tezacaftor/ivacaftor

General

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


Trade Name(s)

  • Symdeko

Ther. Class.

cystic fibrosis therapy adjuncts

Pharm. Class.

transmembrane conductance regulator potentiators

Indications

Genetic implication Treatment of cystic fibrosis (CF) in patients who are homozygous for the  F508del  mutation or who have ≥1 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.

Action

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).  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.

Therapeutic Effect(s):

Improved lung function.

Pharmacokinetics

Tezacaftor

Absorption: Some absorption follows 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 follows 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
Tezacaftor (PO)unknown4 hr12 hr
Ivacaftor (PO)unknown6 hr12 hr

Contraindication/Precautions

Contraindicated in:

  • None.

Use Cautiously in:

  • Moderate or severe hepatic impairment (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

EENT: cataracts, sinus congestion

GI: ↑ liver enzymes, nausea

Neuro: headache, dizziness

Misc: HYPERSENSITIVITY REACTIONS (including anaphylaxis)

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

Interactions

Drug-Drug

Drug-Natural Products:

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

Drug-Food:

Grapefruit juice or Seville oranges may ↑ tezacaftor and ivacaftor levels; avoid concurrent use.

Route/Dosage

PO (Adults and Children ≥12 yr): One tezacaftor 100-mg/ivacaftor 150-mg tablet in AM and one ivacaftor 150-mg tablet in PM (approximately 12 hr apart) with fat-containing food. Concurrent use of strong CYP3A inhibitor: One tezacaftor 100-mg/ivacaftor 150-mg tablet in AM given twice weekly (3–4 days apart). Do not give ivacaftor 150-mg tablet in PM.  Concurrent use of moderate CYP3A inhibitor: One tezacaftor 100-mg/ivacaftor 150-mg tablet or one ivacaftor 150-mg tablet on alternate days in the AM. Do not give ivacaftor 150-mg tablet in PM.

PO (Children 6–<12 yr and ≥30 kg): One tezacaftor 100-mg/ivacaftor 150-mg tablet in AM and one ivacaftor 150-mg tablet in PM (approximately 12 hr apart) with fat-containing food. Concurrent use of strong CYP3A inhibitor: One tezacaftor 100-mg/ivacaftor 150-mg tablet in AM given twice weekly (3–4 days apart). Do not give ivacaftor 150-mg tablet in PM.  Concurrent use of moderate CYP3A inhibitor: One tezacaftor 100-mg/ivacaftor 150-mg tablet or one ivacaftor 150-mg tablet on alternate days in the AM. Do not give ivacaftor 150-mg tablet in PM.

PO (Children 6–<12 yr and <30 kg): One tezacaftor 50-mg/ivacaftor 75-mg tablet in AM and one ivacaftor 75-mg tablet in PM (approximately 12 hr apart) with fat-containing food. Concurrent use of strong CYP3A inhibitor: One tezacaftor 50-mg/ivacaftor 75-mg tablet in AM given twice weekly (3–4 days apart). Do not give ivacaftor 75-mg tablet in PM.  Concurrent use of moderate CYP3A inhibitor: One tezacaftor 50-mg/ivacaftor 75-mg tablet or one ivacaftor 75-mg tablet on alternate days in the AM. Do not give ivacaftor 75-mg tablet in PM.

Hepatic Impairment 
(Adults and Children ≥12 yr): Moderate hepatic impairment: One tezacaftor 100-mg/ivacaftor 150-mg tablet every AM. Do not give ivacaftor 150-mg tablet in PM.  Severe hepatic impairment: One tezacaftor 100-mg/ivacaftor 150-mg tablet every AM (or less frequently). Do not give ivacaftor 150-mg tablet in PM.

Hepatic Impairment 
(Children 6–12 yr and ≥30 kg): Moderate hepatic impairment: One tezacaftor 100-mg/ivacaftor 150-mg tablet every AM. Do not give ivacaftor 150-mg tablet in PM.  Severe hepatic impairment: One tezacaftor 100-mg/ivacaftor 150-mg tablet every AM (or less frequently). Do not give ivacaftor 150-mg tablet in PM.

Hepatic Impairment 
(Children 6–12 yr and <30 kg): Moderate hepatic impairment: One tezacaftor 50 mg/ivacaftor 75-mg tablet every AM. Do not give ivacaftor 75-mg tablet in PM.  Severe hepatic impairment: One tezacaftor 50-mg/ivacaftor 75-mg tablet every AM (or less frequently). Do not give ivacaftor 75-mg tablet in PM.

Availability

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

Assessment

  • Monitor lung function (FEV, lung sounds) before and periodically during therapy.
  • Monitor for signs and symptoms of anaphylaxis (rash, pruritus, laryngeal edema, wheezing). Notify health care professional immediately if these occur.
  • Assess eyes for cataracts/opacities prior to and periodically during therapy.

Lab Test Considerations:

Monitor ALT and AST before starting therapy and every 3 mo during first yr of therapy, and annually thereafter. If ALT or AST >5 times upper limit of normal (ULN), or ALT or AST >3 times ULN with bilirubin >2 times ULN, hold doses until resolution. Consider benefits and risks of resuming therapy.

Implementation

  • PO Dose consists of 2 different tablets. Administer twice daily, about 12 hr apart, with fat-containing food (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 medication as directed with a fat-containing meal to increase absorption. Fat-containing foods include eggs, butter, peanut better, and cheese pizza. If a dose is missed and ≤6 hr since the missed morning or evening dose, take missed dose as soon as possible and continue on the original schedule. If >6 hr since the missed morning or evening dose, omit dose and take next scheduled dose at usual time. Do not double doses.
  • Advise patient to avoid eating Seville oranges and grapefruit and drinking grapefruit juice during therapy.
  • Advise patient to notify health care professional 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 females of reproductive potential to notify health care professional if pregnancy is planned or suspected or if breastfeeding.

Evaluation/Desired Outcomes

Improved lung function.