FOR PATIENTS WITH CF AGED 6 YEARS AND OLDER WITH AT LEAST ONE MUTATION THAT IS RESPONSIVE TO SYMDEKO1
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Indications and Usage
SYMDEKO® (tezacaftor/ivacaftor and ivacaftor) 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
Transaminase (ALT or AST) Elevations
- Elevated transaminases have been observed in patients with CF treated with 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
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
Pediatric Use
- The safety and effectiveness of SYMDEKO in patients with CF younger than 6 years of age have not been studied
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
Click here to access full Prescribing Information.
Reference:
1. SYMDEKO [prescribing information]. Boston, MA: Vertex Pharmaceuticals Incorporated; December 2020.
References:
1. SYMDEKO [prescribing information]. Boston, MA: Vertex Pharmaceuticals Incorporated; December 2020. 2. The Clinical and Functional Translation of CFTR (CFTR2); Available at http://cftr2.org. List of CFTR2 mutations. https://www.cftr2.org/mutations_history/CFTR2_11March2019.xlsx. Accessed December 1, 2020. 3. National Center for Biotechnology Information. ClinVar. Available at https://www.ncbi.nlm.nih.gov/clinvar/. Accessed December 1, 2020.
References:
1. SYMDEKO [prescribing information]. Boston, MA: Vertex Pharmaceuticals Incorporated; June 2019. 2. Taylor-Cousar JL, Munck A, McKone EF, et al. Tezacaftor-ivacaftor in patients with cystic fibrosis homozygous for phe508del. N Engl J Med. 2017;377(21):2013-2023. 3. Cystic Fibrosis Foundation. Patient Registry Annual Data Report 2015. Bethesda, MD. Cystic Fibrosis Foundation; 2016. 4. Taylor-Cousar JL, Munck A, McKone EF, et al. Tezacaftor-ivacaftor in patients with cystic fibrosis homozygous for phe508del. NEngl J Med. 2017;377(21)(suppl1-29):2013-2023. 5. Data on file. Vertex Pharmaceuticals Incorporated. Boston, MA. REF-0258 (v2.0); 2019. 6. Data on file. Vertex Pharmaceuticals Incorporated. Boston, MA. REF-0551 (v2.0); 2019. 7. Quittner AL, Modi AC, Wainwright C, Otto K, Kirihara J, Montgomery AB. Determination of the minimal clinically important difference scores for the Cystic Fibrosis Questionnaire-Revised respiratory symptom scale in two populations of patients with cystic fibrosis and chronic Pseudomonas aeruginosa airway infection. Chest. 2009;135(6):1610-1618.
References:
1. SYMDEKO [prescribing information]. Boston, MA: Vertex Pharmaceuticals Incorporated; June 2019. 2. Rowe SM, Daines C, Ringshausen FC, et al. Tezacaftor-ivacaftor in residual-function heterozygotes with cystic fibrosis. N Engl J Med. 2017;377(21):2024-2035. 3. Rowe SM, Daines C, Ringshausen FC, et al. Tezacaftor-ivacaftor in residual-function heterozygotes with cystic fibrosis. N Engl J Med. 2017;377(21)(suppl1-25):2024-2035. 4. CFQ-R Cystic Fibrosis Questionnaire-REVISED. Cystic Fibrosis Foundation. Quittner, Modi, Watrous and Messer, 2000. Revised 2002. CFQ-R—Parent, English Version 2.0. 5. Quittner AL, Modi AC, Wainwright C, Otto K, Kirihara J, Montgomery AB. Determination of the minimal clinically important difference scores for the Cystic Fibrosis Questionnaire-Revised respiratory symptom scale in two populations of patients with cystic fibrosis and chronic Pseudomonas aeruginosa airway infection. Chest. 2009;135(6):1610-1618.
References:
1. SYMDEKO [prescribing information]. Boston, MA: Vertex Pharmaceuticals Incorporated; December 2020. 2. Walker S, Flume P, McNamara J, et al. A phase 3 study of tezacaftor in combination with ivacaftor in children aged 6 to 11 years with cystic fibrosis. J Cyst Fibros. 2019:1-6. doi: 10.1016/j.jcf.2019.06.009. 3. Walker S, Flume P, McNamara J, et al. A phase 3 study of tezacaftor in combination with ivacaftor in children aged 6 to 11 years with cystic fibrosis. J Cyst Fibros. 2019:(suppl1-10). doi: 10.1016/j.jcf.2019.06.009. 4. Data on file. Vertex Pharmaceuticals Incorporated. Boston, MA. REF-2254; 2019. 5. CFQ-R Cystic Fibrosis Questionnaire- REVISED. Cystic Fibrosis Foundation. Quittner, Modi, Watrous and Messer, 2000. Revised 2002. CFQ-R—Parent, English Version 2.0.
References:
1. SYMDEKO [prescribing information]. Boston, MA: Vertex Pharmaceuticals Incorporated; December 2020. 2. Data on file. Vertex Pharmaceuticals Incorporated. Boston, MA. REF-0004 (v2.0); 2019.
References:
1. SYMDEKO [prescribing information]. Boston, MA: Vertex Pharmaceuticals Incorporated; December 2020. 2. Fauci AS, Braunwald E, Kasper DL, et al, eds. Harrison’s Manual of Medicine. 17th ed. New York, NY: McGraw-Hill Medical; 2009.
References:
1. SYMDEKO [prescribing information]. Boston, MA: Vertex Pharmaceuticals Incorporated; December 2020. 2. Data on file. Vertex Pharmaceuticals Incorporated. Boston, MA. REF-3538; 2019. 3. FDA U.S. Food & Drug Administration. Drugs@FDA: FDA-Approved Drugs. https://www.accessdata.fda.gov/scripts/cder/daf/. Accessed February 1, 2020. 4. Kunze A, Huwyler J, Camenisch G, Poller B. Prediction of organic anion-transporting polypeptide 1B1- and 1B3-mediated hepatic uptake of statins based on transporter protein expression and activity data. Drug Metab Dispos. 2014;42(9):1514-1521.
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Indications and Usage
SYMDEKO® (tezacaftor/ivacaftor and ivacaftor) 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
Transaminase (ALT or AST) Elevations
- Elevated transaminases have been observed in patients with CF treated with 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
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
Pediatric Use
- The safety and effectiveness of SYMDEKO in patients with CF younger than 6 years of age have not been studied
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
Click here to access full Prescribing Information.
Reference:
1. SYMDEKO [prescribing information]. Boston, MA: Vertex Pharmaceuticals Incorporated; December 2020.
References:
1. SYMDEKO [prescribing information]. Boston, MA: Vertex Pharmaceuticals Incorporated; December 2020. 2. The Clinical and Functional Translation of CFTR (CFTR2); Available at http://cftr2.org. List of CFTR2 mutations. https://www.cftr2.org/mutations_history/CFTR2_11March2019.xlsx. Accessed December 1, 2020. 3. National Center for Biotechnology Information. ClinVar. Available at https://www.ncbi.nlm.nih.gov/clinvar/. Accessed December 1, 2020.
References:
1. SYMDEKO [prescribing information]. Boston, MA: Vertex Pharmaceuticals Incorporated; June 2019. 2. Taylor-Cousar JL, Munck A, McKone EF, et al. Tezacaftor-ivacaftor in patients with cystic fibrosis homozygous for phe508del. N Engl J Med. 2017;377(21):2013-2023. 3. Cystic Fibrosis Foundation. Patient Registry Annual Data Report 2015. Bethesda, MD. Cystic Fibrosis Foundation; 2016. 4. Taylor-Cousar JL, Munck A, McKone EF, et al. Tezacaftor-ivacaftor in patients with cystic fibrosis homozygous for phe508del. NEngl J Med. 2017;377(21)(suppl1-29):2013-2023. 5. Data on file. Vertex Pharmaceuticals Incorporated. Boston, MA. REF-0258 (v2.0); 2019. 6. Data on file. Vertex Pharmaceuticals Incorporated. Boston, MA. REF-0551 (v2.0); 2019. 7. Quittner AL, Modi AC, Wainwright C, Otto K, Kirihara J, Montgomery AB. Determination of the minimal clinically important difference scores for the Cystic Fibrosis Questionnaire-Revised respiratory symptom scale in two populations of patients with cystic fibrosis and chronic Pseudomonas aeruginosa airway infection. Chest. 2009;135(6):1610-1618.
References:
1. SYMDEKO [prescribing information]. Boston, MA: Vertex Pharmaceuticals Incorporated; June 2019. 2. Rowe SM, Daines C, Ringshausen FC, et al. Tezacaftor-ivacaftor in residual-function heterozygotes with cystic fibrosis. N Engl J Med. 2017;377(21):2024-2035. 3. Rowe SM, Daines C, Ringshausen FC, et al. Tezacaftor-ivacaftor in residual-function heterozygotes with cystic fibrosis. N Engl J Med. 2017;377(21)(suppl1-25):2024-2035. 4. CFQ-R Cystic Fibrosis Questionnaire-REVISED. Cystic Fibrosis Foundation. Quittner, Modi, Watrous and Messer, 2000. Revised 2002. CFQ-R—Parent, English Version 2.0. 5. Quittner AL, Modi AC, Wainwright C, Otto K, Kirihara J, Montgomery AB. Determination of the minimal clinically important difference scores for the Cystic Fibrosis Questionnaire-Revised respiratory symptom scale in two populations of patients with cystic fibrosis and chronic Pseudomonas aeruginosa airway infection. Chest. 2009;135(6):1610-1618.
References:
1. SYMDEKO [prescribing information]. Boston, MA: Vertex Pharmaceuticals Incorporated; December 2020. 2. Walker S, Flume P, McNamara J, et al. A phase 3 study of tezacaftor in combination with ivacaftor in children aged 6 to 11 years with cystic fibrosis. J Cyst Fibros. 2019:1-6. doi: 10.1016/j.jcf.2019.06.009. 3. Walker S, Flume P, McNamara J, et al. A phase 3 study of tezacaftor in combination with ivacaftor in children aged 6 to 11 years with cystic fibrosis. J Cyst Fibros. 2019:(suppl1-10). doi: 10.1016/j.jcf.2019.06.009. 4. Data on file. Vertex Pharmaceuticals Incorporated. Boston, MA. REF-2254; 2019. 5. CFQ-R Cystic Fibrosis Questionnaire- REVISED. Cystic Fibrosis Foundation. Quittner, Modi, Watrous and Messer, 2000. Revised 2002. CFQ-R—Parent, English Version 2.0.
References:
1. SYMDEKO [prescribing information]. Boston, MA: Vertex Pharmaceuticals Incorporated; December 2020. 2. Data on file. Vertex Pharmaceuticals Incorporated. Boston, MA. REF-0004 (v2.0); 2019.
References:
1. SYMDEKO [prescribing information]. Boston, MA: Vertex Pharmaceuticals Incorporated; December 2020. 2. Fauci AS, Braunwald E, Kasper DL, et al, eds. Harrison’s Manual of Medicine. 17th ed. New York, NY: McGraw-Hill Medical; 2009.
References:
1. SYMDEKO [prescribing information]. Boston, MA: Vertex Pharmaceuticals Incorporated; December 2020. 2. Data on file. Vertex Pharmaceuticals Incorporated. Boston, MA. REF-3538; 2019. 3. FDA U.S. Food & Drug Administration. Drugs@FDA: FDA-Approved Drugs. https://www.accessdata.fda.gov/scripts/cder/daf/. Accessed February 1, 2020. 4. Kunze A, Huwyler J, Camenisch G, Poller B. Prediction of organic anion-transporting polypeptide 1B1- and 1B3-mediated hepatic uptake of statins based on transporter protein expression and activity data. Drug Metab Dispos. 2014;42(9):1514-1521.