General

Genetic Implications:

Pronunciation:
e-lex-a-kaf-tor/tez-a-kaf-tor/eye-va-kaf-tor

Trade Name(s)

• Trikafta

Ther. Class.

cystic fibrosis therapy adjuncts

Pharm. Class.

transmembrane conductance regulator potentiators

Indications

 Cystic fibrosis (CF) in patients who have ≥1  F508del  mutation in the cystic fibrosis transmembrane conductance regulator  (CFTR)  gene or a mutation in the  CFTR  gene that is responsive based on  in vitro  data.

Action

Elexacaftor and tezacaftor– facilitate the cellular processing and trafficking of  F508del -CFTR to increase the amount of mature CFTR protein delivered to the cell surface.  Ivacaftor– acts as a potentiator of the CFTR protein (a chloride channel on the surface of endothelial cells) facilitating chloride transport by increasing the channel-open probability (gating).

Therapeutic Effect(s):

Improved lung function.

Pharmacokinetics

Elexacaftor

Absorption: Well absorbed (88%) following oral administration; absorption is enhanced 2-fold by moderate-fat-containing foods.

Distribution: Well distributed to tissues.

Protein Binding: >99%.

Metabolism and Excretion: Primarily metabolized in liver via the CYP3A4 and CYP3A5 isoenzymes; one metabolite (M23) is pharmacologically active; 87% excreted in feces (primarily as metabolite); <1% excreted in urine.

Half-life: 30 hr.

Tezacaftor

Absorption: Some absorption following oral administration.

Distribution: Widely distributed to tissues.

Protein Binding: >99%.

Metabolism and Excretion: Primarily metabolized in liver via the CYP3A4 and CYP3A5 isoenzymes; one metabolite (M1) is pharmacologically active; 72% excreted in feces as unchanged drug or metabolite; 14% excreted in urine (primarily as metabolite).

Half-life: 15 hr.

Ivacaftor

Absorption: Some absorption following oral administration; absorption is enhanced 3-fold by fat-containing foods.

Distribution: Widely distributed to tissues.

Protein Binding: >99%.

Metabolism and Excretion: Primarily metabolized in liver via the CYP3A4 and CYP3A5 isoenzymes; one metabolite (M1) is pharmacologically active; 87.8% eliminated in feces; negligible urinary elimination.

Half-life: 14 hr.

TIME/ACTION PROFILE (plasma concentrations)

Contraindication/Precautions

Contraindicated in:

• Concurrent use of strong CYP3A inducers;
• Severe hepatic impairment.

Use Cautiously in:

• Moderate hepatic impairment (not recommended; if necessary, use only if benefit outweighs risk; dose ↓ recommended);
• Severe renal impairment (CCr <30 mL/min) or end stage renal disease;
• OB:  Safety not established in pregnancy;
• Lactation: Safety not established in breastfeeding;
• Pedi:  Children <6 yr (safety and effectiveness not established).

Adverse Reactions/Side Effects

Derm: rash

EENT: nasal congestion, cataracts, rhinitis, rhinorrhea, sinusitis

GI: abdominal pain, diarrhea, ↑ liver enzymes, hyperbilirubinemia

MS: ↑ creatine kinase

Neuro: headache

Resp: upper respiratory tract infection

Misc: influenza

* CAPITALS indicate life-threatening.
Underline indicate most frequent.

Interactions

Drug-Drug

•  Strong CYP3A inducers, including  carbamazepine,  phenobarbital,  phenytoin,  rifabutin, and  rifampin , may ↓ elexacaftor, tezacaftor, and ivacaftor levels and effectiveness; avoid concurrent use.
•  Strong CYP3A inhibitors, including  clarithromycin,  itraconazole,  ketoconazole,  posaconazole, and  voriconazole  as well as  moderate CYP3A inhibitors, including erythromycin  and  fluconazole  may ↑ elexacaftor, tezacaftor, and ivacaftor levels and risk of toxicity; dose adjustment recommended.
• May ↑ levels and risk of bleeding with  warfarin ; monitor INR closely.
• May ↑ levels and risk of hypoglycemia with  glimepiride  or  glipizide.
• May ↑ levels of  P-glycoprotein substrates, including  cyclosporine,  digoxin,  everolimus,  sirolimus, and  tacrolimus.
• May ↑ levels of  glyburide,  nateglinide,  repaglinide, and  statins.
•  Hormonal contraceptives  may ↑ risk of rash.

Drug-Natural Products:

 St. John's wort  may ↓ elexacaftor, tezacaftor, and ivacaftor levels and effectiveness; avoid concurrent use.

Drug-Food:

Grapefruit juice may ↑ elexacaftor, tezacaftor, and ivacaftor levels; avoid concurrent use.

Route/Dosage

PO (Adults and Children ≥12 yr): Two elexacaftor 100–mg/tezacaftor 50–mg/ivacaftor 75–mg tablets in AM and one ivacaftor 150–mg tablet in PM (approximately 12 hr apart) with fat-containing food. Concurrent use of strong CYP3A inhibitor– Two elexacaftor 100–mg/tezacaftor 50–mg/ivacaftor 75–mg tablets given twice weekly (3–4 days apart) in AM. Do not give ivacaftor 150–mg tablet in PM.  Concurrent use of moderate CYP3A inhibitor– Two elexacaftor 100–mg/tezacaftor 50–mg/ivacaftor 75–mg tablets in AM on Day 1, then one ivacaftor 150–mg tablet in AM on Day 2; continue this regimen on alternate days in AM. Do not give ivacaftor 150–mg tablet in PM.

PO (Children 6–11 yr and ≥30 kg): Two elexacaftor 100–mg/tezacaftor 50–mg/ivacaftor 75–mg tablets in AM and one ivacaftor 150–mg tablet in PM (approximately 12 hr apart) with fat-containing food. Concurrent use of strong CYP3A inhibitor– Two elexacaftor 100–mg/tezacaftor 50–mg/ivacaftor 75–mg tablets given twice weekly (3–4 days apart) in AM. Do not give ivacaftor 150–mg tablet in PM.  Concurrent use of moderate CYP3A inhibitor– Two elexacaftor 100–mg/tezacaftor 50–mg/ivacaftor 75–mg tablets in AM on Day 1, then one ivacaftor 150–mg tablet in AM on Day 2; continue this regimen on alternate days in AM. Do not give ivacaftor 150–mg tablet in PM.

PO (Children 6–11 yr and <30 kg): Two elexacaftor 50–mg/tezacaftor 25–mg/ivacaftor 37.5–mg tablets in AM and one ivacaftor 75–mg tablet in PM (approximately 12 hr apart) with fat-containing food. Concurrent use of strong CYP3A inhibitor– Two elexacaftor 50–mg/tezacaftor 25–mg/ivacaftor 37.5–mg tablets given twice weekly (3–4 days apart) in AM. Do not give ivacaftor 75–mg tablet in PM.  Concurrent use of moderate CYP3A inhibitor– Two elexacaftor 50–mg/tezacaftor 25–mg/ivacaftor 37.5–mg tablets in AM on Day 1, then one ivacaftor 75–mg tablet in AM on Day 2; continue this regimen on alternate days in AM. Do not give ivacaftor 75–mg tablet in PM.

Hepatic Impairment 
(Adults and Children ≥12 yr): Moderate hepatic impairment (Child-Pugh Class B)– Two elexacaftor 100–mg/tezacaftor 50–mg/ivacaftor 75–mg tablets in AM on Day 1, then one elexacaftor 100–mg/tezacaftor 50–mg/ivacaftor 75–mg tablet in AM on Day 2. Continue this regimen on alternate days in AM. Do not give ivacaftor 150–mg tablet in PM.

Hepatic Impairment 
(Adults and Children 6–11 yr and ≥30 kg): Moderate hepatic impairment (Child-Pugh Class B)– Two elexacaftor 100–mg/tezacaftor 50–mg/ivacaftor 75–mg tablets in AM on Day 1, then one elexacaftor 100–mg/tezacaftor 50–mg/ivacaftor 75–mg tablet in AM on Day 2. Continue this regimen on alternate days in AM. Do not give ivacaftor 150–mg tablet in PM.

Hepatic Impairment 
(Adults and Children 6–11 yr and <30 kg): Moderate hepatic impairment (Child-Pugh Class B)– Two elexacaftor 50–mg/tezacaftor 25–mg/ivacaftor 37.5–mg tablets in AM on Day 1, then one elexacaftor 50–mg/tezacaftor 25–mg/ivacaftor 37.5–mg tablet in AM on Day 2. Continue this regimen on alternate days in AM. Do not give ivacaftor 75–mg tablet in PM.

Availability

Tablets: elexacaftor 100 mg/tezacaftor 50 mg/ivacaftor 75 mg (combo) + ivacaftor 150 mg (separate tablets), elexacaftor 50 mg/tezacaftor 25 mg/ivacaftor 37.5 mg (combo) + ivacaftor 75 mg (separate tablets)

Assessment

• Monitor lung function (FEV, lung sounds) before and periodically during therapy.
• Assess eyes for cataracts/opacities prior to and periodically during therapy.

Lab Test Considerations:

 Determine patient's genotype prior to starting therapy. If genotype is unknown, use an FDA-cleared CF mutation test to detect the presence of a CFTR mutation followed by verification with bidirectional sequencing when recommended by the mutation test instructions for use.

• Monitor liver function (AST, ALT, bilirubin) prior to starting therapy, every 3 mo during 1st year, and yearly thereafter. May cause ↑ serum transaminases and bilirubin. Monitor AST and ALT before, every 3 mo for the first year, and annually thereafter. If AST or ALT >3 x upper limit of normal (ULN) with bilirubin >2 x ULN, interrupt therapy. Once AST or ALT have returned to normal, consider benefits and risks before resuming therapy.

Implementation

• PO Administer tablets twice daily, 12 hr apart, with fat-containing food (meals or snacks that contain fat are those prepared with butter or oils or those containing eggs, cheeses, nuts, whole milk, or meats).  DNC: Swallow tablets whole; do not crush, break or chew.  

Patient/Family Teaching

• Instruct patient to take as directed with a fat-containing meal to increase absorption. Fat-containing foods include eggs, butter, peanut better, cheese pizza. Take missed doses within 6 hr of missed dose. If >6 hr since missed morning dose, take missed dose as soon as possible and omit the evening dose. Take next scheduled morning dose at usual time. If missed evening dose, omit the missed dose. Take next scheduled morning dose at usual time. Do not take morning and evening doses at same time. Advise patient to read  Patient Information  before starting therapy and with each Rx refill in case of changes.
• Advise patient to avoid eating grapefruit or drinking grapefruit juice during therapy.
• May cause dizziness. Advise patient to avoid driving and other activities requiring alertness until response to medication is known.
• Advise patient to notify health care professional immediately if symptoms of liver problems (pain or discomfort in right abdominal area, yellowing of skin or whites of eyes, loss of appetite, nausea, vomiting, dark amber-colored urine) occur.
• Instruct patient to notify health care professional of all Rx or OTC medications, vitamins, or herbal products being taken and to consult with health care professional before taking other medications, especially St. John's Wort.
• Advise females of reproductive potential to notify health care professional if pregnancy is planned or suspected or if breastfeeding.
• Emphasize the importance of blood tests to monitor liver function and eye examinations.

Evaluation/Desired Outcomes

Improved lung function.