Lumacaftor (1 brand name, 2 dosage forms, 1 route)
Available dosage forms: TABLET, GRANULE.
Routes of administration: ORAL.
Brand Names
- ORKAMBI
Indications and Usage
ORKAMBI is indicated for the treatment of cystic fibrosis (CF) in patients aged 1 year and older who are homozygous for the F508del mutation in the CFTR gene. If the patient’s genotype is unknown, an FDA-cleared CF mutation test should be used to detect the presence of the F508del mutation on both alleles of the CFTR gene.
Contraindications
None.
Adverse Reactions
The following adverse reactions are discussed in greater detail in other sections of the label: Use in Patients with Advanced Liver Disease [see Warnings and Precautions (5.1) ] Liver-related Events [see Warnings and Precautions (5.2) ] Hypersensitivity Reactions, Including Anaphylaxis [see Warnings and Precautions (5.3)] Intracranial Hypertension [see Warnings and Precautions (5.4)] Neuropsychiatric Events, Including Suicidal Thoughts and Behaviors [see Warnings and Precautions (5.5)] Respiratory Events [see Warnings and Precautions (5.6) ] Effect on Blood Pressure [see Warnings and Precautions (5.7) ] Cataracts [see Warnings and Precautions (5.9)]
Mechanism of Action
The CFTR protein is a chloride channel present at the surface of epithelial cells in multiple organs. The F508del mutation results in protein misfolding, causing a defect in cellular processing and trafficking that targets the protein for degradation and therefore reduces the quantity of CFTR at the cell surface. The small amount of F508del-CFTR that reaches the cell surface is less stable and has low channel-open probability (defective gating activity) compared to wild-type CFTR protein. Lumacaftor improves the conformational stability of F508del-CFTR, resulting in increased processing and trafficking of mature protein to the cell surface. Ivacaftor is a CFTR potentiator that facilitates increased chloride transport by potentiating the channel-open probability (or gating) of the CFTR protein at the cell surface. In vitro studies have demonstrated that both lumacaftor and ivacaftor act directly on the CFTR protein in primary human bronchial epithelial cultures and other cell lines harboring the F508del-CFTR mutation to increase the quantity, stability, and function of F508del-CFTR at the cell surface, resulting in increased chloride ion transport. In vitro responses do not necessarily correspond to in vivo pharmacodynamic response or clinical benefit.
Overdosage
There have been no reports of overdose with ORKAMBI. The highest repeated dose was lumacaftor 1000 mg once daily/ivacaftor 450 mg q12h administered to 49 healthy subjects for 7 days in a trial evaluating the effect of ORKAMBI on electrocardiograms (ECGs). Adverse events reported at an increased incidence of ≥5% compared to the lumacaftor 600 mg/ivacaftor 250 mg dosing period and placebo included: headache (29%), transaminase increased (18%), and generalized rash (10%). No specific antidote is available for overdose with ORKAMBI. Treatment of overdose consists of general supportive measures including monitoring of vital signs and observation of the clinical status of the patient.