TRIKAFTA (COPACKAGED)
Clinical safety rating: caution
Comprehensive clinical and safety monograph for TRIKAFTA (COPACKAGED) (TRIKAFTA (COPACKAGED)).
Trikafta is a combination of three drugs (elexacaftor, tezacaftor, ivacaftor) that target the defective CFTR protein. Elexacaftor and tezacaftor are CFTR correctors that facilitate the processing and trafficking of the F508del-CFTR protein, increasing its quantity at the cell surface. Ivacaftor is a CFTR potentiator that increases the channel open probability of CFTR at the cell surface, enhancing chloride transport.
| Metabolism | Primarily metabolized by CYP3A4 and CYP3A5. Elexacaftor and tezacaftor undergo extensive metabolism; ivacaftor is metabolized by CYP3A4/5. |
| Excretion | Primarily hepatic metabolism; unchanged drug excreted renally <1% for elexacaftor, tezacaftor, and ivacaftor. Fecal excretion accounts for approximately 87.8% of total dose (elezacaftor), 72.2% (tezacaftor), and 87.8% (ivacaftor). Renal excretion is negligible. |
| Half-life | Elexacaftor: ~24 hours; Tezacaftor: ~13.1 hours; Ivacaftor: ~12.5 hours. Steady state achieved within 7 days; allows once-daily dosing for elexacaftor/tezacaftor and every-12-hour dosing for ivacaftor. |
| Protein binding | Elexacaftor: ~99%; Tezacaftor: ~99%; Ivacaftor: ~99%. Primarily bound to alpha1-acid glycoprotein and albumin. |
| Volume of Distribution | Elexacaftor: 96.5 L (1.4 L/kg for 70 kg); Tezacaftor: 66.8 L (0.95 L/kg); Ivacaftor: 290 L (4.1 L/kg). Indicates extensive tissue distribution. |
| Bioavailability | Oral: Not reported for fixed combination; fat-containing food increases exposure: 3-fold for elexacaftor, 2.5-fold for tezacaftor, and 3-4 fold for ivacaftor. Administer with fat-containing food. |
| Onset of Action | Oral: Improvement in lung function (FEV1) observed within 2-4 weeks; maximal effect by 8-24 weeks. Single-dose acute effects not applicable. |
| Duration of Action | Sustained improvement in lung function and quality of life; continuous therapy required. Persistence of effect for weeks after discontinuation? Not well-characterized; likely declines with drug clearance. |
Two tablets (each containing elexacaftor 100 mg/tezacaftor 50 mg/ivacaftor 75 mg) orally once daily in the morning, plus one ivacaftor 150 mg tablet orally once daily in the evening, approximately 12 hours apart.
| Dosage form | TABLET |
| Renal impairment | No dose adjustment required for mild to moderate renal impairment (eGFR ≥30 mL/min/1.73 m²). Not recommended for use in patients with severe renal impairment (eGFR <30 mL/min/1.73 m²) or end-stage renal disease. |
| Liver impairment | Child-Pugh Class A (mild): No dose adjustment. Child-Pugh Class B (moderate): Reduce dose to one tablet (elexacaftor 100 mg/tezacaftor 50 mg/ivacaftor 75 mg) in the morning and one ivacaftor 150 mg tablet in the evening, or consider use only if benefits outweigh risks. Child-Pugh Class C (severe): Not recommended. |
| Pediatric use | Approved for children aged 6 years and older: For weight 30 kg to <40 kg: two tablets (elexacaftor 75 mg/tezacaftor 37.5 mg/ivacaftor 62.5 mg) in the morning and one ivacaftor 75 mg tablet in the evening. For weight ≥40 kg: same as adult dosing (two tablets of elexacaftor 100 mg/tezacaftor 50 mg/ivacaftor 75 mg in the morning and one ivacaftor 150 mg tablet in the evening). |
| Geriatric use | No specific dose adjustment required for elderly patients (65 years and older). However, due to age-related decline in renal function, monitor renal function and consider cautious use in severe impairment. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for TRIKAFTA (COPACKAGED) (TRIKAFTA (COPACKAGED)).
| Breastfeeding | No data on presence in human milk, effects on infant, or milk production. Consider developmental benefits of breastfeeding vs. maternal need for drug. M/P ratio unknown. |
| Teratogenic Risk | Insufficient human data; animal studies at doses 2-4 times the recommended human dose (based on AUC comparisons) show no adverse developmental outcomes. Risk cannot be ruled out; use only if benefit outweighs risk. |
| Fetal Monitoring |
■ FDA Black Box Warning
None
| Serious Effects |
["History of severe hypersensitivity reaction to any component of Trikafta (e.g., anaphylaxis, serious skin reactions)","Concomitant use with strong CYP3A inducers (e.g., rifampin, carbamazepine, St. John's wort)"]
| Precautions | ["Hepatotoxicity: Elevations in transaminases and bilirubin; monitor liver function tests at baseline, every 3 months for the first year, and annually thereafter","Use with CYP3A inducers/strong inhibitors: Dose adjustments required; avoid concomitant use with strong CYP3A inducers","Cataracts: Cases reported in pediatric patients; baseline and follow-up ophthalmological exams recommended","Elevated liver enzymes: Closely monitor patients with a history of liver disease or elevated transaminases"] |
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| Monitor hepatic function (ALT, AST, bilirubin) before and during therapy. Assess respiratory status and pulmonary exacerbations. No specific fetal monitoring required beyond routine prenatal care. |
| Fertility Effects | No human data on fertility. Animal studies show no impairment of male or female fertility at doses up to 4 times the MRHD (based on AUC). |