Safety Profile
SAFETY DATA FROM 3 PLACEBO-CONTROLLED CLINICAL TRIALS1
- The overall safety profile is based on data from three double-blind, placebo-controlled Phase 3 clinical trials: 2 parallel-group trials of 12- and 24-week duration and one cross-over design trial of 8-week duration. Eligible patients were also able to participate in an open‑label extension safety study (up to 96 weeks of SYMDEKO)
- In the three placebo-controlled Phase 3 trials, a total of 496 patients with CF aged 12 years and older received at least one dose of SYMDEKO
- The proportion of patients who discontinued study drug prematurely due to adverse events was1:
1.6% OF PATIENTS
TREATED WITH SYMDEKO
2.0% OF PATIENTS
TREATED WITH PLACEBO
- The safety profile of SYMDEKO was generally similar across all subgroups of patients, including analysis by age, sex, baseline ppFEV1, and geographic regions1
Laboratory abnormalities: Transaminase elevations¹
Incidence of maximum transaminases during placebo-controlled trials1
Elevated ALT or AST
SYMDEKO
Placebo
>3 x ULN
3.4%
3.4%
>5 x ULN
1.0%
1.0%
>8 x ULN
0.2%
0.4%
- The incidence of transaminase elevations was similar between treatment groups
- One patient (0.2%) on SYMDEKO and 2 patients (0.4%) on placebo permanently discontinued treatment for elevated transaminases
- No patients treated with SYMDEKO experienced a transaminase elevation >3 x ULN associated with elevated total bilirubin >2 x ULN
CATARACTS1
- Cases of non-congenital lens opacities have been reported in pediatric patients treated with SYMDEKO, as well as with ivacaftor monotherapy. Baseline and follow-up ophthalmological examinations are recommended in pediatric patients initiating treatment with SYMDEKO
SERIOUS ADVERSE REACTIONS1
- Serious adverse reactions, whether considered drug-related or not by the investigators, that occurred more frequently in patients treated with SYMDEKO compared to placebo included distal intestinal obstruction syndrome, 3 (0.6%) patients treated with SYMDEKO vs. 0 placebo patients
MOST COMMON ADVERSE REACTIONS1
Incidence of adverse reactions in ≥3% of patients taking SYMDEKO and greater than placebo (EVOLVE [Trial 1] and Trial 3*)1
Adverse Reactions
(Preferred Term)
SYMDEKO (N=334)
n (%)
Placebo (N=343)
n (%)
Headache
49 (15)
44 (13)
Nausea
29 (9)
24 (7)
Sinus congestion
13 (4)
6 (2)
Dizziness
12 (4)
8 (2)
- The safety profile for patients with CF enrolled in EXPAND (Trial 2) was similar to that observed in EVOLVE and Trial 31
*Trial 3 was a two-arm study that compared SYMDEKO to placebo in patients with CF aged 12 years and older who were heterozygous for the F508del mutation and had a second CFTR mutation not responsive to SYMDEKO. This study was terminated following the planned interim analysis because the pre-specified futility criteria were met.1
RATES OF RESPIRATORY ADVERSE EVENTS2,a
11.3% OF PATIENTS
TREATED WITH SYMDEKO (N=56)
14.7% OF PATIENTS
TREATED WITH PLACEBO (N=74)
Pooled analysis of respiratory events2,a
Respiratory Events
SYMDEKO (N=496)
Patients with events, n (%)
Placebo (N=505)
Patients with events, n (%)
Dyspnea
30 (6.0)
36 (7.1)
Respiration abnormal
15 (3.0)
20 (4.0)
Wheezing
9 (1.8)
13 (2.6)
Asthma
4 (0.8)
6 (1.2)
Chest discomfort
3 (0.6)
3 (0.6)
Bronchospasm
2 (0.4)
4 (0.8)
Bronchial hyperreactivity
0
0
aData pooled from EVOLVE (Trial 1), EXPAND (Trial 2), and Trial 3.1
PATIENTS WITH SEVERE LUNG DYSFUNCTION (ppFEV1 <40)1
- EVOLVE (Trial 1) and EXPAND (Trial 2) included a total of 39 patients treated with SYMDEKO with ppFEV1 <40 at baseline (range 30 to 40)
- In EVOLVE, 23 patients treated with SYMDEKO and 24 placebo-treated patients had ppFEV1 <40
- In EXPAND, 16 patients treated with SYMDEKO, 15 placebo-treated, and 13 ivacaftor-treated patients had ppFEV1 <40
- The safety profile in this subgroup was comparable to the overall results observed in both EVOLVE and EXPAND
ALT, alanine transaminase; AST, aspartate transaminase; ppFEV1, percent predicted forced expiratory volume in 1 second; ULN, upper limit of normal.
INDICATIONS AND USAGE
SYMDEKO is indicated for the treatment of cystic fibrosis (CF) in patients age 6 years and older who are homozygous for the F508del mutation or who have at least one mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene that is responsive to tezacaftor/ivacaftor based on in vitro data and/or clinical evidence.
If the patient’s genotype is unknown, an FDA-cleared CF mutation test should be used to detect the presence of a CFTR mutation followed by verification with bi-directional sequencing when recommended by the mutation test instructions for use.
INDICATIONS AND USAGE
SYMDEKO is indicated for the treatment of cystic fibrosis (CF) in patients age 6 years and older who are homozygous for the F508del mutation or who have at least one mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene that is responsive to tezacaftor/ivacaftor based on in vitro data and/or clinical evidence.
If the patient’s genotype is unknown, an FDA-cleared CF mutation test should be used to detect the presence of a CFTR mutation followed by verification with bi-directional sequencing when recommended by the mutation test instructions for use.
IMPORTANT SAFETY INFORMATION
WARNINGS AND PRECAUTIONS
Transaminase (ALT or AST) Elevations
- Elevated transaminases have been observed in patients with CF receiving SYMDEKO, as well as with ivacaftor monotherapy. Assessments of transaminases (ALT and AST) are recommended prior to initiating SYMDEKO, every 3 months during the first year of treatment, and annually thereafter. For patients with a history of transaminase elevations, more frequent monitoring should be considered
- Dosing should be interrupted in patients with significant elevations of transaminases (e.g., ALT or AST >5x upper limit of normal [ULN], or ALT or AST >3x ULN with bilirubin >2x ULN) and laboratory tests should be closely followed until abnormalities resolve. Following resolution of transaminase elevations, consider the benefits and risks of resuming treatment
Hypersensitivity Reactions, Including Anaphylaxis
- Hypersensitivity reactions, including cases of anaphylaxis, have been reported in the postmarketing setting. If signs or symptoms of serious hypersensitivity reactions develop during treatment, discontinue SYMDEKO and institute appropriate therapy. Consider the benefits and risks for the individual patient to determine whether to resume treatment with SYMDEKO
Concomitant Use With CYP3A Inducers
- Exposure to ivacaftor is significantly decreased and exposure to tezacaftor may be reduced by concomitant use of CYP3A inducers, which may reduce the therapeutic effectiveness of SYMDEKO. Co-administration of SYMDEKO with strong CYP3A inducers, such as rifampin, rifabutin, phenobarbital, carbamazepine, phenytoin, and St. John’s wort, is not recommended
Cataracts
- Cases of non-congenital lens opacities have been reported in pediatric patients treated with SYMDEKO, as well as with ivacaftor monotherapy. Baseline and follow-up ophthalmological examinations are recommended in pediatric patients initiating treatment with SYMDEKO
ADVERSE REACTIONS
Serious Adverse Reactions
- Serious adverse reactions, whether considered drug-related or not by the investigators, that occurred more frequently in patients treated with SYMDEKO compared to placebo included distal intestinal obstruction syndrome, 3 (0.6%) patients treated with SYMDEKO vs. 0 placebo patients
Most Common Adverse Reactions
- The most common adverse reactions in Trials 1 and 3 occurring in ≥3% of patients treated with SYMDEKO (N=334) and at a higher rate than for placebo (N=343) were headache, nausea, sinus congestion, and dizziness
- The safety profile in patients age 6 to less than 12 years from an open-label Phase 3 trial (N=70) was similar to that observed in Trials 1 and 3
USE IN SPECIFIC POPULATION
Pediatric Use
- The safety and effectiveness of SYMDEKO in patients with CF younger than 6 years of age have not been studied
Click here to access full Prescribing Information.
References:
1. SYMDEKO [prescribing information]. Boston, MA: Vertex Pharmaceuticals Incorporated; August 2023. 2. Data on file. Vertex Pharmaceuticals Incorporated. Boston, MA. REF-0004 (v2.0); 2019.
INDICATIONS AND USAGE
SYMDEKO is indicated for the treatment of cystic fibrosis (CF) in patients age 6 years and older who are homozygous for the F508del mutation or who have at least one mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene that is responsive to tezacaftor/ivacaftor based on in vitro data and/or clinical evidence.
If the patient’s genotype is unknown, an FDA-cleared CF mutation test should be used to detect the presence of a CFTR mutation followed by verification with bi-directional sequencing when recommended by the mutation test instructions for use.
IMPORTANT SAFETY INFORMATION
WARNINGS AND PRECAUTIONS
Transaminase (ALT or AST) Elevations
- Elevated transaminases have been observed in patients with CF receiving SYMDEKO, as well as with ivacaftor monotherapy. Assessments of transaminases (ALT and AST) are recommended prior to initiating SYMDEKO, every 3 months during the first year of treatment, and annually thereafter. For patients with a history of transaminase elevations, more frequent monitoring should be considered
- Dosing should be interrupted in patients with significant elevations of transaminases (e.g., ALT or AST >5x upper limit of normal [ULN], or ALT or AST >3x ULN with bilirubin >2x ULN) and laboratory tests should be closely followed until abnormalities resolve. Following resolution of transaminase elevations, consider the benefits and risks of resuming treatment
Hypersensitivity Reactions, Including Anaphylaxis
- Hypersensitivity reactions, including cases of anaphylaxis, have been reported in the postmarketing setting. If signs or symptoms of serious hypersensitivity reactions develop during treatment, discontinue SYMDEKO and institute appropriate therapy. Consider the benefits and risks for the individual patient to determine whether to resume treatment with SYMDEKO
Concomitant Use With CYP3A Inducers
- Exposure to ivacaftor is significantly decreased and exposure to tezacaftor may be reduced by concomitant use of CYP3A inducers, which may reduce the therapeutic effectiveness of SYMDEKO. Co-administration of SYMDEKO with strong CYP3A inducers, such as rifampin, rifabutin, phenobarbital, carbamazepine, phenytoin, and St. John’s wort, is not recommended
Cataracts
- Cases of non-congenital lens opacities have been reported in pediatric patients treated with SYMDEKO, as well as with ivacaftor monotherapy. Baseline and follow-up ophthalmological examinations are recommended in pediatric patients initiating treatment with SYMDEKO
ADVERSE REACTIONS
Serious Adverse Reactions
- Serious adverse reactions, whether considered drug-related or not by the investigators, that occurred more frequently in patients treated with SYMDEKO compared to placebo included distal intestinal obstruction syndrome, 3 (0.6%) patients treated with SYMDEKO vs. 0 placebo patients
Most Common Adverse Reactions
- The most common adverse reactions in Trials 1 and 3 occurring in ≥3% of patients treated with SYMDEKO (N=334) and at a higher rate than for placebo (N=343) were headache, nausea, sinus congestion, and dizziness
- The safety profile in patients age 6 to less than 12 years from an open-label Phase 3 trial (N=70) was similar to that observed in Trials 1 and 3
USE IN SPECIFIC POPULATIONS
Pediatric Use
- The safety and effectiveness of SYMDEKO in patients with CF younger than 6 years of age have not been studied
Click here to access full Prescribing Information.
References:
1. SYMDEKO [prescribing information]. Boston, MA: Vertex Pharmaceuticals Incorporated; August 2023. 2. Data on file. Vertex Pharmaceuticals Incorporated. Boston, MA. REF-0004 (v2.0); 2019.