LUMACAFTOR AND IVACAFTOR

Other

Oral

Mechanism of Action

12.1 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

Indications

an FDA-cleared CF mutation test should be used to detect the presence of the F508del mutation on both alleles of the CFTR gene. ORKAMBI is a combination of ivacaftor

a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator

and lumacaftor

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

Contraindications

• 4 CONTRAINDICATIONS None. None. ( 4 )

FDA Warnings

5 WARNINGS AND PRECAUTIONS Use in patients with advanced liver disease: ORKAMBI should be used with caution in these patients and only if the benefits are expected to outweigh the risks
Liver function decompensation, including liver failure leading to death, has been reported in CF patients with pre-existing cirrhosis with portal hypertension
Following resolution, consider the benefits and risks of resuming dosing
4 ) Neuropsychiatric events, including suicidal thoughts and behaviors : Serious neuropsychiatric events, including symptoms of anxiety, depression, suicidal ideation and behavior, and sleep disturbances, have been reported in the postmarketing setting for ORKAMBI or drugs containing the same or similar active ingredients

Known Side Effects

6 documented side effects by frequency

Shortness of Breath

1-10%

Cough

1-10%

General Unwellness

0.1-1%

Upper Respiratory Infection

0.1-1%

Fatigue

0.1-1%

Diarrhea

0.1-1%

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Formulations

Dosage Forms

Tablet

Route

Oral