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Tezacaftor and Ivacaftor

Medically reviewed on August 12, 2018

Pronunciation

(tez a KAF tor & eye va KAF tor)

Index Terms

  • Symdeko

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet Therapy Pack, Oral:

Symdeko: 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 (12 to <18 years of age) is similar to adult patients with the same dosing.

Use: Labeled Indications

Cystic fibrosis: Treatment of patients with cystic fibrosis (CF) aged ≥12 years 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 manufacturer's labeling.

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

Cystic fibrosis: Children ≥12 years of age and Adolescents: Oral: Refer to adult dosing.

Dosing: Renal Impairment

CrCl >30 mL/minute: No dosage adjustment necessary.

CrCl ≤30 mL/minute: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied); use with caution.

ESRD: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied); use with caution.

Dosing: Hepatic Impairment

Mild impairment (Child-Pugh class A): No dosage adjustment necessary.

Moderate impairment (Child-Pugh class B): Tezacaftor 100 mg/ivacaftor 150 mg once daily in the morning. The evening dose of ivacaftor 150 mg should not be administered.

Severe impairment (Child-Pugh class C): Tezacaftor 100 mg/ivacaftor 150 mg once daily in the morning (or less frequently). The evening dose of ivacaftor 150 mg should not be administered.

Dosing: Adjustment for Toxicity

Children ≥12 years of age, Adolescents, and Adults:

ALT or AST >5 × ULN without concomitant elevated bilirubin: Temporarily discontinue tezacaftor/ivacaftor; may resume if elevated transaminases resolved and after assessing benefits versus risks of continued treatment.

ALT or AST >3 × ULN with concomitant bilirubin >2 × ULN: Temporarily discontinue tezacaftor/ivacaftor; may resume if elevated transaminases resolved and after assessing benefits versus risks of continued treatment.

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: Per US labeling: reduce afatinib by 10mg if not tolerated. Per Canadian labeling: avoid combination if possible; if used, administer the P-gp inhibitor simultaneously with or after the dose of afatinib. Consider therapy modification

ARIPiprazole: CYP3A4 Inhibitors (Weak) may increase the serum concentration of ARIPiprazole. Management: Monitor for increased aripiprazole pharmacologic effects. Aripiprazole dose adjustments may or may not be required based on concomitant therapy and/or indication. Consult full interaction monograph for specific recommendations. Monitor therapy

Betrixaban: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Betrixaban. Management: Decrease the 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

Bitter Orange: May increase the serum concentration of Ivacaftor. Avoid combination

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

Ceritinib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Use of ceritinib with a narrow therapeutic index CYP3A substrate (eg, alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus) should be avoided when possible. 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 CYP3A4 Substrates (High risk with Inducers). Monitor therapy

CYP3A4 Inducers (Strong): May decrease the serum concentration of Ivacaftor. Avoid combination

CYP3A4 Inhibitors (Moderate): May increase the serum concentration of Ivacaftor. Management: Ivacaftor dose reductions are required; consult full monograph content for specific age- and weight-based recommendations. No dose adjustment is needed when using ivacaftor/lumacaftor with a moderate CYP3A4 inhibitor. Consider therapy modification

CYP3A4 Inhibitors (Moderate): May increase the serum concentration of Tezacaftor. Management: When combined with moderate CYP3A4 inhibitors, tezacaftor/ivacaftor (100 mg/150 mg) should be given in the morning, every other day. Ivacaftor (150 mg) alone should be given in the evening, every other day, on alternate days from tezacaftor/ivacaftor. Consider therapy modification

CYP3A4 Inhibitors (Strong): May increase the serum concentration of Ivacaftor. Management: Ivacaftor dose reductions are required; consult full monograph content for specific age- and weight-based recommendations. Consider therapy modification

CYP3A4 Inhibitors (Strong): May increase the serum concentration of Tezacaftor. Management: When combined with strong CYP3A4 inhibitors, tezacaftor/ivacaftor (100 mg/150 mg) should be administered in the morning, twice a week, approximately 3 to 4 days apart. No evening doses of ivacaftor (150 mg) 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. Management: Dabigatran dose reductions may be needed. Specific recommendations vary considerably according to US vs Canadian labeling, specific P-gp inhibitor, renal function, and indication for dabigatran treatment. Refer to full monograph or dabigatran labeling. Consider therapy modification

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

Dofetilide: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Dofetilide. 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 inhibitors. Similar dose adjustment is not recommended for edoxaban use in atrial fibrillation. Consider therapy modification

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

Flibanserin: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Flibanserin. 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

Grapefruit Juice: May increase the serum concentration of 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

Lomitapide: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Lomitapide. Management: Patients on lomitapide 5 mg/day may continue that dose. Patients taking lomitapide 10 mg/day or more should decrease the lomitapide dose by half. The lomitapide dose may then be titrated up to a max adult dose of 30 mg/day. 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

NiMODipine: CYP3A4 Inhibitors (Weak) may increase the serum concentration of NiMODipine. 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

Pimozide: CYP3A4 Inhibitors (Weak) may increase the serum concentration of Pimozide. Avoid combination

Pitolisant: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Combined use of pitolisant with a CYP3A4 substrate that has a narrow therapeutic index should be avoided. Other CYP3A4 substrates should be monitored more closely when used with pitolisant. Consider therapy modification

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

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. Avoid combination

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 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

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

Venetoclax: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Venetoclax. Management: Reduce the venetoclax dose by at least 50% in patients requiring these combinations. Consider therapy modification

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

Adverse Reactions

>10%: Central nervous system: Headache (15%)

1% to 10%:

Central nervous system: Dizziness (4%)

Gastrointestinal: Nausea (9%)

Respiratory: Sinus congestion (4%)

<1%, postmarketing, and/or case reports: Cataract (children), gastrointestinal obstruction

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

Adverse events were not observed in animal reproduction studies. Refer to the ivacaftor monograph for additional information.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience headache, nausea, dizziness, rhinitis, or rhinorrhea. Have patient report immediately to prescriber signs of liver problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or jaundice) (HCAHPS).

• Educate patient about signs of a significant reaction (eg, 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. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

Further information

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

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