elexacaftor + ivacaftor + tezacaftor: clinical use

Prescribing considerations

• Confirm at least one F508del CFTR mutation using an accurate validated method if genotype is not already established.
• Prescribing should be undertaken by clinicians experienced in cystic fibrosis.
• Review all prescribed, over-the-counter and herbal products for CYP3A and transporter interactions.
• Use in moderate hepatic impairment only when clearly necessary after specialist benefit–risk assessment; exercise caution in advanced liver disease.
• Use in severe renal impairment, older adults and pregnancy or breastfeeding requires careful individual assessment because evidence is limited.
• Use after organ transplantation is not recommended because it has not been studied and important immunosuppressant interactions are possible.

Contraindications and cautions

• Hypersensitivity to elexacaftor, tezacaftor, ivacaftor or an excipient.
• Patients with severe hepatic impairment should not be treated.
• Granules contain lactose and should not be used in specified rare hereditary disorders of galactose or glucose-galactose handling.

Monitoring

• Check ALT, AST and total bilirubin before treatment, every three months during the first year and annually thereafter; monitor more often with liver disease or previous enzyme elevation.
• Promptly reassess liver tests if symptoms suggest hepatic injury; interrupt treatment at the SmPC thresholds and closely monitor any subsequent restart.
• Arrange baseline and follow-up ophthalmological examinations for paediatric patients because lens opacities have been reported with ivacaftor-containing regimens.
• Monitor for new or worsening mood, sleep, concentration or behavioural changes, particularly during early treatment.
• Apply medicine-specific monitoring for interacting agents, including INR with warfarin and concentrations or toxicity markers for narrow-therapeutic-index transporter substrates.

Clinical pharmacology

Elexacaftor and tezacaftor are complementary CFTR correctors that improve processing and trafficking of F508del-CFTR. Ivacaftor potentiates channel opening. All three undergo substantial CYP3A metabolism, explaining many clinically important interactions.

Formulation and product differences

• The selected granules are intended for younger children and are mixed with soft food or liquid; they contain lactose.
• The selected film-coated tablets are for eligible older children and adults and must be swallowed whole.
• Both formulations are used with a separate ivacaftor product; the appropriate presentation is selected by the specialist team.

Sachet

Route: Oral

Strengths: 60 mg + 40 mg + 80 mg, 75 mg + 50 mg + 100 mg

Tablet

Route: Oral

Strengths: 37.5 mg + 25 mg + 50 mg, 75 mg + 50 mg + 100 mg