Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet Therapy Pack, Oral:
Symdeko: Tezacaftor 50 mg and ivacaftor 75 mg (28s); Ivacator 75 mg (28s) (56 ea); Tezacaftor 100 mg and ivacaftor 150 mg (28s); Ivacaftor 150 mg (28s) (56 ea) [contains fd&c blue #2 (indigotine)]
Pharmacology
Mechanism of Action
Tezacaftor: Facilitates the cellular processing and trafficking of normal and select mutant forms of CFTR (including F508del-CFTR) to increase the amount of mature CFTR protein delivered to the cell surface.
Ivacaftor: CFTR potentiator that facilitates increased chloride transport by potentiating the channel-open probability (or gating) of the CFTR protein at the cell surface.
Pharmacokinetics/Pharmacodynamics
Absorption
Ivacaftor and tezacaftor: Variable; increased (by ~3-fold) when administered with fatty foods compared with fasting.
Distribution
Ivacaftor: 206 L ± 82.9 L
Tezacaftor: 271 L ± 157 L
Metabolism
Ivacaftor: Hepatic; extensive via CYP3A and CYP3A5; forms 2 major metabolites (M1 [active; 1/6 potency] and M6 [inactive])
Tezacaftor: Hepatic; extensive via CYP3A and CYP3A5; forms 3 major metabolites (M1 and M2 active; M5 inactive)
Excretion
Ivacaftor: Feces (87.8%); urine (6.6%)
Tezacaftor: Feces (72% as unchanged drug or M2 metabolite); urine (14% [mostly as M2 metabolite], <1% of administered dose as unchanged drug)
Time to Peak
Ivacaftor: Median: ~6 hours (range: 3 to 10 hours)
Tezacaftor: Median: ~4 hours (range: 2 to 6 hours)
Half-Life Elimination
Ivacaftor: 13.7 ± 6.06 hours
Tezacaftor: 15 ± 3.44 hours
Protein Binding
Ivacaftor: ~99%; primarily to alpha1-acid glycoprotein and albumin
Tezacaftor: ~99%; primarily to albumin
Use in Specific Populations
Special Populations: Hepatic Function Impairment
AUC was ~36% higher and Cmax was ~10% higher for tezacaftor, and a 1.5- to 2-fold increase in ivacaftor AUC in patients with moderate hepatic impairment.
Special Populations: Children
Exposure (AUC) in pediatric patients (6 to <18 years of age) is similar to adult patients.
Use: Labeled Indications
Cystic fibrosis: Treatment of patients with cystic fibrosis ≥6 years of age 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.
Note: A list of CFTR gene mutations that produce CFTR protein and are responsive to tezacaftor/ivacaftor include: A455E, A1067T, D110E, D110H, D579G, D1152H, D1270N, E56K, E193K, E831X, F1052V, F1074L, F508del (two copies of mutation or at least 1 copy of a responsive mutation), K1060T, L206W, P67L, R74W, R1070W, R117C, R347H, R352Q, 51070W, S945L, S977F, 711+3A→G, 2789+5G→A, 3272-26A→G, 3849+10kbC→T.
Contraindications
There are no contraindications listed in the US manufacturer's labeling.
Canadian labeling: Hypersensitivity to ivacaftor, tezacaftor, or any component of the formulation.
Dosage and Administration
Dosing: Adult
Note: Symdeko is supplied as copackaged tezacaftor 100 mg/ivacaftor 150 mg fixed-dose combination (yellow) tablets and ivacaftor 150 mg (light blue) tablets.
Cystic fibrosis: Oral: Tezacaftor 100 mg/ivacaftor 150 mg in the morning and ivacaftor 150 mg in the evening, ~12 hours apart.
Missed dose: If a dose is missed ≤6 hours of the usual time it is taken, take the dose as soon as possible; if >6 hours has passed since the missed dose, skip the missed dose and resume the normal dosing schedule.
Dosage adjustment with concomitant medications:
Coadministration with moderate CYP3A inhibitors (eg, erythromycin, fluconazole): On day 1, administer tezacaftor 100 mg/ivacaftor 150 mg once daily in the morning, and on day 2, administer ivacaftor 150 mg once daily in the morning; continue this dosing schedule with tezacaftor 100 mg/ivacaftor 150 mg or ivacaftor 150 mg on alternate days in the morning; the evening dose of ivacaftor 150 mg should not be administered.
Coadministration with strong CYP3A inhibitors (eg, clarithromycin, itraconazole, ketoconazole, posaconazole, telithromycin, voriconazole): On day 1, administer tezacaftor 100 mg/ivacaftor 150 mg once daily in the morning; do not administer any tablets on days 2 and 3; on day 4, administer tezacaftor 100 mg/ivacaftor 150 mg once daily in the morning. Continue dosing with tezacaftor 100 mg/ivacaftor 150 tablets twice a week, administered ~3 to 4 days apart; the evening dose of ivacaftor 150 mg should not be administered.
Dosing: Geriatric
Refer to adult dosing.
Dosing: Pediatric
Note: Symdeko is supplied as two separate products packaged together: tezacaftor/ivacaftor tablets in a fixed-dose combination and ivacaftor tablets; use caution when selecting dosage form; multiple strengths are available.
Cystic fibrosis:
Children ≥6 years to <12 years weighing <30 kg: Oral: Tezacaftor 50 mg/ivacaftor 75 mg (1 tablet) in the morning and ivacaftor 75 mg in the evening, approximately 12 hours apart.
Children ≥6 years to <12 years weighing ≥30 kg, Children ≥12 years, and Adolescents: Oral: Tezacaftor 100 mg/ivacaftor 150 mg (1 tablet) in the morning and ivacaftor 150 mg in the evening, approximately 12 hours apart.
Missed dose: If a dose is missed ≤6 hours of the usual time it is taken, take the dose as soon as possible; if >6 hours has passed since the missed dose, skip the missed dose and resume the normal dosing schedule.
Dosing adjustment with concomitant medications:
Coadministration with moderate CYP3A inhibitors (eg, erythromycin, fluconazole): Oral:
Children ≥6 years to <12 years weighing <30 kg: An alternating schedule is necessary; on day 1, administer tezacaftor 50 mg/ivacaftor 75 mg once daily in the morning, and on day 2, administer ivacaftor 75 mg only once daily in the morning; continue this dosing schedule with tezacaftor 50 mg/ivacaftor 75 mg or ivacaftor 75 mg on alternate days in the morning; no evening dose of ivacaftor 75 mg should be administered on any day.
Children ≥6 years to <12 years weighing ≥30 kg, Children ≥12 years, and Adolescents: An alternating schedule is necessary; on day 1, administer tezacaftor 100 mg/ivacaftor 150 mg once daily in the morning, and on day 2, administer ivacaftor 150 mg only once daily in the morning; continue this dosing schedule with tezacaftor 100 mg/ivacaftor 150 mg or ivacaftor 150 mg on alternate days in the morning; no evening dose of ivacaftor 150 mg should be administered on any day.
Coadministration with strong CYP3A inhibitors (eg, clarithromycin, itraconazole, ketoconazole, posaconazole, telithromycin, voriconazole): Oral:
Children ≥6 years to <12 years weighing <30 kg: Twice-weekly schedule: On day 1, administer tezacaftor 50 mg/ivacaftor 75 mg once daily in the morning; do not administer any tablets on days 2 and 3; on day 4, administer tezacaftor 50 mg/ivacaftor 75 mg once daily in the morning. Continue dosing with tezacaftor 50 mg/ivacaftor 75 tablets twice a week, administered ~3 to 4 days apart; no evening dose of ivacaftor 75 mg should be administered on any day.
Children ≥6 years to <12 years weighing ≥ 30 kg, Children ≥12 years, and Adolescents: Twice-weekly schedule: On day 1, administer tezacaftor 100 mg/ivacaftor 150 mg once daily in the morning; do not administer any tablets on days 2 and 3; on day 4, administer tezacaftor 100 mg/ivacaftor 150 mg once daily in the morning. Continue dosing with tezacaftor 100 mg/ivacaftor 150 tablets twice a week, administered ~3 to 4 days apart; no evening dose of ivacaftor 150 mg should be administered on any day.
Administration
Oral: Swallow tablet whole. Administer with fat-containing food (eg, eggs, butter, oils, cheese, nuts, peanut butter, meats, whole-milk dairy products). Avoid food or drink containing grapefruit or Seville oranges.
Dietary Considerations
Take with fat-containing food (eg, eggs, butter, cheese, nuts, peanut butter, cheese pizza, meats, whole-milk dairy products [eg, whole milk, cheese, yogurt]). Avoid food or drink containing grapefruit or Seville oranges during treatment.
Storage
Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F).
Drug Interactions
Afatinib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Afatinib. Management: Reduce afatinib by 10 mg if not tolerated. Some non-US labeling recommends avoiding combination if possible. If used, administer the P-gp inhibitor simultaneously with or after the dose of afatinib. Consider therapy modification
Betrixaban: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Betrixaban. Management: Decrease the adult betrixaban dose to an initial single dose of 80 mg followed by 40 mg once daily if combined with a P-glycoprotein inhibitor. Consider therapy modification
Bilastine: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Bilastine. Management: Consider alternatives when possible; bilastine should be avoided in patients with moderate to severe renal insufficiency who are receiving p-glycoprotein inhibitors. Consider therapy modification
Bosentan: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy
Brentuximab Vedotin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Brentuximab Vedotin. Specifically, concentrations of the active monomethyl auristatin E (MMAE) component may be increased. Monitor therapy
Celiprolol: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Celiprolol. Monitor therapy
Clofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy
Colchicine: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Colchicine. Colchicine distribution into certain tissues (e.g., brain) may also be increased. Management: Colchicine is contraindicated in patients with impaired renal or hepatic function who are also receiving a p-glycoprotein inhibitor. In those with normal renal and hepatic function, reduce colchicine dose as directed. See full monograph for details. Consider therapy modification
Conivaptan: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination
CYP3A4 Inducers (Moderate): May decrease the serum concentration of Tezacaftor and Ivacaftor. Monitor therapy
CYP3A4 Inducers (Strong): May decrease the serum concentration of Tezacaftor and Ivacaftor. Avoid combination
CYP3A4 Inhibitors (Moderate): May increase the serum concentration of Tezacaftor and Ivacaftor. Management: When combined with moderate CYP3A4 inhibitors, tezacaftor/ivacaftor should be given in the morning, every other day. Ivacaftor alone should be given in the morning, every other day on alternate days. Exceptions: Grapefruit Juice. Consider therapy modification
CYP3A4 Inhibitors (Strong): May increase the serum concentration of Tezacaftor and Ivacaftor. Management: When combined with strong CYP3A4 inhibitors, tezacaftor/ivacaftor should be administered in the morning, twice a week, approximately 3 to 4 days apart. No evening doses of ivacaftor alone should be administered. Consider therapy modification
Dabigatran Etexilate: P-glycoprotein/ABCB1 Inhibitors may increase serum concentrations of the active metabolite(s) of Dabigatran Etexilate. Monitor therapy
Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification
Deferasirox: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy
Digoxin: Tezacaftor and Ivacaftor may increase the serum concentration of Digoxin. Monitor therapy
DOXOrubicin (Conventional): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of DOXOrubicin (Conventional). Management: Seek alternatives to P-glycoprotein inhibitors in patients treated with doxorubicin whenever possible. One U.S. manufacturer (Pfizer Inc.) recommends that these combinations be avoided. Consider therapy modification
Edoxaban: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Edoxaban. Management: See full monograph for details. Reduced doses are recommended for patients receiving edoxaban for venous thromboembolism in combination with certain P-gp inhibitors. Similar dose adjustment is not recommended for edoxaban use in atrial fibrillation. Consider therapy modification
Erdafitinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy
Erdafitinib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy
Everolimus: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Everolimus. Monitor therapy
Fosaprepitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy
Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination
Glimepiride: Tezacaftor and Ivacaftor may increase the serum concentration of Glimepiride. Monitor therapy
GlipiZIDE: Tezacaftor and Ivacaftor may increase the serum concentration of GlipiZIDE. Monitor therapy
Grapefruit Juice: May increase the serum concentration of Tezacaftor and Ivacaftor. Avoid combination
Idelalisib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination
Ivosidenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy
Larotrectinib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy
Larotrectinib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Larotrectinib. Monitor therapy
Lefamulin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Lefamulin. Management: Avoid concomitant use of lefamulin tablets with P-glycoprotein/ABCB1 inhibitors. If concomitant use is required, monitor for lefamulin adverse effects. Consider therapy modification
Lorlatinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Avoid concurrent use of lorlatinib with any CYP3A4 substrates for which a minimal decrease in serum concentrations of the CYP3A4 substrate could lead to therapeutic failure and serious clinical consequences. Consider therapy modification
MiFEPRIStone: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Minimize doses of CYP3A4 substrates, and monitor for increased concentrations/toxicity, during and 2 weeks following treatment with mifepristone. Avoid cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus. Consider therapy modification
Naldemedine: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Naldemedine. Monitor therapy
Naloxegol: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Naloxegol. Monitor therapy
Palbociclib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy
PAZOPanib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of PAZOPanib. Avoid combination
P-glycoprotein/ABCB1 Substrates: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inhibitors may also enhance the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Exceptions: Loperamide. Monitor therapy
Prucalopride: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Prucalopride. Monitor therapy
Ranolazine: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Ranolazine. Monitor therapy
Rifabutin: May decrease the serum concentration of Tezacaftor and Ivacaftor. Specifically, the serum concentration of ivacaftor may be decreased. Monitor therapy
RifAXIMin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of RifAXIMin. Monitor therapy
Sarilumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy
Silodosin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Silodosin. Monitor therapy
Siltuximab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy
Simeprevir: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy
St John's Wort: May decrease the serum concentration of Tezacaftor and Ivacaftor. Avoid combination
Stiripentol: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring. Consider therapy modification
Talazoparib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Talazoparib. Management: These listed exceptions are discussed in detail in separate interaction monographs. Monitor therapy
Tegaserod: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Tegaserod. Monitor therapy
Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy
Topotecan: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Topotecan. Avoid combination
Ubrogepant: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Ubrogepant. Management: Use an initial ubrogepant dose of 50 mg and second dose (if needed) of 50 mg when used with a P-gp inhibitor. Consider therapy modification
Venetoclax: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Venetoclax. Management: Consider a venetoclax dose reduction by at least 50% in patients requiring concomitant treatment with P-glycoprotein (P-gp) inhibitors. Consider therapy modification
VinCRIStine (Liposomal): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of VinCRIStine (Liposomal). Avoid combination
Warfarin: Tezacaftor and Ivacaftor may increase the serum concentration of Warfarin. Monitor therapy
Adverse Reactions
Also see Ivacaftor.
>10%: Central nervous system: Headache (15%)
1% to 10%:
Central nervous system: Dizziness (4%)
Gastrointestinal: Nausea (9%)
Respiratory: Paranasal sinus congestion (4%)
<1%: Gastrointestinal obstruction
Postmarketing: Cataract
Warnings/Precautions
Concerns related to adverse effects:
- Cataracts: Noncongenital lens opacities and cataracts have been reported in pediatric patients treated with tezacaftor/ivacaftor and ivacaftor; other risk factors were present in some cases (eg, corticosteroid use, exposure to radiation), but a possible risk related to tezacaftor/ivacaftor cannot be excluded. Baseline and follow-up ophthalmological examinations are recommended in pediatric patients.
- CNS effects: May cause dizziness, which may impair physical or mental abilities; patients must be cautioned about performing tasks that require mental alertness (eg, operating machinery, driving).
- Hepatic effects: May increase hepatic transaminases. Monitor ALT, AST, and bilirubin at baseline, every 3 months for the first year of therapy, and annually thereafter; increased monitoring may be necessary in patients with a history of elevated hepatic transaminases. Temporarily discontinue treatment if ALT or AST >5 × ULN or if ALT or AST >3 × ULN with concomitant bilirubin >2 × ULN. Following resolution of transaminase elevations, consider the benefits and risks of resuming therapy.
Disease-related concerns:
- Hepatic impairment: Use with caution in patients with hepatic impairment; dosage adjustment recommended in patients with moderate to severe (Child-Pugh class B or C) impairment.
- Renal impairment: Use with caution in patients with severe impairment (CrCl ≤30 mL/minute) or ESRD.
Concurrent drug therapy issues:
- Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.
Other warnings/precautions:
- Appropriate use: 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 bidirectional sequencing when recommended by the mutation test instructions for use.
Monitoring Parameters
CF mutation test (prior to therapy if genotype is unknown); ophthalmological examinations (baseline and follow-up in pediatric patients); ALT and AST (baseline, every 3 months for the first year of therapy, and annually thereafter; increased monitoring may be necessary in patients with a history of elevated hepatic transaminases or bilirubin).
Pregnancy
Pregnancy Considerations
Ivacaftor crosses the placenta (Trimble 2018).
Refer to the ivacaftor monograph for additional information.
Patient Education
What is this drug used for?
- It is used to treat cystic fibrosis.
Frequently reported side effects of this drug
- Headache
- Nausea
- Dizziness
- Stuffy nose
- Running nose
Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:
- Liver problems like dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin
- Vision changes
- Signs of a significant reaction like wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat.
Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.
Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.
