elexacaftor/tezacaftor/ivacaftor

General

Genetic Implications: 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

Genetic implication 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 clinical and/or 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)

ROUTEONSETPEAKDURATION
Elexacaftor (PO)unknown6 hr24 hr
Tezacaftor (PO)unknown4 hr12 hr
Ivacaftor (PO)unknown6 hr12 hr

Contraindication/Precautions

Contraindicated in:

  • Severe hepatic impairment.

Use Cautiously in:

  • Moderate hepatic impairment (not recommended; if necessary, use only if benefit outweighs risk; dose ↓ recommended);
  • Severe renal impairment 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: ↑ liver enzymes, abdominal pain, diarrhea, HEPATOTOXICITY, hyperbilirubinemia

MS: ↑ CK

Neuro: headache

Resp: upper respiratory tract infection

Misc: HYPERSENSITIVITY REACTIONS (including anaphylaxis), influenza

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

Interactions

Drug-Drug

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 pm ivacaftor dose on any of the days.  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 pm ivacaftor dose on any of the days.

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 pm ivacaftor dose on any of the days.  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 pm ivacaftor dose on any of the days.

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 pm ivacaftor dose on any of the days.  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 pm ivacaftor dose on any of the days.

PO (Children  2–5 yr and ≥14 kg): One packet (containing elexacaftor 100 mg/tezacaftor 50 mg/ivacaftor 75 mg oral granules) in am and one packet (containing ivacaftor 75-mg oral granules) in pm (approximately 12 hr apart) with fat-containing food.  Concurrent use of strong CYP3A inhibitor:  One packet (containing elexacaftor 100 mg/tezacaftor 50 mg/ivacaftor 75 mg oral granules) twice weekly (given 3–4 days apart). Do not give pm ivacaftor dose on any of the days.  Concurrent use of moderate CYP3A inhibitor:  One packet (containing elexacaftor 100 mg/tezacaftor 50 mg/ivacaftor 75 mg oral granules) in am on Day 1; then one packet (containing ivacaftor 75-mg oral granules) in am on Day 2; continue this regimen on alternate days in am. Do not give pm ivacaftor dose on any of the days.

PO (Children  2–5 yr and <14 kg): One packet (containing elexacaftor 80 mg/tezacaftor 40 mg/ivacaftor 60 mg oral granules) in am and one packet (containing ivacaftor 59.5-mg oral granules) in pm (approximately 12 hr apart) with fat-containing food.  Concurrent use of strong CYP3A inhibitor:  One packet (containing elexacaftor 80 mg/tezacaftor 40 mg/ivacaftor 60 mg oral granules) twice weekly (given 3–4 days apart). Do not give pm ivacaftor dose on any of the days.  Concurrent use of moderate CYP3A inhibitor:  One packet (containing elexacaftor 80 mg/tezacaftor 40 mg/ivacaftor 60 mg oral granules) in am on Day 1; then one packet (containing ivacaftor 59.5-mg oral granules) in am on Day 2; continue this regimen on alternate days in am. Do not give pm ivacaftor dose on any of the days.

Hepatic Impairment 
(Adults and Children  ≥12 yr): Moderate hepatic impairment:  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 on any day.

Hepatic Impairment 
(Adults and Children  6–11 yr and ≥30 kg): Moderate hepatic impairment:  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 on any day.

Hepatic Impairment 
(Adults and Children  6–11 yr and <30 kg): Moderate hepatic impairment:  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 on any day.

Hepatic Impairment 
(Adults and Children  2–5 yr and ≥14 kg): Moderate hepatic impairment:  One packet (containing elexacaftor 100 mg/tezacaftor 50 mg/ivacaftor 75 mg oral granules) in am on Days 1–3. No dose on Day 4. One packet (containing elexacaftor 100 mg/tezacaftor 50 mg/ivacaftor 75 mg oral granules) in am on Days 5 and 6. No dose on Day 7. Continue this weekly dosing schedule in am. Do not give pm ivacaftor dose on any day of weekly dosing schedule.

Hepatic Impairment 
(Adults and Children  2–5 yr and <14 kg): Moderate hepatic impairment:  One packet (containing elexacaftor 80 mg/tezacaftor 40 mg/ivacaftor 60 mg oral granules) in am on Days 1–3. No dose on Day 4. One packet (containing elexacaftor 80 mg/tezacaftor 40 mg/ivacaftor 60 mg oral granules) in am on Days 5 and 6. No dose on Day 7. Continue this weekly dosing schedule in am. Do not give pm ivacaftor dose on any day of weekly dosing schedule.

Availability

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

Oral granules: elexacaftor 80 mg/tezacaftor 40 mg/ivacaftor 60 mg (combo) + ivacaftor 59.5 mg (separate oral granules), elexacaftor 100 mg/tezacaftor 50 mg/ivacaftor 75 mg (combo) + ivacaftor 75 mg (separate oral granules)

Assessment

  • Monitor lung function (FEV, lung sounds) before and periodically during therapy.
  • Assess eyes for cataracts/opacities prior to and periodically during therapy.
  • Monitor for signs and symptoms of hypersensitivity reactions (rash, urticaria, pruritus, flushing, dizziness, vomiting, abdominal pain) and angioedema (swelling of throat, lips, tongue, or face; dyspnea; wheezing; hoarseness). Discontinue immediately and provide supportive care.
  • Monitor for signs and symptoms of hepatic impairment (fatigue, nausea, upper abdominal pain, jaundice, scleral icterus, dark urine, clay-colored stools).

Lab Test Considerations:

  • Genetic implication 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.
  • Prior to initiation, obtain liver function (ALT, AST, alkaline phosphatase, and bilirubin) for all patients; then monitor every 3 mo during the 1st yr and annually thereafter. May cause ↑ serum transaminases and bilirubin. More frequent monitoring may be warranted in patients with a history of hepatobiliary disease or ↑ liver function tests. ALT or AST >5 times upper limit of normal (ULN) or ALT or AST >3 times ULN with bilirubin >2 times ULN and/or clinical symptoms suggestive of liver injury; hold 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. 
    • Administer oral granules immediately before or after ingestion of fat-containing food. Mix entire contents of each packet of oral granules with one teaspoon (5 mL) of age-appropriate soft food or liquid (pureed fruits or vegetables, yogurt, applesauce, water, milk, juice) that is at or below room temperature. Once mixed, consume product completely within 1 hr.

Patient/Family Teaching

  • Explain the purpose and side effects of elexacaftor/tezacaftor/ivacaftor. Instruct patient to tablet take as directed with a fat-containing meal to ↑ absorption. Examples of fat-containing foods include whole milk, eggs, avocado, butter, peanut butter, or cheese pizza. Instruct patient or caregiver to mix entire contents of the granule packet with one teaspoon of soft food (pureed fruits or vegetables, yogurt, pudding, applesauce) or liquid (whole milk, breast milk, infant formula, juice) that is at or below room temperature and consume within 1 hr. 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 or caregiver to read  Patient Information  before starting therapy and with each Rx refill in case of changes.
  • Emphasize importance of regular follow-up, blood tests to monitor liver function, and eye examinations.
  • 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.
  • Rep:  Advise women of reproductive potential to notify health care professional if pregnancy is planned or suspected or if breastfeeding.

Evaluation/Desired Outcomes

Improved lung function.