmHg and a >10 mmHg increase from baseline on at least 2 occasions vs. 3.3% of patients treated with ETI
- 1.7% of patients treated with ALYFTREK had diastolic blood pressure >90 mmHg and a >5 mmHg increase from baseline on at least 2 occasions vs. 1.8% of patients treated with ETI
- The mean systolic and diastolic blood pressures remained in the normal range from both ALYFTREK and ETI treatment arms
Important Safety Information
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 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.
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, every 3 months for the next 12 months, and at least annually thereafter. Consider more frequent monitoring for patients with a history of liver disease or elevated liver function tests (LFTs) at baseline.
Interrupt ALYFTREK for significant elevations in LFTs 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 resolved, resume treatment only if benefit is expected to outweigh risk. Closer monitoring is advised after resuming ALYFTREK.
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 benefit outweighs risk. If used, monitor patients closely.
Warnings and Precautions
Drug-Induced Liver Injury and Liver Failure
- Assess LFTs (ALT, AST, alkaline phosphatase, and bilirubin) in all patients prior to initiating ALYFTREK, every month during the first 6 months of treatment, every 3 months for the next 12 months, and at least annually thereafter. Consider more frequent monitoring in patients with a history of liver disease, elevated LFTs at baseline, or a history of elevated LFTs with drugs containing ELX, TEZ, and/or IVA
- Interrupt ALYFTREK in the event of signs or symptoms of liver injury, which may include:
- Significant elevations in LFTs (e.g., ALT or AST >5x the upper limit of normal (ULN) or ALT or AST >3x ULN with bilirubin >2x 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 resolved and if benefit is expected to outweigh risk, resume ALYFTREK with close monitoring
- ALYFTREK should not be used in patients with severe hepatic impairment. ALYFTREK is not recommended in patients with moderate hepatic impairment and should only be considered when there is a clear medical need and benefit outweighs risk. If used, monitor patients closely
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 (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 benefits and risks for the individual patient to determine whether to resume ALYFTREK
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 ELX/TEZ/IVA 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
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
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 adverse reactions associated with ALYFTREK. Reduce the ALYFTREK dosage with concomitant use of strong or moderate CYP3A inhibitors
Cataracts
- Non-congenital lens opacities have been reported in pediatric patients treated with drugs containing ivacaftor (similar to an active ingredient in ALYFTREK). Baseline and follow-up ophthalmological examinations are recommended in pediatric patients treated with ALYFTREK
Adverse Reactions
Serious Adverse Reactions
- Serious adverse reactions that occurred more frequently with ALYFTREK than with ELX/TEZ/IVA 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%)
Most Common Adverse Reactions
- The most common adverse reactions to ALYFTREK (≥5% of patients and at a frequency higher than ELX/TEZ/IVA by ≥1%) were cough, nasopharyngitis, upper respiratory tract infection, headache, oropharyngeal pain, influenza, fatigue, increased ALT, rash, increased AST, and sinus congestion
Use in Specific Populations
Pediatric Use
- The safety and effectiveness of ALYFTREK in patients <6 years of age have not been established
Please see full Prescribing Information, including Boxed WARNING, for ALYFTREK.
References:
1. ALYFTREK [prescribing information]. Boston, MA: Vertex Pharmaceuticals Incorporated; December 2024. 2. Keating C, Yonker LM, Vermeulen F, et al. Vanzacaftor–tezacaftor–deutivacaftor versus elexacaftor–tezacaftor–ivacaftor in individuals with cystic fibrosis aged 12 years and older (SKYLINE Trials VX20-121-102 and VX20-121-103): Results from two randomised, active-controlled, Phase 3 trials. Lancet Respir Med. 2025. doi:10.1016/2213-2600(24)00411-9. 3. Supplement to: Keating C, Yonker LM, Vermeulen F, et al. Vanzacaftor–tezacaftor–deutivacaftor versus elexacaftor–tezacaftor–ivacaftor in individuals with cystic fibrosis aged 12 years and older (SKYLINE Trials VX20-121-102 and VX20-121-103): Results from two randomised, active-controlled, Phase 3 trials. Lancet Respir Med. 2025. doi:10.1016/2213-2600(24)00411-9. 4. Data on file. Vertex Pharmaceuticals Incorporated. Boston, MA. REF-28934 (v1.0); 2024. 5. Data on file. Vertex Pharmaceuticals Incorporated. Boston, MA. REF-28378 (v1.0); 2024.