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. |
| Molecular Weight | 598.5 |
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 | Limited human data; animal studies show no teratogenicity at exposures up to 8 times the recommended human dose. Use only if potential benefit justifies risk. |
| 2nd trimester | No well-controlled studies; theoretical risk of electrolyte disturbances and respiratory infections. Consider benefit vs risk. |
| 3rd trimester | No well-controlled studies; may pose risk of low birth weight or preterm delivery due to respiratory effects. Only if clearly needed. |
Clinical note
Comprehensive clinical and safety monograph for TRIKAFTA (COPACKAGED) (TRIKAFTA (COPACKAGED)).
| Placental transfer | Data not available. Based on molecular weight, expected to cross placenta to some extent. |
| Breastfeeding | Not known if distributed in human milk. Due to high molecular weight, excretion likely low. Consider developmental and health benefits of breastfeeding along with mother's clinical need. |
■ FDA Black Box Warning
None
| Serious Effects |
Hypersensitivity to any component
| 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 |
| Food/Dietary | Must be taken with fat-containing food to ensure adequate absorption. Avoid grapefruit, Seville oranges, and pomelos (and their juices) due to CYP3A inhibition potential. Avoid alcohol due to liver toxicity risk. |
Loading safety data…
| Lactation Rating | L3 (Moderately Safe) |
| 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 | 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). |
| Clinical Pearls | Initiate only after confirmation of at least one F508del mutation in CFTR. Monitor liver function tests (ALT, AST, bilirubin) before and every 3 months during first year, then annually. Avoid use with strong CYP3A inducers (e.g., rifampin, St. John's wort). Dose adjustment required with moderate CYP3A inhibitors (e.g., fluconazole, erythromycin) and strong CYP3A inhibitors (e.g., ketoconazole, ritonavir). Contraindicated in patients with advanced liver disease (e.g., history of portal hypertension, cirrhosis with ascites or varices). Monitor for cataracts (especially pediatric patients). |
| Patient Advice | Take with fat-containing food (e.g., eggs, avocado, nuts, butter) to enhance absorption. · Swallow tablets whole; do not crush, chew, or break them. · If a dose is missed by less than 6 hours, take it with fat-containing food. If more than 6 hours, skip the missed dose and take next dose at scheduled time. · Avoid grapefruit, Seville oranges, and pomelos as they can increase drug levels and risk of side effects. · Report any signs of liver problems (yellow skin/eyes, dark urine, abdominal pain, nausea) immediately. · Do not take St. John's wort or rifampin while on this medication. · Use effective contraception during treatment and for 1 month after stopping, as the drug may reduce hormonal contraceptive effectiveness. · Regular eye exams are recommended, especially for children. |