Symdeko
(ivacaftor / tezacaftor)Dosage & Administration
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Symdeko Prescribing Information
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.
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)].
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.
| 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.
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)].
| 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) | |
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)].
| Day 1 | Day 2 | Day 3 | Day 4 * | |
|---|---|---|---|---|
| ||||
| 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)].
| Day 1 | Day 2 and Day 3 | Day 4 * | |
|---|---|---|---|
| |||
| Patients Aged 6 to <12 Years Weighing <30 kg | |||
| Morning | |||
| Tezacaftor 50 mg/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 | ✓ | - | ✓ |
| 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)].
Tablets: Tezacaftor 50 mg/ivacaftor 75 mg fixed-dose combination tablets co-packaged with ivacaftor 75 mg tablets
- Tezacaftor 50 mg/ivacaftor 75 mg tablets are white, oblong-shaped, and debossed with "V50" on one side and plain on the other.
- Ivacaftor 75 mg tablets are light blue, oblong-shaped, and printed with "V 75" in black ink on one side and plain on the other.
Tablets: Tezacaftor 100 mg/ivacaftor 150 mg fixed-dose combination tablets co-packaged with ivacaftor 150 mg tablets
- Tezacaftor 100 mg/ivacaftor 150 mg tablets are yellow, oblong-shaped, and debossed with "V100" on one side and plain on the other.
- Ivacaftor 150 mg tablets are light blue, oblong-shaped, and printed with "V 150" in black ink on one side and plain on the other.
Pregnancy
Risk Summary
There are limited and incomplete human data from clinical trials and postmarketing reports on the use of SYMDEKO or its individual components, tezacaftor and ivacaftor, in pregnant women to inform a drug-associated risk. Although there are no animal reproduction studies with the concomitant administration of tezacaftor and ivacaftor, separate reproductive and developmental studies were conducted with tezacaftor and ivacaftor in pregnant rats and rabbits. In animal reproduction studies, oral administration of tezacaftor to pregnant rats and rabbits during organogenesis demonstrated no teratogenicity or adverse developmental effects at doses that produced maternal exposures up to approximately 3 times the exposure at the maximum recommended human dose (MRHD) in rats and 0.2 times the MRHD in rabbits (based on summed AUCs for tezacaftor and M1 metabolite). Oral administration of ivacaftor to pregnant rats and rabbits during organogenesis demonstrated no teratogenicity or adverse developmental effects at doses that produced maternal exposures up to approximately 6 and 16 times the exposure at the MRHD, respectively. No adverse developmental effects were observed after oral administration of either tezacaftor or ivacaftor to pregnant rats from the period of organogenesis through lactation at doses that produced maternal exposures approximately 1 and 4 times the exposures at the MRHD, respectively (see Data).
The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
Data
Animal Data
Tezacaftor
In an embryo-fetal development study in pregnant rats dosed during the period of organogenesis from gestation Days 6-17, tezacaftor was not teratogenic and did not affect fetal development or survival at exposures up to 3 times the MRHD (based on summed AUCs for tezacaftor and M1 metabolite at maternal oral doses up to 100 mg/kg/day). In an embryo-fetal development study in pregnant rabbits dosed during the period of organogenesis from gestation Days 7-20, tezacaftor was not teratogenic and did not affect fetal development or survival at exposures up to 0.2 times the MRHD (based on summed AUCs for tezacaftor and M1 metabolite at maternal oral doses up to 25 mg/kg/day). Lower fetal body weights were observed in rabbits at a maternally toxic dose that produced exposures approximately 1 times the MRHD (at a maternal dose of 50 mg/kg/day). In a pre- and postnatal development (PPND) study in pregnant rats dosed from gestation Day 6 through lactation Day 18, tezacaftor had no adverse developmental effects on pups at an exposure of approximately 1 times the MRHD (based on summed AUCs for tezacaftor and M1 metabolite at a maternal dose of 25 mg/kg/day). Decreased fetal body weights and early developmental delays in pinna detachment, eye opening, and righting reflex occurred at a maternally toxic dose (based on maternal weight loss) that produced exposures approximately 2 times the exposure at the MRHD (based on summed AUCs for tezacaftor and M1 metabolite at a maternal oral dose of 50 mg/kg/day). Placental transfer of tezacaftor was observed in pregnant rats.
Ivacaftor
In an embryo-fetal development study in pregnant rats dosed during the period of organogenesis from gestation Days 7-17, ivacaftor was not teratogenic and did not affect fetal survival at exposures up to 6 times the MRHD (based on summed AUCs for ivacaftor and its metabolites at a maternal oral dose of 200 mg/kg/day). In an embryo-fetal development study in pregnant rabbits dosed during the period of organogenesis from gestation Days 7-19, ivacaftor was not teratogenic and did not affect fetal development or survival at exposures up to 16 times the MRHD (on an ivacaftor AUC basis at maternal oral doses up to 100 mg/kg/day). In a PPND study in pregnant rats dosed from gestation Day 7 through lactation Day 20, ivacaftor had no effects on delivery or growth and development of offspring at exposures up to 4 times the MRHD (based on summed AUCs for ivacaftor and its metabolites at maternal oral doses up to 100 mg/kg/day). Decreased fetal body weights were observed at a maternally toxic dose that produced exposures 6 times the MRHD. Placental transfer of ivacaftor was observed in pregnant rats and rabbits.
Lactation
Risk Summary
There is no information regarding the presence of tezacaftor or ivacaftor in human milk, the effects on the breastfed infant, or the effects on milk production. Both tezacaftor and ivacaftor are excreted into the milk of lactating rats (see Data). The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for SYMDEKO and any potential adverse effects on the breastfed child from SYMDEKO or from the underlying maternal condition.
Data
Tezacaftor
Lacteal excretion of tezacaftor in rats was demonstrated following a single oral dose (30 mg/kg) of 14C-tezacaftor administered 6 to 10 days postpartum to lactating dams. Exposure of 14C-tezacaftor in milk was approximately 3 times higher than in plasma (based on AUC0-72h).
Ivacaftor
Lacteal excretion of ivacaftor in rats was demonstrated following a single oral dose (100 mg/kg) of 14C-ivacaftor administered 9 to 10 days postpartum to lactating dams. Exposure of 14C-ivacaftor in milk was approximately 1.5 times higher than in plasma (based on AUC0-24h).
Pediatric Use
The safety and effectiveness of SYMDEKO for the treatment of CF have been established in pediatric patients aged 6 to less than 18 years who are homozygous for the F508del mutation or who have at least one mutation in the 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)].
Clinical trials included the following patients with CF:
- 12 to less than 18 years of age who are homozygous for the F508del mutation [see Adverse Reactions (6) and Clinical Studies (14)].
- 12 to less than 18 years of age who are heterozygous for the F508del mutation and a second mutation predicted to be responsive to tezacaftor/ivacaftor [see Adverse Reactions (6) and Clinical Studies (14)].
- 6 to less than 12 years of age who are either homozygous for the F508del mutation or heterozygous for the F508del mutation and a second mutation predicted to be responsive to tezacaftor/ivacaftor [see Adverse Reactions (6) and Clinical Pharmacology (12)].
The effectiveness of SYMDEKO in patients aged 6 to less than 12 years was extrapolated from patients aged 12 years and older with support from population pharmacokinetic analyses showing similar tezacaftor and ivacaftor exposure levels in patients aged 6 to less than 12 years and in patients aged 12 years and older [see Clinical Pharmacology (12.3)]. Safety of SYMDEKO in this population was derived from a 24-week, open-label, clinical trial in 70 patients aged 6 to less than 12 years (mean age at screening 8.1 years) administered either tezacaftor 50 mg/ivacaftor 75 mg and ivacaftor 75 mg or tezacaftor 100 mg/ivacaftor 150 mg and ivacaftor 150 mg, 12 hours apart (Trial 4). The safety profile for patients in this trial was similar to that observed in Trials 1 and 3 [see Adverse Reactions (6.1)].
The safety and effectiveness of SYMDEKO in patients with CF younger than 6 years of age have not been studied.
Juvenile Animal Toxicity Data
Findings of cataracts were observed in juvenile rats dosed from postnatal Day 7 through 35 with ivacaftor dose levels of 10 mg/kg/day and higher (0.25 times the MRHD based on systemic exposure of ivacaftor and its metabolites). This finding has not been observed in older animals.
Geriatric Use
Clinical trials of SYMDEKO did not include sufficient numbers of patients 65 years of age and over to determine whether they respond differently from younger patients.
Hepatic Impairment
No dosage adjustment is necessary for patients with mild hepatic impairment (Child-Pugh Class A). A reduced dosage of SYMDEKO is recommended in patients with moderate hepatic impairment (Child-Pugh Class B). There is no experience in patients with severe hepatic impairment (Child-Pugh Class C), but tezacaftor/ivacaftor exposure is expected to be higher than in patients with moderate hepatic impairment. Therefore, use with caution at a reduced dosage in patients with severe hepatic impairment after weighing the risks and benefits of treatment [see Dosage and Administration (2.3), Clinical Pharmacology (12.3), and Patient Counseling Information (17)].
Renal Impairment
SYMDEKO has not been studied in patients with moderate or severe renal impairment or in patients with end-stage renal disease. No dosage adjustment is recommended for mild and moderate renal impairment. Caution is recommended in patients with severe renal impairment or end-stage renal disease [Clinical Pharmacology (12.3)].
Patients with Severe Lung Dysfunction
Trial 1 and Trial 2 included a total of 39 SYMDEKO-treated patients with ppFEV1 <40 at baseline (range: 30-40); 23 patients in Trial 1 and 16 patients in Trial 2. There were 24 placebo-treated patients in Trial 1, and 15 placebo- and 13 ivacaftor-treated patients in Trial 2, with ppFEV1 <40 at baseline. The safety and efficacy in this subgroup were comparable to the overall results observed in both Trials 1 and 2.
None.
Transaminase (AST/ALT) 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 for all patients 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. In the event of 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, dosing should be interrupted and laboratory tests closely followed until the abnormalities resolve. Following the resolution of transaminase elevations consider the benefits and risks of resuming treatment [see Adverse Reactions (6)].
Hypersensitivity Reactions, Including Anaphylaxis
Hypersensitivity reactions, including cases of anaphylaxis, have been reported in the postmarketing setting [see Adverse Reactions (6.2)]. 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 the concomitant use of CYP3A inducers, which may reduce the therapeutic effectiveness of SYMDEKO. Therefore, co-administration with strong CYP3A inducers is not recommended [see Drug Interactions (7.1), Clinical Pharmacology (12.3), and Patient Counseling Information (17)].
Cataracts
Cases of non-congenital lens opacities have been reported in pediatric patients treated with SYMDEKO, as well as with ivacaftor monotherapy. Although other risk factors were present in some cases (such as corticosteroid use, exposure to radiation), a possible risk attributable to treatment with SYMDEKO cannot be excluded. Baseline and follow-up ophthalmological examinations are recommended in pediatric patients initiating treatment with SYMDEKO [see Use in Specific Populations (8.4) and Patient Counseling Information (17)].