Introduction
Orkambi (lumacaftor/ivacaftor) is a fixed-dose combination medication approved for the treatment of cystic fibrosis (CF) in patients with specific genetic mutations. Developed by Vertex Pharmaceuticals, it represents a significant advancement in CF therapy by targeting the underlying cause of the disease rather than just managing symptoms. Orkambi was first approved by the FDA in July 2015 for patients aged 1 year and older who are homozygous for the F508del mutation in the CFTR gene.
Mechanism of Action
Orkambi combines two CFTR (cystic fibrosis transmembrane conductance regulator) modulators with complementary mechanisms:
Lumacaftor: A CFTR corrector that facilitates the cellular processing and trafficking of F508del-CFTR protein to the cell surface, increasing the number of functional CFTR channels available. Ivacaftor: A CFTR potentiator that enhances the channel-open probability (gating) of CFTR proteins at the cell surface, increasing chloride transport.Together, these agents work synergistically to address both the processing defect and the gating abnormality characteristic of the F508del mutation, resulting in improved CFTR function and chloride ion transport across epithelial membranes.
Indications
Orkambi is indicated for the treatment of cystic fibrosis in patients:
- Aged 1 year and older
- Who are homozygous for the F508del mutation in the CFTR gene
Genetic testing is required to confirm F508del homozygosity before initiating treatment.
Dosage and Administration
Standard Dosing:- Patients ≥12 years: 2 tablets (lumacaftor 200 mg/ivacaftor 125 mg per tablet) taken every 12 hours with fat-containing food
- Patients 6 to <12 years: 2 tablets every 12 hours with fat-containing food
- Patients 2 to <6 years: 1 packet of granules (lumacaftor 100 mg/ivacaftor 125 mg) mixed with food every 12 hours
- Patients 1 to <2 years: 1 packet of granules mixed with food every 12 hours
- Take with fat-containing food to enhance absorption (approximately 10-15 grams of fat per meal)
- Tablets should be swallowed whole; do not crush or break
- Granules should be mixed with 1 teaspoon of soft food or liquid at room temperature
- Missed dose should be taken within 6 hours of scheduled time; otherwise, skip and resume normal schedule
- Hepatic impairment: Use with caution in moderate to severe hepatic impairment (Child-Pugh Class B or C)
- Renal impairment: No dosage adjustment recommended
- Elderly: Limited data available; use clinical judgment
Pharmacokinetics
Absorption:- Lumacaftor: Tmax ~4 hours; high-fat meal increases AUC by ~2-fold
- Ivacaftor: Tmax ~4 hours; high-fat meal increases AUC by ~3-fold
- Lumacaftor: >99% protein bound; Vd ~86 L
- Ivacaftor: ~99% protein bound; Vd ~353 L
- Primarily hepatic metabolism via CYP3A
- Lumacaftor: Extensive metabolism; strong CYP3A inducer
- Ivacaftor: Major metabolites include M1 and M6 (hydroxylation)
- Lumacaftor: Feces (51%) and urine (unknown); half-life ~26 hours
- Ivacaftor: Feces (87.8%) and urine (minor); half-life ~9 hours
Contraindications
- Hypersensitivity to lumacaftor, ivacaftor, or any component of the formulation
- Concomitant use with strong CYP3A inducers (rifampin, rifabutin, phenobarbital, carbamazepine, phenytoin, St. John's wort)
- Concomitant use with sensitive CYP3A substrates with narrow therapeutic index (alfentanil, everolimus, sirolimus, etc.)
Warnings and Precautions
Hepatic Toxicity:- Elevated transaminases reported; monitor liver function before initiation and periodically during treatment
- Consider dosage interruption or reduction for significant elevations
- Increased bronchospasm and chest tightness may occur during initiation
- Monitor respiratory status closely during first weeks of treatment
- Non-congenital lens opacities/cataracts reported in pediatric patients
- Baseline and follow-up ophthalmological examinations recommended
- Lumacaftor is a strong CYP3A inducer; may reduce concentrations of many medications
- Ivacaftor is a CYP3A substrate; concentrations affected by CYP3A inhibitors/inducers
- Pregnancy Category B: Use only if potential benefit justifies potential risk
- Not recommended during breastfeeding due to potential serious adverse reactions
Drug Interactions
Significant Interactions:- CYP3A Inducers: Contraindicated (decreased ivacaftor exposure)
- CYP3A Inhibitors: Avoid strong inhibitors (ketoconazole, itraconazole)
- Hormonal Contraceptives: Reduced efficacy; recommend alternative non-hormonal contraception
- Warfarin: Monitor INR closely (potential decreased warfarin exposure)
- Cyclosporine, Tacrolimus: Monitor concentrations closely
- Midazolam, Triazolam: Reduced efficacy
- Statins: Potential reduced efficacy of atorvastatin, simvastatin
Adverse Effects
Most Common Adverse Reactions (≥5% incidence):- Respiratory: Dyspnea, chest discomfort, nasal congestion, rhinorrhea
- Gastrointestinal: Nausea, diarrhea, flatulence
- Neurological: Headache, dizziness
- Musculoskeletal: Arthralgia, muscle spasms
- Other: Fatigue, rash, elevated transaminases
- Hepatic transaminase elevations (2% of patients)
- Respiratory events (bronchospasm, chest tightness)
- Cataracts (pediatric patients)
- Hypersensitivity reactions (angioedema, rash)
Monitoring Parameters
Baseline Assessment:- CFTR genotype confirmation
- Liver function tests (ALT, AST, bilirubin)
- Ophthalmological examination (pediatric patients)
- Respiratory assessment
- Medication reconciliation for potential interactions
- Liver function tests every 3 months for first year, then annually
- Respiratory status, especially during initiation
- Growth and nutritional parameters in pediatric patients
- Ophthalmological exams annually in pediatric patients
- Therapeutic drug monitoring for concomitant medications affected by CYP3A induction
- Pulmonary function tests (FEV1)
- Nutritional parameters (BMI, weight)
- CF-related hospitalizations
- Quality of life measures
Patient Education
Key Points for Patients and Caregivers:- Take Orkambi exactly as prescribed with fat-containing food
- Do not stop taking without consulting your healthcare provider
- Report any signs of liver problems (yellowing skin/eyes, dark urine, nausea)
- Be aware of potential respiratory symptoms during treatment initiation
- Inform all healthcare providers about Orkambi use due to numerous drug interactions
- Use non-hormonal contraception if taking hormonal birth control
- Keep all scheduled follow-up appointments and laboratory tests
- Store at room temperature; protect from light and moisture
- Report any vision changes or eye problems immediately
- Orkambi is not a cure for cystic fibrosis
- Continue all other prescribed CF therapies unless directed otherwise
- Carry medical alert information indicating Orkambi use
- Be aware that missed doses may affect treatment efficacy
References
1. FDA Orkambi Prescribing Information. (2022). Food and Drug Administration. 2. Wainwright CE, et al. Lumacaftor-Ivacaftor in Patients with Cystic Fibrosis Homozygous for Phe508del CFTR. N Engl J Med. 2015;373(3):220-231. 3. Taylor-Cousar JL, et al. Lumacaftor/Ivacaftor in Patients Aged 6-11 Years with Cystic Fibrosis and Homozygous for F508del-CFTR. Am J Respir Crit Care Med. 2017;195(7):912-920. 4. Ratjen F, et al. Long-term safety and efficacy of lumacaftor/ivacaftor therapy in children aged 2-5 years with cystic fibrosis homozygous for F508del-CFTR. J Cyst Fibros. 2022;21(5):797-804. 5. Clinical Pharmacology and Therapeutics. 2016;99(6):673-684. 6. Cystic Fibrosis Foundation Consensus Guidelines for Diagnosis of CFTR-Related Disorders. J Cyst Fibros. 2021;20(1):1-2. 7. European Cystic Fibrosis Society Standards of Care. J Cyst Fibros. 2018;17(2):153-178.
Note: This information is for educational purposes only and should not replace professional medical advice. Always consult with qualified healthcare providers for medical decisions.