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Tezacaftor and Ivacaftor

Medically reviewed by Drugs.com. Last updated on Oct 2, 2020.

Pronunciation

(tez a KAF tor & eye va KAF tor)

Index Terms

  • Ivacaftor and Tezacaftor

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)]

Brand Names: U.S.

  • Symdeko

Pharmacologic Category

  • Cystic Fibrosis Transmembrane Conductance Regulator Corrector
  • Cystic Fibrosis Transmembrane Conductance Regulator Potentiator

Pharmacology

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.

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

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.

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 for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

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.

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

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

Abametapir: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

Afatinib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Afatinib. Management: If combined, administer the P-gp inhibitor simultaneously with, or after, the dose of afatinib. Monitor closely for signs and symptoms of afatinib toxicity and if the combination is not tolerated, reduce the afatinib dose by 10 mg. Consider therapy modification

Aliskiren: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Aliskiren. Monitor therapy

Betrixaban: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Betrixaban. Management: Decrease adult betrixaban dose to an initial single dose of 80 mg followed by 40 mg once daily if combined with a P-gp inhibitor. Avoid concomitant use of betrixaban and P-gp inhibitors in patients with severe renal impairment (CrCL less than 30 mL/min). Consider therapy modification

Bilastine: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Bilastine. Avoid combination

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-gp inhibitor. In those with normal renal and hepatic function, reduce colchicine dose as directed. See interaction monograph for details. Consider therapy modification

Conivaptan: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

CycloSPORINE (Systemic): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of CycloSPORINE (Systemic). Monitor therapy

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: If combined with moderate CYP3A4 inhibitors, give tezacaftor/ivacaftor in the morning, every other day; give ivacaftor in the morning, every other day on alternate days. Tezacaftor/ivacaftor dose depends on age and weight; see full Lexi-Interact monograph Exceptions: Grapefruit Juice. Consider therapy modification

CYP3A4 Inhibitors (Strong): May increase the serum concentration of Tezacaftor and Ivacaftor. Management: If combined with strong CYP3A4 inhibitors, tezacaftor/ivacaftor should be administered in the morning, twice a week, approximately 3 to 4 days apart. Tezacaftor/ivacaftor dose depends on age and weight; see full Lexi-Interact monograph for details. 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

Digitoxin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Digitoxin. Monitor therapy

Digoxin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Digoxin. Management: Measure digoxin serum concentrations before initiating treatment with these P-glycoprotein (P-gp) inhibitors. Reduce digoxin concentrations by either reducing the digoxin dose by 15% to 30% or by modifying the dosing frequency. Consider therapy modification

DOXOrubicin (Conventional): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of DOXOrubicin (Conventional). Avoid combination

Edoxaban: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Edoxaban. Management: Exceptions to this monograph are discussed in separate Lexi-Interact monographs. Monitor therapy

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

Etoposide: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Etoposide. Monitor therapy

Etoposide Phosphate: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Etoposide Phosphate. 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

Glecaprevir and Pibrentasvir: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Glecaprevir and Pibrentasvir. Monitor therapy

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

Lapatinib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Lapatinib. 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

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

Morphine (Systemic): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Morphine (Systemic). Monitor therapy

Nadolol: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Nadolol. Monitor therapy

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

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

Rimegepant: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Rimegepant. Avoid combination

RisperiDONE: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of RisperiDONE. Monitor therapy

RomiDEPsin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of RomiDEPsin. 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

Sirolimus: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Sirolimus. Management: Avoid concurrent use of sirolimus with P-glycoprotein (P-gp) inhibitors when possible and alternative agents with lesser interaction potential with sirolimus should be considered. Monitor for increased sirolimus concentrations/toxicity if combined. Consider therapy modification

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

Tacrolimus (Systemic): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Tacrolimus (Systemic). Monitor therapy

Talazoparib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Talazoparib. Monitor therapy

Tegaserod: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Tegaserod. Monitor therapy

Teniposide: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Teniposide. Monitor therapy

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Tolvaptan: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Tolvaptan. 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 (at least 2 hours later 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: Reduce the venetoclax dose by at least 50% in patients requiring concomitant treatment with P-glycoprotein (P-gp) inhibitors. Resume the previous venetoclax dose 2 to 3 days after discontinuation of a P-gp inhibitor. 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 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.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Headache

• Nausea

• Dizziness

• Stuffy nose

• Running nose

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Liver problems like dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin

• Vision changes

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing, swallowing, or talking; unusual hoarseness; or swelling of the mouth, 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 limited summary of general information about the medicine's uses from the patient education leaflet and is not intended to be comprehensive. This limited summary does NOT include all information available about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not intended to provide medical advice, diagnosis or treatment and does not replace information you receive from the healthcare provider. For a more detailed summary of information about the risks and benefits of using this medicine, please speak with your healthcare provider and review the entire patient education leaflet.

Further information

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.

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