Safety data from 510 patients aged 12 years and older with CF with at least one F508del mutation in 2 double‑blind, controlled, Phase 3 trials of 24 weeks (Trial 1) and 4 weeks (Trial 2) treatment duration1
- Except where otherwise noted, the safety data provided below are from Trial 1, the placebo-controlled 24-week trial with patients heterozygous for F508del and another specific mutation. The safety profiles for the patients with CF enrolled in Trials 2, 3, and 4 were similar to that observed in Trial 1
- With the exception of sex differences in rash, the safety profile of TRIKAFTA was generally similar across all subgroups of patients regardless of age, sex, baseline ppFEV₁, and geographic region
Adverse event-related discontinuations1,2
1% OF PATIENTS
TREATED WITH TRIKAFTA (n=2)
0% OF PATIENTS
TREATED WITH PLACEBO (n=0)
Serious adverse reactions1-5
- In Trial 1, serious adverse reactions that occurred more frequently in patients treated with TRIKAFTA compared to placebo were rash (1% vs <1%) and influenza (1% vs 0%). There were no deaths in Trials 1, 2, 3, and 4
Most common adverse reactions in Trial 11
Incidence of adverse drug reactions in ≥5% of patients treated with TRIKAFTA and higher than placebo by ≥1%
TRIKAFTA n (%) (N=202)
Placebo n (%) (N=201)
Headache
35 (17)
30 (15)
Upper respiratory tract infection*
32 (16)
25 (12)
Abdominal pain†
29 (14)
18 (9)
Diarrhea
26 (13)
14 (7)
Rash‡
21 (10)
10 (5)
ALT increased
20 (10)
7 (3)
Nasal congestion
19 (9)
15 (7)
Blood CPK increased
19 (9)
9 (4)
AST increased
19 (9)
4 (2)
Rhinorrhea
17 (8)
6 (3)
Rhinitis
15 (7)
11 (5)
Influenza
14 (7)
3 (1)
Sinusitis
11 (5)
8 (4)
Blood bilirubin increased
10 (5)
2 (1)
TRIKAFTA n (%) (N=202)
Headache
35 (17)
Upper respiratory tract infection*
32 (16)
Abdominal pain†
29 (14)
Diarrhea
26 (13)
Rash‡
21 (10)
ALT increased
20 (10)
Nasal congestion
19 (9)
Blood CPK increased
19 (9)
AST increased
19 (9)
Rhinorrhea
17 (8)
Rhinitis
15 (7)
Influenza
14 (7)
Sinusitis
11 (5)
Blood bilirubin increased
10 (5)
Placebo n (%) (N=201)
Headache
30 (15)
Upper respiratory tract infection*
25 (12)
Abdominal pain†
18 (9)
Diarrhea
14 (7)
Rash‡
10 (5)
ALT increased
7 (3)
Nasal congestion
15 (7)
Blood CPK increased
9 (4)
AST increased
4 (2)
Rhinorrhea
6 (3)
Rhinitis
11 (5)
Influenza
3 (1)
Sinusitis
8 (4)
Blood bilirubin increased
2 (1)
*Includes upper respiratory tract infection and viral upper respiratory tract infection.
†Includes abdominal pain, abdominal pain upper, and abdominal pain lower.
‡Includes rash, rash generalized, rash erythematous, rash macular, and rash pruritic.
- Additional adverse reactions that occurred in TRIKAFTA-treated patients at a frequency of 2% to <5% and higher than placebo ≥1% include the following: Flatulence, abdominal distension, conjunctivitis, pharyngitis, respiratory tract infection, tonsillitis, urinary tract infection, c-reactive protein increased, hypoglycemia, dizziness, dysmenorrhea, acne, eczema, and pruritus.
Rash events1
- The overall incidence of rash events was 10% in patients treated with TRIKAFTA and 5% in placebo-treated patients
- The incidence of rash events was higher in female patients treated with TRIKAFTA (16%) than in male patients treated with TRIKAFTA (5%)
- A role of hormonal contraceptives in the occurrence of rash cannot be excluded
Additional information on rash6
- The median time to onset of first rash event was 12 days (range 5-157 days) in patients treated with TRIKAFTA and 23 days (range 1-157 days) in placebo-treated patients. The median duration of rash events was 8 days (range 1-92 days) in patients treated with TRIKAFTA and 9 days (range 3-61 days) in placebo-treated patients
- The rash events were exanthematous—consistent with a typical drug eruption
Laboratory and vital sign abnormalities
Liver function test elevations1,7
TRIKAFTA (N=202) |
Placebo (N=201) |
|||||
---|---|---|---|---|---|---|
Elevated ALT or AST, n (%) | >3x ULN | 16 (8) | 11 (5) | |||
>5x ULN | 5 (2) | 3 (1) | ||||
>8x ULN | 3 (1) | 2 (1) | ||||
Total bilirubin elevation >2x ULN, % | 4 | <1 |
TRIKAFTA (N=202) | ||
---|---|---|
Elevated ALT or AST, n (%) | >3x ULN | 16 (8) |
>5x ULN | 5 (2) | |
>8x ULN | 3 (1) | |
Total bilirubin elevation >2x ULN, % | 4 | |
Placebo (N=201) | ||
Elevated ALT or AST, n (%) | >3x ULN | 11 (5) |
>5x ULN | 3 (1) | |
>8x ULN | 2 (1) | |
Total bilirubin elevation >2x ULN, % | <1 |
- The incidence of adverse reactions of transaminase elevations (AST and/or ALT) was 11% in patients treated with TRIKAFTA and 4% in placebo-treated patients1
- No patients treated with TRIKAFTA discontinued due to transaminase elevations2
- Maximum indirect bilirubin elevations >1.5x ULN occurred in 11% of patients treated with TRIKAFTA. Maximum direct bilirubin elevations >1.5x ULN occurred in 3% of patients treated with TRIKAFTA1
- No patients treated with TRIKAFTA developed maximum direct bilirubin elevation >2x ULN1
Increased creatine phosphokinase1
- The incidence of maximum CPK >5x ULN was 10% in patients treated with TRIKAFTA and 5% in placebo-treated patients
- Among the patients treated with TRIKAFTA with CPK elevation >5x ULN, 14% (3/21) required treatment interruption and none discontinued treatment
Increased blood pressure1
TRIKAFTA (N=202) | Placebo (N=201) | |||||
---|---|---|---|---|---|---|
Mean systolic blood pressure, mmHg | Baseline | 113 | 114 | |||
Maximum increase from baseline | 3.5 | 0.9 | ||||
Mean diastolic blood pressure, mmHg | Baseline | 69 | 70 | |||
Maximum increase from baseline | 1.9 | 0.5 |
Mean systolic blood pressure (mmHg) |
TRIKAFTA (N=202) |
Baseline 113 |
Maximum increase from baseline 3.5 |
Placebo (N=201) |
Baseline 114 |
Maximum increase from baseline 0.9 |
Mean diastolic blood pressure (mmHg) |
TRIKAFTA (N=202) |
Baseline 69 |
Maximum increase from baseline 1.9 |
Placebo (N=201) |
Baseline 70 |
Maximum increase from baseline 0.5 |
- The proportion of patients who had an increase in systolic blood pressure of >140 mmHg and 10 mmHg from baseline on at least 2 occasions:
- 4% of patients treated with TRIKAFTA and 1% of placebo-treated patients
- The proportion of patients who had an increase in diastolic blood pressure of >90 mmHg and 5 mmHg from baseline on at least 2 occasions:
- 1% of patients treated with TRIKAFTA and 2% of placebo-treated patients
Safety data from postmarketing experience1
The following adverse reactions have been identified during postapproval use of TRIKAFTA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
- Hepatobiliary: liver injury, fatal liver failure, liver transplantation
- Immune System Disorders: anaphylaxis, angioedema
ALT, alanine aminotransferase; AST, aspartate aminotransferase; CPK, creatine phosphokinase; ULN, upper limit of normal.
IMPORTANT SAFETY INFORMATION
WARNING: DRUG-INDUCED LIVER INJURY AND LIVER FAILURE
- TRIKAFTA can cause serious and potentially fatal drug-induced liver injury. Cases of liver failure leading to transplantation and death have been reported in patients with and without a history of liver disease taking TRIKAFTA, in both clinical trials and the postmarketing setting. Liver injury has been reported within the first month of therapy and up to 15 months following initiation of TRIKAFTA.
- Assess liver function tests (ALT, AST, alkaline phosphatase, and bilirubin) in all patients prior to initiating TRIKAFTA, then 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 liver function test (LFT) elevations at baseline.
- Interrupt TRIKAFTA 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 TRIKAFTA.
- TRIKAFTA should not be used in patients with severe hepatic impairment (Child-Pugh Class C). TRIKAFTA is not recommended in patients with moderate hepatic impairment (Child-Pugh Class B). If used, use with caution at a reduced dosage and monitor patients closely.
INDICATIONS AND USAGE
TRIKAFTA is indicated for the treatment of cystic fibrosis (CF) in patients aged 2 years and older who have at least one F508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene or a mutation in the CFTR gene that is responsive based on clinical and/or in vitro data.
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.
WARNINGS AND PRECAUTIONS
Drug-Induced Liver Injury and Liver Failure
- TRIKAFTA can cause serious and potentially fatal drug-induced liver injury. Liver failure leading to transplantation and death has been reported in patients with and without a history of liver disease taking TRIKAFTA. Liver injury has been reported within the first month of therapy and up to 15 months following initiation of TRIKAFTA
- Assess LFTs (ALT, AST, alkaline phosphatase, and bilirubin) in all patients prior to initiating TRIKAFTA, then 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 LFT elevations at baseline
- Interrupt TRIKAFTA 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 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 TRIKAFTA with close monitoring
- TRIKAFTA should not be used in patients with severe hepatic impairment. TRIKAFTA 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, use with caution at a reduced dosage and monitor patients closely
Hypersensitivity Reactions, Including Anaphylaxis
- Hypersensitivity reactions, including cases of angioedema and anaphylaxis, have been reported in the postmarketing setting. If signs or symptoms of serious hypersensitivity reactions develop during treatment, discontinue TRIKAFTA and institute appropriate therapy. Consider benefits and risks for the individual patient to determine whether to resume treatment with TRIKAFTA
Concomitant Use With CYP3A Inducers
- Exposure to ivacaftor is significantly decreased and exposure to elexacaftor and tezacaftor are expected to decrease by concomitant use of strong CYP3A inducers, which may reduce therapeutic effectiveness of TRIKAFTA. Concomitant use with strong CYP3A inducers is not recommended
Concomitant Use With CYP3A Inhibitors
- Exposure to elexacaftor, tezacaftor, and ivacaftor are increased when used concomitantly with strong or moderate CYP3A inhibitors. The dose of TRIKAFTA should be reduced when used concomitantly with moderate or strong CYP3A inhibitors
Cataracts
- Non-congenital lens opacities have been reported in pediatric patients treated with ivacaftor-containing regimens. Baseline and follow‑up ophthalmological examinations are recommended in pediatric patients initiating treatment with TRIKAFTA
ADVERSE REACTIONS
Serious Adverse Reactions
- Serious adverse reactions that occurred more frequently in patients treated with TRIKAFTA compared to placebo were rash (1% vs <1%) and influenza (1% vs 0%)
Most Common Adverse Reactions
- The most common adverse reactions occurring in ≥5% of patients treated with TRIKAFTA and higher than placebo by ≥1% were headache, upper respiratory tract infection, abdominal pain, diarrhea, rash, alanine aminotransferase increased, nasal congestion, blood creatine phosphokinase increased, aspartate aminotransferase increased, rhinorrhea, rhinitis, influenza, sinusitis, blood bilirubin increased and constipation
USE IN SPECIFIC POPULATIONS
Pediatric Use
- The safety and effectiveness of TRIKAFTA in patients with CF younger than 2 years of age have not been established
Please see full Prescribing Information, including Boxed WARNING.
References:
1. TRIKAFTA [prescribing information]. Boston, MA: Vertex Pharmaceuticals Incorporated; August 2023. 2. Middleton PG, Mall MA, Drevinek P, et al. Elexacaftor–tezacaftor–ivacaftor for cystic fibrosis with a single Phe508del allele. N Engl J Med. 2019;381(19):1809-1819. 3.Heijerman HG, McKone EF, Downey DG, et al. Efficacy and safety of the elexacaftor plus tezacaftor plus ivacaftor combination regimen in people with cystic fibrosis homozygous for the F508del mutation: a double-blind, randomised, phase 3 trial [published correction appears in Lancet. 2020;395(10238):1694]. Lancet. 2019;394(10212):1940-1948. doi:10.1016/S0140-6736(19)32597-8 4. Zemanick ET, Taylor-Cousar JL, Davies J, et al. A phase 3 open-label study of ELX/TEZ/IVA in children 6 through 11 years of age with CF and at least one F508del allele. Am J Respir Crit Care Med. 2021;203(12):1522-1532. doi:10.1164/rccm.202102-0509OC 5. A phase 3 study evaluating the safety, tolerability, and pharmacokinetics of elexacaftor/tezacaftor/ivacaftor triple combination therapy in cystic fibrosis subjects 2 through 5 years of age. European Union Clinical Trials Register. Updated October 21, 2021. Accessed January 2, 2025. https://www.clinicaltrialsregister.eu/ctr-search/rest/download/result/zip/pdf/2020-002251-38/1 6. Data on file. Vertex Pharmaceuticals Incorporated. Boston, MA. REF-3535 (v1.0); 2019. 7. Data on file. Vertex Pharmaceuticals Incorporated. Boston, MA. REF-3493 (v1.0); 2019.