Lumacaftor/Ivacaftor

Lumacaftor/ivacaftor addresses two distinct molecular defects of the most common CFTR mutation (F508del) by acting at sequential steps in CFTR protein life cycle: first, lumacaftor corrects the misfolding-related processing defect so that more protein reaches the cell surface; then ivacaftor potentiates the gating of the rescued channels.

Mechanism of Action

F508del biology

In approximately 70% of cystic fibrosis chromosomes worldwide, the F508del mutation produces a CFTR protein with a phenylalanine-508 deletion. The mutated protein:

1. Misfolds and is targeted by the endoplasmic-reticulum quality-control system for proteasomal degradation, so very little reaches the cell surface (a class II — trafficking — defect).
2. The small fraction that does reach the membrane has reduced channel-open probability and reduced surface stability (a class III/VI — gating and stability — defect).

Lumacaftor (corrector)

• Acts as a protein-folding chaperone — binds F508del-CFTR during biosynthesis and improves its conformational stability, allowing the protein to evade ER quality control and traffic to the apical membrane.
• In vitro, increases the quantity, stability, and function of F508del-CFTR at the cell surface in primary human bronchial epithelial cultures.

Ivacaftor (potentiator)

• Binds the CFTR channel directly at the membrane and increases its open probability in a phosphorylation-dependent, ATP-independent manner.
• The amount of chloride and bicarbonate transport restored is the product of (number of channels at the surface) × (open probability) — which is why the corrector and potentiator are pharmacologically complementary in F508del homozygotes.

Pharmacodynamic effect

• In trials, mean reduction of sweat chloride of approximately 20–32 mmol/L from baseline at week 24 across age groups (re-elevation toward baseline within 2 weeks of treatment cessation).
• Mean absolute improvement in ppFEV1 over placebo of 2.6–3.0 percentage points at 24 weeks in adults; clinical benefit is modest and not strictly correlated with sweat chloride change.
• Reduction in pulmonary exacerbation rate, hospitalisation, and intravenous antibiotic use; modest weight gain.
• No clinically meaningful QTc prolongation; a small reduction in heart rate (up to ~8 bpm) observed at initiation.

Pharmacokinetics

Lumacaftor

• Absorption: extensive first-pass effect; food-containing fat approximately doubles exposure — administration with a fat-containing meal is mandatory.
• Tmax 4 hours fed.
• Volume of distribution: ~86 L (apparent).
• Protein binding: 99%, primarily to albumin.
• Metabolism: minimal — predominantly excreted unchanged in faeces.
• Half-life: ~26 hours.
• Elimination: ~51% unchanged in faeces; ~8.6% in urine (mostly as metabolites; <0.2% unchanged).
• Apparent clearance: ~2.4 L/h.
• Strong inducer of CYP3A: major source of drug-drug interactions in the combination.

Ivacaftor (in this combination)

• See the dedicated Ivacaftor product page for monotherapy pharmacokinetics. In combination with lumacaftor, ivacaftor exposure is reduced (~80% lower AUC) due to lumacaftor’s CYP3A induction; the granule and tablet dose strengths in Orkambi are calibrated to compensate. Tmax ~4 h fed; half-life ~9 h.

• Cystic fibrosis in patients aged 1 year and older who are homozygous for the F508del mutation in the CFTR gene. If the genotype is unknown, an FDA-cleared CF mutation test should confirm the presence of F508del on both alleles.

Lumacaftor/ivacaftor is not effective in patients heterozygous for F508del with a second non-responsive allele; those patients are candidates for tezacaftor/ivacaftor or elexacaftor/tezacaftor/ivacaftor combinations.

• Hypersensitivity to lumacaftor, ivacaftor, or any of the excipients.

Very common (≥1/10): dyspnoea, nasopharyngitis, upper respiratory tract infection, headache, abdominal pain, diarrhoea, nausea, oropharyngeal pain, rash, increased blood creatine phosphokinase (CPK).

Common (≥1/100 to <1/10): rhinitis, sinusitis, influenza, gastrointestinal discomfort, vomiting, flatulence, transaminase elevations (ALT, AST), menstrual abnormalities (especially in females on hormonal contraception), bacteria in sputum.

Uncommon: hypersensitivity reactions, hepatic encephalopathy in advanced CF liver disease.

Specific signal — respiratory symptoms on initiation: 5–10% of patients experience worsening dyspnoea or chest tightness during the first 1–3 weeks; usually self-limited but occasionally requires brief interruption and slower re-introduction.

Blood pressure: small mean increases observed; monitor in patients with pre-existing hypertension.

Cataracts: non-congenital lens opacities have been reported in paediatric patients receiving ivacaftor-containing products; ophthalmological monitoring is recommended.

Lumacaftor is a strong CYP3A inducer and an inhibitor of CYP2C8 and CYP2C9, with modest effects on P-glycoprotein. Ivacaftor is a sensitive CYP3A substrate. This profile creates many clinically important interactions, and prescribing should be reviewed alongside all concomitant medications.

• Hormonal contraceptives (oral, injectable, transdermal, implantable): efficacy markedly reduced by CYP3A induction — non-hormonal contraception (e.g., copper IUD, barrier methods) is recommended.
• Strong CYP3A inhibitors (ketoconazole, itraconazole, voriconazole, posaconazole, clarithromycin, ritonavir): no dose adjustment required for the combination (lumacaftor induces CYP3A, partly offsetting). For ivacaftor monotherapy, restrictions apply.
• Strong CYP3A inducers (rifampicin, rifabutin, phenytoin, carbamazepine, phenobarbital, St John’s Wort): contraindicated — substantially decrease ivacaftor exposure.
• Sensitive CYP3A substrates (midazolam, alfentanil, fentanyl, ciclosporin, tacrolimus, sirolimus, dihydropyridine calcium channel blockers, statins metabolised by CYP3A): exposure reduced — monitor and consider dose adjustment of the substrate.
• Warfarin and other narrow-therapeutic-index CYP-metabolised drugs: monitor INR (warfarin) or appropriate parameters closely.
• Itraconazole and other antifungals used for ABPA in CF: efficacy may be reduced.
• Inhaled and systemic corticosteroids: exposure may be reduced.
• Grapefruit juice and Seville oranges: avoid — CYP3A interactions.
• Food: must be taken with fat-containing food.

Take orally every 12 hours with fat-containing food (eggs, butter, peanut butter, cheese, whole-fat dairy, meats). Granules-for-oral-suspension are mixed thoroughly with 5 mL of soft food or liquid at or below room temperature and consumed within 1 hour.

Adults and Adolescents ≥12 Years

• Two tablets of lumacaftor 200 mg / ivacaftor 125 mg, twice daily (total daily dose: lumacaftor 800 mg + ivacaftor 500 mg).

Children 6–11 Years

• Two tablets of lumacaftor 100 mg / ivacaftor 125 mg, twice daily (total daily dose: lumacaftor 400 mg + ivacaftor 500 mg).

Children 2–5 Years (Weight-Banded Granules)

• <14 kg: lumacaftor 100 mg / ivacaftor 125 mg granules, one sachet twice daily.
• ≥14 kg: lumacaftor 150 mg / ivacaftor 188 mg granules, one sachet twice daily.

Children 1 to <2 Years (Weight-Banded Granules)

• 7 to <9 kg: lumacaftor 75 mg / ivacaftor 94 mg granules, one sachet twice daily.
• 9 to <14 kg: lumacaftor 100 mg / ivacaftor 125 mg granules, one sachet twice daily.
• ≥14 kg: lumacaftor 150 mg / ivacaftor 188 mg granules, one sachet twice daily.

Renal Impairment

• Mild to moderate: no dose adjustment.
• Severe (CrCl <30 mL/min) and end-stage renal disease: use with caution; pharmacokinetic data limited.

Hepatic Impairment

• Mild (Child-Pugh A): no dose adjustment.
• Moderate (Child-Pugh B): reduce to two tablets in the morning and one tablet in the evening (or proportionate granules reduction); equivalent to ~75% of the standard daily dose.
• Severe (Child-Pugh C): use with caution and at further reduced dose (1 tablet twice daily or paediatric equivalent) — benefit-risk should be carefully assessed.

Strong CYP3A Inhibitor Co-Administration

When initiating in a patient already on a strong CYP3A inhibitor (azole antifungal, certain antivirals), start at one tablet daily for the first week to allow CYP3A induction to develop, then increase to the standard dose.

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 are common; severe hepatic injury has been reported, including in patients with pre-existing advanced CF liver disease. Measure ALT, AST, and bilirubin before initiation, every 3 months during the first year, then annually. For elevations >5× ULN, or >3× ULN with bilirubin elevation, interrupt and re-evaluate.

Respiratory Initiation Effect

Counsel patients (and caregivers) about the possibility of transient worsening of respiratory symptoms during the first 1–3 weeks. Consider initiating during a period of clinical stability, with bronchodilator pre-treatment, and with close follow-up. Severe or persistent worsening warrants interruption.

Blood Pressure

Monitor at baseline and periodically; initiation may be associated with small mean increases.

Cataracts (Paediatric)

Baseline and follow-up ophthalmological examinations are recommended in paediatric patients receiving ivacaftor-containing products.

Contraception

Hormonal contraception is unreliable due to CYP3A induction; counsel on non-hormonal alternatives.

Mutation Testing

Genotype confirmation of F508del homozygosity is mandatory before initiation. Heterozygous F508del patients with a second non-responsive allele will not benefit and should be considered for tezacaftor/ivacaftor or elexacaftor/tezacaftor/ivacaftor combinations.

Pregnancy and Lactation

• Pregnancy: limited human data; animal data do not show fetal harm but use only if clearly needed. CF specialist obstetric guidance required.
• Breastfeeding: lumacaftor and ivacaftor are excreted in animal milk; benefit-risk for the infant should be assessed.

Comparison with Newer Triple Modulator

Most F508del homozygous patients eligible for both treatments now receive elexacaftor/tezacaftor/ivacaftor (Kaftrio/Trikafta) instead, given its substantially greater efficacy. Orkambi remains relevant where the triple combination is unavailable, not tolerated, or contraindicated.

Effect on Driving

Dizziness has been reported with ivacaftor-containing products; affected patients should not drive or operate machinery.

Coordination of CF Care

Initiated and monitored within accredited cystic fibrosis centres alongside airway clearance, nutritional support, pancreatic enzyme replacement, and microbiological surveillance.

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

3 years for the 100 mg/125 mg tablets and 4 years for the 200 mg/125 mg tablets. 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.