elexacaftor/tezacaftor/ivacaftor (Rx)

Brand and Other Names:Trikafta
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Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

elexacaftor/tezacaftor/ivacaftor

fixed-dose tablet copackaged with ivacaftor tablet

  • 100mg/50mg/75mg plus ivacaftor 150 mg

Cystic Fibrosis

Indicated for cystic fibrosis in patients who have at least 1 F508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which is estimated to represent 90% of the cystic fibrosis population

2 fixed-dose tablets (elexacaftor 100 mg, tezacaftor 50 mg, and ivacaftor 75 mg) PO qAM and 1 ivacaftor 150-mg tablet PO qPM; ~12 hr apart

Dosage Modifications

Renal impairment

  • Mild or moderate (eGFR 30 to <90 mL/min/1.73 m2): No dosage adjustment required
  • Severe (eGFR <30 mL/min/1.73 m2) or ESRD: Use caution

Hepatic impairment

  • Mild (Child-Pugh A): No dosage adjustment required
  • Moderate (Child-Pugh B): Not recommended unless benefit exceeds risk; reduce dose by omitting evening ivacaftor 150-mg tab; monitor liver function tests
  • Severe (Child-Pugh C): Do not use

Coadministration with moderate or strong CYP3A inhibitors

  • Moderate CYP3A inhibitors
    • Alternate daily dose between 2 fixed-dose tablets qAM and 1 ivacaftor 150-mg tablet qAM
    • Do not take an evening dose
  • Strong CYP3A inhibitors
    • Take 2 fixed-dose tablets PO twice weekly, ~3-4 days apart
    • Do not take an evening dose

Elevated liver function tests

  • Interrupt therapy
    • ALT or AST >5x ULN, or
    • ALT or AST >3x ULN with bilirubin >2x ULN
    • Consider benefits and risks of resuming treatment following resolution of transaminase elevations

Dosing Considerations

Laboratory monitoring

  • Assess liver function tests (ALT, AST, and bilirubin) for all patients before initiating, q3Months during the first year, and annually thereafter
  • For patients with history of hepatobiliary disease or liver function test elevations, consider more frequent monitoring

Dosage Forms & Strengths

elexacaftor/tezacaftor/ivacaftor

fixed-dose tablet copackaged with ivacaftor tablet

  • 100mg/50mg/75mg plus ivacaftor 150 mg

Cystic Fibrosis

Indicated for cystic fibrosis in children aged ≥12 years who have at least 1 F508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which is estimated to represent 90% of the cystic fibrosis population

2 fixed-dose tablets (elexacaftor 100 mg, tezacaftor 50 mg, and ivacaftor 75 mg) PO qAM and 1 ivacaftor 150-mg tablet PO qPM; ~12 hr apart

Dosage Modifications

Renal impairment

  • Mild or moderate (eGFR 30 to <90 mL/min/1.73 m2): No dosage adjustment required
  • Severe (eGFR <30 mL/min/1.73 m2) or ESRD: Use caution

Hepatic impairment

  • Mild (Child-Pugh A): No dosage adjustment required
  • Moderate (Child-Pugh B): Not recommended unless benefit exceeds risk; reduce dose by omitting evening ivacaftor 150-mg tab; monitor liver function tests
  • Severe (Child-Pugh C): Do not use

Coadministration with moderate or strong CYP3A inhibitors

  • Moderate CYP3A inhibitors
    • Alternate daily dose between 2 fixed-dose tablets qAM and 1 ivacaftor 150-mg tablet qAM
    • Do not take an evening dose
  • Strong CYP3A inhibitors
    • Take 2 fixed-dose tablets PO twice weekly, ~3-4 days apart
    • Do not take an evening dose

Elevated liver function tests

  • Interrupt therapy
    • ALT or AST >5x ULN, or
    • ALT or AST >3x ULN with bilirubin >2x ULN
    • Consider benefits and risks of resuming treatment following resolution of transaminase elevations

Dosing Considerations

Laboratory monitoring

  • Assess liver function tests (ALT, AST, and bilirubin) for all patients before initiating, q3Months during the first year, and annually thereafter
  • For patients with history of hepatobiliary disease or liver function test elevations, consider more frequent monitoring
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Interactions

Interaction Checker

and elexacaftor/tezacaftor/ivacaftor

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    Interactions Found

    Contraindicated

      Serious - Use Alternative

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            Adverse Effects

            >10%

            Headache (17%)

            Upper respiratory tract infection (16%)

            Abdominal pain (14%)

            Diarrhea (13%)

            1-10%

            Rash (10%)

            Increased ALT (10%)

            Increased AST (9%)

            Increased BUN (9%)

            Nasal congestion (9%)

            Rhinorrhea (8%)

            Rhinitis (7%)

            Influenza (7%)

            Sinusitis (5%)

            Increased bilirubin (5%)

            2 to <5%

            • Flatulence
            • Abdominal distension
            • Conjunctivitis
            • Pharyngitis
            • Respiratory tract infection
            • Tonsillitis
            • Urinary tract infection
            • Increased C-reactive protein
            • Hypoglycemia
            • Dizziness
            • Dysmenorrhea
            • Acne
            • Eczema
            • Pruritus
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            Warnings

            Contraindications

            None

            Cautions

            Elevated liver transaminases and bilirubin levels observed; measure levels before initiating, q3Months during first year, and annually thereafter; consider more frequent monitoring for those with history of hepatic disease; interrupt dosing for significant elevations

            Noncongenital lens opacities reported with ivacaftor-containing regimens; other risk factors were present in some cases (eg, corticosteroid use, radiation exposure); a possible risk attributable to treatment with ivacaftor cannot be excluded

            Drug interaction overview

            • CYP3A inhibitors or inducers
              • Coadministration with moderate or strong CYP3A inhibitors increases systemic exposure of elexacaftor/tezacaftor/ivacaftor; dosage adjustment is required if coadministered
              • Coadministration with strong CYP3A inducers is not recommended; ivacaftor systemic exposure is significantly decreased and exposure to elexacaftor and tezacaftor are expected to decrease if coadministered with a strong CYP3A inducer
            • Potential for elexacaftor/tezacaftor/ivacaftor to affect other drugs
              • Ivacaftor may inhibit CYP2C9; monitor INR if coadministered with warfarin; caution with other CYP2C9 substrates (eg, glimepiride, glipizide)
              • Coadministration of ivacaftor or tezacaftor/ivacaftor with digoxin, a sensitive P-gp substrate, increased digoxin AUC by 1.3-fold, consistent with weak inhibition of P-gp by ivacaftor
              • Elexacaftor and its active metabolite (M23-ELX) inhibit uptake by OATP1B1 and OATP1B3 in vitro; coadministration may increase exposures of drugs that are substrates of these transporters (eg, statins, glyburide, nateglinide, repaglinide)
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            Pregnancy & Lactation

            Pregnancy

            Human data are limited and incomplete from clinical trials on the use of elexacaftor/tezacaftor/ivacaftor or its individual components in pregnant women to inform a drug-associated risk

            Although there are no animal reproduction studies with the concomitant administration of elexacaftor, tezacaftor, and ivacaftor, separate reproductive and developmental studies were conducted with each active component in pregnant rats and rabbits

            Animal data

            • In animal embryofetal development studies, oral administration of elexacaftor to pregnant rats and rabbits during organogenesis demonstrated no teratogenicity or adverse developmental effects at doses that produced maternal exposures up to ~2 times the exposure at the maximum recommended human dose (MRHD) in rats and 4 times the MRHD in rabbits

            Lactation

            No data are available regarding the presence of elexacaftor, tezacaftor, or ivacaftor in human milk, the effects on the breastfed infant, or the effects on milk production.

            Elexacaftor, tezacaftor, and ivacaftor are excreted into the milk of lactating rats

            Pregnancy Categories

            A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

            B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

            C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

            D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

            X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

            NA: Information not available.

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            Pharmacology

            Mechanism of Action

            Elexacaftor and tezacaftor bind to different sites on the cystic fibrosis transmembrane conductance regulator (CFTR) protein and have an additive effect in facilitating the cellular processing and trafficking of F508del-CFTR to increase the amount of CFTR protein delivered to the cell surface compared with either molecule alone

            Ivacaftor potentiates the channel open probability (or gating) of the CFTR protein at the cell surface

            Absorption

            Absolute bioavailability

            • Elexacaftor: 80%
            • Tezacaftor: Not determined
            • Ivacaftor: Not determined

            Peak plasma time

            • Elexacaftor: 6 hr
            • Tezacaftor: 3 hr
            • Ivacaftor: 4 hr

            Peak plasma concentration

            • Elexacaftor: 8.7 mcg/ml
            • Tezacaftor: 6.8 mcg/mL
            • Ivacaftor: 1.2 mcg/mL

            AUC

            • Elexacaftor: 162 mcg⋅h/mL
            • Tezacaftor: 94.5 mcg⋅h/mL
            • Ivacaftor: 11.7 mcg⋅h/mL

            Time to steady-state

            • Elexacaftor: Within 14 days
            • Tezacaftor: Within 8 days
            • Ivacaftor: Within 3-5 days

            Distribution

            Protein bound

            • Elexacaftor: >99%
            • Tezacaftor: ~99%
            • Ivacaftor: ~99%

            Vd

            • Elexacaftor: 53.7 L
            • Tezacaftor: 82 L
            • Ivacaftor: 293 L

            Metabolism

            Elexacaftor

            • Primary pathway: CYP3A4/5
            • Active metabolite: M23-ELX
            • Metabolite potency relative to parent: Similar

            Tezacaftor

            • Primary pathway: CYP3A4/5
            • Active metabolite: M1-TEZ
            • Metabolite potency relative to parent: Similar

            Ivacaftor

            • Primary pathway: CYP3A4/5
            • Active metabolite: M1-IVA
            • Metabolite potency relative to parent: ~1/6

            Elimination

            Half-life

            • Elexacaftor: 29.8 hr
            • Tezacaftor: 17.4 hr
            • Ivacaftor: 15 hr

            Clearance

            • Elexacaftor: 1.18 L/hr
            • Tezacaftor: 0.79 L/hr
            • Ivacaftor: 10.2 L/hr

            Excretion

            • Elexacaftor: Feces (87.3%; primarily as metabolites); urine (0.23%)
            • Tezacaftor: Feces (72%; unchanged or as M2-TEZ); urine (14%; 0.79% unchanged)
            • Ivacaftor: Feces (87.8%); urine (6.6%)
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            Administration

            Oral Administration

            Swallow tablets whole; do not chew, crush, or split

            Take with fat-containing food (eg, meals or snacks prepared with butter or oils or those containing eggs, cheeses, nuts, whole milk, or meats)

            Missed dose

            • ≤6 hr since missing a morning or evening dose: Take missed dose as soon as possible and continue on the original schedule
            • >6 hr since a missed morning dose: Take missed dose as soon as possible and NOT take the evening dose; the next scheduled morning dose should be taken at the usual time
            • >6 hr since a missed evening dose: Do NOT take the missed dose; the next scheduled morning dose should be taken at the usual time
            • Morning and evening doses should not be taken at the same time

            Storage

            Store at 68-77ºF (20-25ºC); excursions permitted to 59-86ºF (15-30ºC)

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            Formulary

            FormularyPatient Discounts

            Adding plans allows you to compare formulary status to other drugs in the same class.

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            • Compare formulary status to other drugs in the same class.
            • Access your plan list on any device – mobile or desktop.

            The above information is provided for general informational and educational purposes only. Individual plans may vary and formulary information changes. Contact the applicable plan provider for the most current information.

            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
            2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
            3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
            4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            6 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            NC NOT COVERED – Drugs that are not covered by the plan.
            Code Definition
            PA Prior Authorization
            Drugs that require prior authorization. This restriction requires that specific clinical criteria be met prior to the approval of the prescription.
            QL Quantity Limits
            Drugs that have quantity limits associated with each prescription. This restriction typically limits the quantity of the drug that will be covered.
            ST Step Therapy
            Drugs that have step therapy associated with each prescription. This restriction typically requires that certain criteria be met prior to approval for the prescription.
            OR Other Restrictions
            Drugs that have restrictions other than prior authorization, quantity limits, and step therapy associated with each prescription.
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            Medscape prescription drug monographs are based on FDA-approved labeling information, unless otherwise noted, combined with additional data derived from primary medical literature.