Ivacaftor

Ivacaftor is a potentiator of the CFTR chloride channel — it does not address the absence of CFTR at the cell surface, but for CFTR proteins that are present at the membrane yet defective in gating, ivacaftor increases the probability that the channel is open and conducting chloride and bicarbonate. The result is restored anion transport at the airway, intestinal, pancreatic, and sweat-duct epithelia, with measurable improvements in lung function, weight gain, sweat chloride concentration, and pulmonary exacerbation rate.

Mechanism of Action

• CFTR biology: CFTR is an epithelial chloride and bicarbonate channel essential for normal mucus hydration, airway surface liquid maintenance, and exocrine secretion. Cystic fibrosis arises from mutations in the CFTR gene that disrupt protein production (class I), folding/trafficking (class II — most commonly F508del, present in ~70% of CF chromosomes worldwide), gating (class III — G551D and related), conductance (class IV), or splicing/stability (classes V–VII).
• Ivacaftor target population: ivacaftor as monotherapy benefits patients in whom CFTR reaches the cell surface but gates poorly — chiefly the class III gating mutation G551D (originally) and an expanded list of more than 30 ivacaftor-responsive mutations approved by the FDA in 2017, including residual-function and conductance variants (e.g., E56K, R117H, R347H, A455E, S549N/R, G551S, S1251N, G1244E, D1152H, S977F, S1255P, D1270N, G1349D).
• Potentiation mechanism: ivacaftor binds CFTR directly and increases channel open probability in a phosphorylation-dependent but ATP-independent manner. F508del-CFTR alone shows minimal benefit because too few channels reach the membrane — hence the need for correctors (lumacaftor, tezacaftor, elexacaftor) that improve trafficking, with ivacaftor providing potentiation of the rescued channels.
• Combination logic:
  • Orkambi (lumacaftor + ivacaftor): one Class II corrector + potentiator — modest clinical benefit in F508del homozygotes.
  • Symkevi/Symdeko (tezacaftor + ivacaftor): improved corrector tolerability vs lumacaftor.
  • Kaftrio/Trikafta (elexacaftor + tezacaftor + ivacaftor): two structurally distinct correctors plus ivacaftor — transformative efficacy in patients with at least one F508del allele.

Pharmacokinetics

• Absorption: well absorbed orally; Tmax ~4 hours. Co-administration with a fat-containing meal increases exposure 2.5- to 4-fold and is required for adequate bioavailability.
• Volume of distribution: ~353 L (apparent), reflecting wide tissue distribution.
• Protein binding: approximately 99% — primarily to α1-acid glycoprotein and albumin.
• Metabolism: extensive hepatic metabolism via CYP3A (CYP3A4 > CYP3A5). The major metabolite M1 (hydroxymethyl-ivacaftor) retains ~1/6 of parent activity; the minor metabolite M6 (ivacaftor carboxylate) is essentially inactive.
• Half-life: terminal elimination half-life ~12 hours (12–14 hours in some sources).
• Excretion: predominantly faecal (~88% of dose, primarily as metabolites M1 and M6); negligible urinary excretion of unchanged drug.
• Clearance: apparent oral clearance ~17.3 L/h in healthy adults.

• Cystic fibrosis as monotherapy (Kalydeco) in patients ≥1 month of age who have at least one CFTR mutation responsive to ivacaftor potentiation based on clinical and/or in vitro assay data.
• Cystic fibrosis as part of fixed-dose combinations:
  • Orkambi (lumacaftor/ivacaftor) — patients ≥1 year homozygous for F508del.
  • Symkevi/Symdeko (tezacaftor/ivacaftor) — patients ≥6 years with at least one tezacaftor/ivacaftor-responsive mutation.
  • Kaftrio/Trikafta (elexacaftor/tezacaftor/ivacaftor) — patients ≥2 years with at least one F508del allele or another responsive mutation per current labelling.

• Hypersensitivity to ivacaftor or any of the excipients.
• Combination-specific contraindications apply to the corrector partners (e.g., Kaftrio in severe hepatic impairment) — refer to the specific combination product label.

Very common (≥1/10): headache, oropharyngeal pain, upper respiratory tract infection, nasal congestion, abdominal pain, diarrhoea, rash.

Common (≥1/100 to <1/10): dizziness, ear discomfort, tinnitus, ear congestion, sinus congestion, oropharyngeal erythema, nasopharyngitis, nausea, transaminase elevations (ALT/AST), bacteria in sputum.

Uncommon (≥1/1,000 to <1/100): lens opacities/cataracts in paediatric patients (causal relationship not established but observed in clinical studies).

Rare: hypersensitivity reactions.

Class effect with the corrector partners: rash (especially in females taking hormonal contraception with elexacaftor/tezacaftor/ivacaftor), respiratory adverse events on initiation (with lumacaftor), elevated bilirubin (Kaftrio/Trikafta).

Ivacaftor is a sensitive CYP3A substrate; co-medication management is essential.

• Strong CYP3A inhibitors (ketoconazole, itraconazole, voriconazole, posaconazole, clarithromycin, telithromycin, ritonavir/cobicistat-boosted antivirals): substantially increase ivacaftor exposure — reduce dose to 150 mg twice weekly (mono) or follow combination-product-specific guidance.
• Moderate CYP3A inhibitors (fluconazole, erythromycin): reduce dose to 150 mg once daily (mono) or combination-specific schedule.
• Strong CYP3A inducers (rifampicin, rifabutin, phenytoin, carbamazepine, phenobarbital, St John’s Wort): substantially reduce ivacaftor exposure — co-administration is not recommended.
• Grapefruit juice and Seville orange products: avoid — they inhibit intestinal CYP3A.
• Sensitive CYP3A substrates and substrates of P-gp (midazolam, alfentanil, fentanyl, cyclosporine, tacrolimus, sirolimus, digoxin): ivacaftor is a weak CYP3A inhibitor and P-gp inhibitor — monitor for substrate toxicity and consider dose adjustments.
• Hormonal contraceptives: with elexacaftor/tezacaftor/ivacaftor combinations, increased rash risk; with ivacaftor monotherapy, no clinically significant interaction reported.
• Food: must be taken with fat-containing food — vital for adequate absorption.

Ivacaftor is taken orally every 12 hours with fat-containing food (e.g., eggs, butter, peanut butter, cheese, full-fat dairy, meats). Granules-for-oral-suspension must be mixed thoroughly with 5 mL of soft food or liquid at or below room temperature and consumed within 1 hour.

Monotherapy (Kalydeco) — by Age and Weight

• ≥6 years and ≥25 kg: 150 mg orally every 12 hours.
• Age 6 months to <6 years (and weight bands below 25 kg): weight-based granules dosing per specialist guidance — typically 25 mg, 50 mg, or 75 mg per sachet every 12 hours.
• Age 1 to <6 months: weight-based granules per specialist guidance.

As Part of Combination Therapy

Dose schedules are defined by the specific combination product (Orkambi, Symkevi/Symdeko, Kaftrio/Trikafta). Refer to current labelling and CF-centre protocols; doses may differ from monotherapy.

Renal Impairment

• Mild to moderate: no dose adjustment.
• Severe / end-stage renal disease: use with caution; pharmacokinetic data are limited.

Hepatic Impairment

• Mild (Child-Pugh A): no dose adjustment.
• Moderate (Child-Pugh B): reduce to 150 mg once daily (mono); combination-specific guidance applies.
• Severe (Child-Pugh C): not recommended for monotherapy; combinations are generally contraindicated.

CYP3A Inhibitor or Inducer Co-Administration

See Drug Interactions for dose modifications.

Missed Dose

If a dose is missed and less than 6 hours have passed, take it as soon as remembered and resume the normal schedule. If more than 6 hours have passed, skip the missed dose and resume the normal schedule. Do not double up.

Hepatotoxicity Monitoring

Transaminase elevations (ALT, AST) are common and occasionally severe. Measure ALT and AST before initiation, every 3 months during the first year of treatment, and annually thereafter. For elevations >5× ULN or >3× ULN with bilirubin elevation, interrupt and re-evaluate.

Ophthalmological Monitoring (Paediatric)

Non-congenital lens opacities have been observed in paediatric patients receiving ivacaftor; causality is uncertain but baseline and follow-up ophthalmological examinations are recommended in paediatric patients.

Mutation Testing

An FDA-cleared CFTR mutation panel or sequencing is required to confirm eligibility — ivacaftor is ineffective and not indicated for patients without a responsive mutation.

Fertility, Pregnancy, and Lactation

• Pregnancy: animal data show no fetal harm; human data are limited. Use only if clearly needed; consult specialist obstetric guidance for CF patients.
• Breastfeeding: ivacaftor is excreted in breast milk in animals; human data are limited — discontinue breastfeeding or the medicine based on benefit-risk.

Paediatric Use

Approved from age 1 month for monotherapy; specific combination products have higher minimum ages. Dosing is body-weight-based for younger children.

Effect on Driving

Dizziness has been reported; affected patients should not drive or operate machinery.

Coordination of CF Care

Ivacaftor and its combinations should be initiated and monitored within accredited cystic fibrosis centres, with airway clearance, nutritional support, pancreatic enzyme replacement, and microbiological surveillance maintained.

This medicinal product does not require any special storage conditions. Keep in the original packaging.

4 years for unopened tablet bottles or blister packs and granule sachets. Once a granule sachet is mixed with soft food or liquid, administer within 1 hour.

Prescription required (Rx). Distribution is controlled — typically supplied through specialty pharmacy channels affiliated with accredited cystic fibrosis centres given the cost, mutation-eligibility verification, and pharmacovigilance requirements.