SYMDEKO (COPACKAGED)
Clinical safety rating: caution
Comprehensive clinical and safety monograph for SYMDEKO (COPACKAGED) (SYMDEKO (COPACKAGED)).
Symdeko is a combination of tezacaftor and ivacaftor. Tezacaftor is a CFTR corrector that facilitates the cellular processing and trafficking of the F508del-CFTR protein to the cell surface, while ivacaftor is a CFTR potentiator that increases the open probability of CFTR channels at the cell surface, thereby enhancing chloride transport in epithelial cells.
| Metabolism | Tezacaftor is primarily metabolized by CYP3A4 and CYP3A5. Ivacaftor is primarily metabolized by CYP3A4 and CYP3A5. Both drugs are substrates of CYP3A enzymes. |
| Excretion | Tezacaftor is primarily metabolized, with <1% excreted unchanged in urine and 72% of the dose recovered in feces (mainly as metabolites). Ivacaftor is extensively metabolized; 87% of the dose is excreted in feces (mostly as metabolites) and <1% in urine. Biliary/fecal elimination is the major route for both. |
| Half-life | Tezacaftor: terminal half-life approximately 15 hours; ivacaftor: terminal half-life approximately 12 hours (range 9–15 hours). The half-lives support twice-daily dosing (every 12 hours) for steady state. |
| Protein binding | Tezacaftor: >99% bound to plasma proteins (albumin and alpha-1-acid glycoprotein). Ivacaftor: approximately 99% bound, primarily to albumin and alpha-1-acid glycoprotein. |
| Volume of Distribution | Tezacaftor: Vd/F approximately 98 L (approx. 1.4 L/kg for a 70 kg adult), indicating extensive tissue distribution. Ivacaftor: Vd/F approximately 303 L (approx. 4.3 L/kg), suggesting wide distribution into tissues. |
| Bioavailability | Tezacaftor: oral bioavailability not reported; absorption is rapid with peak concentrations at ~2 hours. Ivacaftor: oral bioavailability not reported; peak plasma concentrations occur at ~4 hours when taken with fat-containing food. Administration with fat increases ivacaftor exposure approximately 2-4 fold. |
| Onset of Action | Improvement in lung function (FEV1) is observed within 2 weeks of starting therapy; maximal effect typically seen by 4 weeks. |
| Duration of Action | The duration of clinical effect (improved FEV1 and reduced pulmonary exacerbations) persists with continued twice-daily dosing; effect declines upon discontinuation. |
Two tablets orally every 12 hours: one tablet tezacaftor 50mg/ivacaftor 75mg and one tablet ivacaftor 150mg, taken with fat-containing food.
| Dosage form | TABLET |
| Renal impairment | No dose adjustment required for mild or moderate renal impairment. Not recommended for severe renal impairment (eGFR <30 mL/min/1.73m2) due to lack of data. |
| Liver impairment | Child-Pugh Class A: No adjustment. Child-Pugh Class B: Reduce dose to one tablet tezacaftor 50mg/ivacaftor 75mg in the morning and one tablet ivacaftor 150mg in the evening, every 12 hours. Child-Pugh Class C: Not recommended. |
| Pediatric use | Approved for patients aged 6 years and older. Weight-based dosing not required; same as adult dose for ≥30 kg. For 6 to <12 years and <30 kg: one tablet tezacaftor 25mg/ivacaftor 37.5mg and one tablet ivacaftor 62.5mg every 12 hours. |
| Geriatric use | No specific dose adjustment recommended; use with caution due to higher prevalence of renal and hepatic impairment. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for SYMDEKO (COPACKAGED) (SYMDEKO (COPACKAGED)).
| Breastfeeding | No data on presence in human milk, effects on breastfed infant, or milk production. Ivacaftor is excreted into rat milk at concentrations up to 10-fold higher than maternal plasma. M/P ratio unknown. Consider developmental and health benefits of breastfeeding along with mother's clinical need for drug and potential infant effects. |
| Teratogenic Risk | In animal reproduction studies, tezacaftor/ivacaftor and ivacaftor alone showed no evidence of fetal harm at exposures up to 6 times the human exposure at the maximum recommended dose. There are no adequate and well-controlled studies in pregnant women. Use only if potential benefit justifies risk. First trimester: No known teratogenic effects. Second and third trimesters: No known adverse fetal effects; however, limited human data. |
■ FDA Black Box Warning
None
| Serious Effects |
["Concomitant use with strong CYP3A inducers (e.g., rifampin, St. John's wort) is contraindicated due to potential loss of efficacy."]
| Precautions | ["Use with caution in patients with hepatic impairment (moderate to severe) with dose adjustment recommended.","Elevated liver enzymes (ALT, AST) have been reported; monitor liver function tests at baseline and periodically.","Use with strong CYP3A inducers (e.g., rifampin) may reduce efficacy; avoid coadministration.","Use with strong CYP3A inhibitors (e.g., ketoconazole, clarithromycin) increases exposure; reduce dose of tezacaftor/ivacaftor to one tablet daily.","Monitor for cataracts in pediatric patients."] |
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| Fetal Monitoring | Monitor pulmonary function and clinical status. No specific fetal monitoring required; routine prenatal care recommended. |
| Fertility Effects | No human fertility data. In animal studies, ivacaftor and tezacaftor/ivacaftor did not affect fertility or reproductive performance in male and female rats. |