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SYMDEKO

TEZACAFTOR AND IVACAFTOR

Standard Dose

2 DOSAGE AND ADMINISTRATION Pediatric patients aged 6 to less than 12 years weighing less than 30 kg: one tablet (containing tezacaftor 50 mg/ivacaftor 75 mg) in the morning and one tablet (containing ivacaftor 75 mg) in the evening, approximately 12 hours apart. SYMDEKO should be taken with fat-containing food. ( 2.1 , 2.2 , 12.3 ) Adults and pediatric patients aged 12 years and older or pediatric patients aged 6 to less than 12 years weighing 30 kg or more: one tablet (containing tezacaftor 100 mg/ivacaftor 150 mg) in the morning and one tablet (containing ivacaftor 150 mg) in the evening, approximately 12 hours apart. SYMDEKO should be taken with fat-containing food. ( 2.1 , 2.2 , 12.3 ) Reduce dosage in patients with moderate and severe hepatic impairment. ( 2.3 , 8.6 , 12.3 ) See full prescribing information for dosage modifications due to drug interactions with SYMDEKO. ( 2.4 , 7.2 , 12.3 ) 2.1 General Dosage Information Swallow the tablets whole. SYMDEKO should be taken with fat-containing food, such as food recommended in standard nutritional guidelines. Examples of meals or snacks that contain fat are those prepared with butter or oils or those containing eggs, cheeses, nuts, whole milk, or meats, etc. [see Clinical Pharmacology (12.3) ] . 2.2 Recommended Dosage in Adults, Adolescents, and Children Aged 6 Years and Older Adults, adolescents, and children aged 6 years and older should be dosed according to Table 1. The morning and the evening doses should be taken approximately 12 hours apart. Table 1: Recommended Dosage for Patients Aged 6 Years and Older Age Morning (one tablet) Evening (one tablet) 6 to <12 years weighing <30 kg tezacaftor 50 mg/ivacaftor 75 mg ivacaftor 75 mg 6 to <12 years weighing ≥30 kg tezacaftor 100 mg/ivacaftor 150 mg ivacaftor 150 mg ≥12 years tezacaftor 100 mg/ivacaftor 150 mg ivacaftor 150 mg Information for Missed Doses: If 6 hours or less have passed since the missed morning or evening dose, the patient should take the missed dose as soon as possible and continue on the original schedule. If more than 6 hours have passed since the missed morning or evening dose, the patient should not take the missed dose. The next scheduled dose can be taken at the usual time. More than one dose should not be taken at the same time. 2.3 Recommended Dosage for Patients with Hepatic Impairment For dosage adjustment for patients with hepatic impairment, refer to Table 2. Studies have not been conducted in patients with severe hepatic impairment (Child-Pugh Class C), but exposure of tezacaftor and ivacaftor is expected to be higher than in patients with moderate hepatic impairment. Therefore, SYMDEKO should be used with caution at an adjusted dosage after weighing the risks and benefits of treatment in these patients [see Use in Specific Populations (8.6) , Clinical Pharmacology (12.3) , and Patient Counseling Information (17) ]. Table 2: Recommended Dosage for Patients with Hepatic Impairment Hepatic Impairment Morning Evening Patients Aged 6 to <12 Years Weighing <30 kg Patients Aged 6 to <12 Years Weighing ≥30 kg and Patients Age ≥12 Years All Patients Mild (Child-Pugh Class A) No dose adjustment No dose adjustment No dose adjustment Moderate (Child-Pugh Class B) One tablet of tezacaftor 50 mg/ivacaftor 75 mg once daily One tablet of tezacaftor 100 mg/ivacaftor 150 mg once daily No ivacaftor dose Severe (Child-Pugh Class C) One tablet of tezacaftor 50 mg/ivacaftor 75 mg once daily (or less frequently) One tablet of tezacaftor 100 mg/ivacaftor 150 mg once daily (or less frequently) 2.4 Dosage Adjustment for Patients Taking Drugs that are CYP3A Inhibitors The dosing regimen of SYMDEKO should be adjusted when co-administered with moderate and strong CYP3A inhibitors. Moderate CYP3A inhibitors: When co-administered with moderate CYP3A inhibitors (e.g., fluconazole, erythromycin), the dosing regimen should be adjusted as in Table 3 [see Drug Interactions (7.2) , Clinical Pharmacology (12.3) , and Patient Counseling Information (17) ] . Table 3: Dosing Schedule for Concomitant Use of SYMDEKO with Moderate CYP3A Inhibitors Day 1 Day 2 Day 3 Day 4 Continue dosing with tezacaftor/ivacaftor or ivacaftor tablets on alternate days. Patients Aged 6 to <12 Years Weighing <30 kg Morning Tezacaftor 50 mg/ivacaftor 75 mg tablet ✓ - ✓ - Ivacaftor 75 mg tablet - ✓ - ✓ Evening Ivacaftor 75 mg tablet - - - - Patients Aged 6 to <12 Years Weighing ≥30 kg and Patients Age ≥12 Years Morning Tezacaftor 100 mg/ivacaftor 150 mg tablet ✓ - ✓ - Ivacaftor 150 mg tablet - ✓ - ✓ Evening Ivacaftor 150 mg tablet - - - - Strong CYP3A inhibitors: When co-administered with strong CYP3A inhibitors (e.g., ketoconazole, itraconazole, posaconazole, voriconazole, telithromycin, and clarithromycin), the dosing regimen should be adjusted as in Table 4 [see Drug Interactions (7.2) , Clinical Pharmacology (12.3) , and Patient Counseling Information (17) ] . Table 4: Dosing Schedule for Concomitant Use of SYMDEKO with Strong CYP3A Inhibitors Day 1 Day 2 and Day 3 Day 4 Continue dosing with tezacaftor/ivacaftor tablets twice a week, taken approximately 3 to 4 days apart. Patients Aged 6 to <12 Years Weighing <30 kg Morning Tezacaftor 50 mg/ivacaftor 75 mg tablet ✓ - ✓ Evening The evening dose of ivacaftor should not be taken on any day. Ivacaftor 75 mg tablet - - - Patients Aged 6 to <12 Years Weighing ≥30 kg and Patients Age ≥12 Years Morning Tezacaftor 100 mg/ivacaftor 150 mg tablet ✓ - ✓ Evening Ivacaftor 150 mg tablet - - - Food or drink containing grapefruit should be avoided during treatment with SYMDEKO [see Drug Interactions (7.2) and Patient Counseling Information (17) ] .

Max Dose

See official label

Primary Use

1 INDICATIONS AND USAGE SYMDEKO is indicated for the treatment of cystic fibrosis (CF) in patients aged 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 [see Clinical Pharmacology (12.1) and Clinical Studies (14) ] .

Summary

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.

Structured Monograph

Clinical summary

Indications and usage 1 INDICATIONS AND USAGE SYMDEKO is indicated for the treatment of cystic fibrosis (CF) in patients aged 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 [see Clinical Pharmacology (12.1) and Clinical Studies (14) ] . 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. SYMDEKO is a combination of tezacaftor and ivacaftor, indicated for the treatment of cystic fibrosis (CF) in patients aged 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. ( 12.1 , 14 ) 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. ( 1 ) Dosage and administration 2 DOSAGE AND ADMINISTRATION Pediatric patients aged 6 to less than 12 years weighing less than 30 kg: one tablet (containing tezacaftor 50 mg/ivacaftor 75 mg) in the morning and one tablet (containing ivacaftor 75 mg) in the evening, approximately 12 hours apart. SYMDEKO should be taken with fat-containing food. ( 2.1 , 2.2 , 12.3 ) Adults and pediatric patients aged 12 years and older or pediatric patients aged 6 to less than 12 years weighing 30 kg or more: one tablet (containing tezacaftor 100 mg/ivacaftor 150 mg) in the morning and one tablet (containing ivacaftor 150 mg) in the evening, approximately 12 hours apart. SYMDEKO should be taken with fat-containing food. ( 2.1 , 2.2 , 12.3 ) Reduce dosage in patients with moderate and severe hepatic impairment. ( 2.3 , 8.6 , 12.3 ) See full prescribing information for dosage modifications due to drug interactions with SYMDEKO. ( 2.4 , 7.2 , 12.3 ) 2.1 General Dosage Information Swallow the tablets whole. SYMDEKO should be taken with fat-containing food, such as food recommended in standard nutritional guidelines. Examples of meals or snacks that contain fat are those prepared with butter or oils or those containing eggs, cheeses, nuts, whole milk, or meats, etc. [see Clinical Pharmacology (12.3) ] . 2.2 Recommended Dosage in Adults, Adolescents, and Children Aged 6 Years and Older Adults, adolescents, and children aged 6 years and older should be dosed according to Table 1. The morning and the evening doses should be taken approximately 12 hours apart. Table 1: Recommended Dosage for Patients Aged 6 Years and Older Age Morning (one tablet) Evening (one tablet) 6 to <12 years weighing <30 kg tezacaftor 50 mg/ivacaftor 75 mg ivacaftor 75 mg 6 to <12 years weighing ≥30 kg tezacaftor 100 mg/ivacaftor 150 mg ivacaftor 150 mg ≥12 years tezacaftor 100 mg/ivacaftor 150 mg ivacaftor 150 mg Information for Missed Doses: If 6 hours or less have passed since the missed morning or evening dose, the patient should take the missed dose as soon as possible and continue on the original schedule. If more than 6 hours have passed since the missed morning or evening dose, the patient should not take the missed dose. The next scheduled dose can be taken at the usual time. More than one dose should not be taken at the same time. 2.3 Recommended Dosage for Patients with Hepatic Impairment For dosage adjustment for patients with hepatic impairment, refer to Table 2. Studies have not been conducted in patients with severe hepatic impairment (Child-Pugh Class C), but exposure of tezacaftor and ivacaftor is expected to be higher than in patients with moderate hepatic impairment. Therefore, SYMDEKO should be used with caution at an adjusted dosage after weighing the risks and benefits of treatment in these patients [see Use in Specific Populations (8.6) , Clinical Pharmacology (12.3) , and Patient Counseling Information (17) ]. Table 2: Recommended Dosage for Patients with Hepatic Impairment Hepatic Impairment Morning Evening Patients Aged 6 to <12 Years Weighing <30 kg Patients Aged 6 to <12 Years Weighing ≥30 kg and Patients Age ≥12 Years All Patients Mild (Child-Pugh Class A) No dose adjustment No dose adjustment No dose adjustment Moderate (Child-Pugh Class B) One tablet of tezacaftor 50 mg/ivacaftor 75 mg once daily One tablet of tezacaftor 100 mg/ivacaftor 150 mg once daily No ivacaftor dose Severe (Child-Pugh Class C) One tablet of tezacaftor 50 mg/ivacaftor 75 mg once daily (or less frequently) One tablet of tezacaftor 100 mg/ivacaftor 150 mg once daily (or less frequently) 2.4 Dosage Adjustment for Patients Taking Drugs that are CYP3A I

Monitoring

• 5 WARNINGS AND PRECAUTIONS Elevated transaminases (ALT or AST): Transaminases (ALT and AST) should be assessed prior to initiating SYMDEKO, every 3 months during the first year of treatment, and annually thereafter.
• In 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., patients with ALT or AST >5 × upper limit of normal (ULN), or ALT or AST >3 × ULN with bilirubin >2 × ULN.
• Following resolution of transaminase elevations, consider the benefits and risks of resuming treatment.

Interaction Notes

• 7 DRUG INTERACTIONS Potential for other drugs to affect tezacaftor/ivacaftor CYP3A inhibitors: Reduce SYMDEKO dosage when co-administered with strong (e.g., ketoconazole) or moderate (e.g., fluconazole) CYP3A inhibitors.
• Avoid food containing grapefruit.
• ( 2.4 , 7.2 , 12.3 ) 7.1 Inducers of CYP3A Tezacaftor and ivacaftor are substrates of CYP3A (ivacaftor is a sensitive substrate of CYP3A).
• Concomitant use of CYP3A inducers may result in reduced exposures and thus reduced SYMDEKO efficacy.