CFTR Triple Modulator (Cystic Fibrosis — F508del)
Pregnancy: Use with specialist oversight — CF patients on Kaftrio have improved fertility. Limited human data on Kaftrio in pregnancy. Animal studies show no teratogenicity but insufficient data. Discuss risks/benefits with CF team and obstetrics.
Elexacaftor / Tezacaftor / Ivacaftor
Brand names: Kaftrio (EU/UK), Trikafta (US)
Adult dose
Dose: Elexacaftor 100 mg / tezacaftor 50 mg / ivacaftor 75 mg (ELX/TEZ/IVA): 2 tablets in the morning + ivacaftor 150 mg (Kalydeco) in the evening with fat-containing food
Route: Oral
Frequency: Morning: ELX/TEZ/IVA tablets ×2; Evening: ivacaftor 150 mg. Both with fat
Max: ELX/TEZ/IVA 200/100/150 mg per morning dose; IVA 150 mg per evening dose
CF patients with at least one F508del mutation (homozygous F508del or heterozygous F508del/minimal function mutation). Most common CF genotype covered. Adults and children ≥2 years (paediatric formulations available from 2 years). Source: BNF 90; NICE TA795.
Paediatric dose
Dose: Age 2–5 years: ELX/TEZ/IVA granules (weight-based). 6–11 years: reduced-strength ELX/TEZ/IVA tablets. ≥12 years: adult tablet dose See age/weight-banded formulations/kg
Route: Oral (granules 2–5 years; film-coated tablets from 6 years)
Frequency: Morning + evening (with fat-containing food)
Max: Age and weight-dependent — see MHRA SPC
Licensed from 2 years for F508del-containing genotypes. Age/weight-banded granule formulations for youngest children. Must take with fat-containing food (fat increases elexacaftor and ivacaftor absorption). Critical not to exceed approved age/weight doses in young children — paediatric formulations are not the same as adult doses. Source: BNF for Children 2024; MHRA SPC Kaftrio.
Dose adjustments
Renal
No dose adjustment for renal impairment.
Hepatic
Moderate hepatic impairment (Child-Pugh B): reduce morning dose to 1 tablet (not 2) + continue evening ivacaftor. Severe: avoid.
Paediatric weight-based calculator
Licensed from 2 years for F508del-containing genotypes. Age/weight-banded granule formulations for youngest children. Must take with fat-containing food (fat increases elexacaftor and ivacaftor absorption). Critical not to exceed approved age/weight doses in young children — paediatric formulations are not the same as adult doses. Source: BNF for Children 2024; MHRA SPC Kaftrio.
Clinical pearls
- VX-445 trial (NEJM 2019): elexacaftor/tezacaftor/ivacaftor improved FEV1 by 13.8% in F508del homozygous patients vs tezacaftor/ivacaftor alone. In F508del/minimal-function heterozygous patients (NEJM 2019, second trial): 14.3% FEV1 improvement vs placebo. This covers 90% of CF patients — transformative for the entire CF population.
- Triple therapy mechanism — addressing the root cause: F508del mutation causes CFTR protein misfolding → ER retention (not reaching cell surface). Elexacaftor and tezacaftor are correctors that stabilise the misfolded CFTR and help it traffic to the cell surface. Ivacaftor is the potentiator that opens the CFTR channel once it reaches the membrane. The three-drug combination achieves far greater function restoration than any single or dual CFTR modulator.
- Life-changing outcomes: patients on Kaftrio from childhood are expected to have near-normal lung function preservation, dramatically reduced hospitalisation, improved nutrition, and potential normal life expectancy — transforming CF from a life-limiting disease to a chronic manageable condition for most patients. Fertility restoration in males and females — contraception counselling essential.
- Liver monitoring critical: ALT/AST must be monitored monthly for first 3 months, quarterly for first year, then annually. If ALT/AST >5× ULN — interrupt and investigate. Rare cases of serious hepatotoxicity reported. Document clearly in clinical notes.
- Access and equity: Kaftrio was initially available only after significant negotiation between NICE and Vertex Pharmaceuticals. NICE TA795 (2021) approved. Early access scheme preceded formal approval. Eligible patients (genotype-confirmed) should be referred to specialist CF centre for initiation. Source: BNF for Children 2024; Heijerman et al. NEJM 2019; Middleton et al. NEJM 2019; NICE TA795; MHRA SPC Kaftrio.
Contraindications
- Patients without an F508del mutation or responsive gating mutation — will not work
- Concurrent strong CYP3A4 inducers (rifampicin) — contraindicated
- Severe hepatic impairment
Side effects
- Elevated liver transaminases (MHRA monitoring requirement — monthly initially)
- Rash (includes drug rash — monitor for severe hypersensitivity)
- Headache, upper respiratory tract infections
- Increase in sputum production/cough (initial CF mucus clearance — usually beneficial sign)
- Elevated blood pressure — ivacaftor component
- Cataracts in children (ophthalmological annual exam — ivacaftor component)
Interactions
- Strong CYP3A4 inducers (rifampicin, carbamazepine, St John's Wort): reduce elexacaftor/ivacaftor — contraindicated
- Strong CYP3A4 inhibitors (itraconazole, clarithromycin): increase ELX/IVA — reduce to ELX/TEZ/IVA morning dose ×1 tablet every other day + IVA 150 mg evening dose twice weekly
- Grapefruit juice: increases exposure — avoid
- Fat-containing food: mandatory — both elexacaftor and ivacaftor require dietary fat for adequate absorption
Monitoring
- LFTs (ALT, AST) monthly for 3 months, then 3-monthly for year 1, then annually
- Lung function (FEV1, FVC, LCI) at 3 months, 6 months, then 6-monthly
- Sweat chloride testing (response marker — expected marked reduction towards normal range)
- Ophthalmological exam annually (cataracts — ivacaftor component)
- Blood pressure annually
- Contraception status (fertility restoration — document discussion)
Reference: BNF for Children 2024; BNF 90; Heijerman et al. NEJM 2019; Middleton et al. NEJM 2019; NICE TA795; MHRA SPC Kaftrio. Verify against your local formulary and the latest BNF before prescribing.
Related
Curated clinical cross-links plus same-class fallbacks.
Calculators