Drug information of lumacaftor and Ivacaftor
Mechanism of effect
Lumacaftor improves CF symptoms and underlying disease pathology by aiding the conformational stability of F508del-mutated CFTR, resulting in increased processing and trafficking of mature protein to the cell surface. More specifically, lumacaftor acts as a protein-folding chaperone, preventing misfolding of CFTR ion channels and consequent destruction during processing in the endoplasmic reticulum.
The CFTR protein is a chloride channel present at the surface of epithelial cells in multiple organs; ivacaftor facilitates increased chloride transport by potentiating the channel-open probability (or gating) of mutated CFTR proteins
Indicated for R117H, G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R mutations in the CFTR gene
Results from clinical trials indicated that treatment with This combination (lumacaftor/ Ivacaftor) results in improved lung function, reduced chance of experiencing a pulmonary exacerbation, reduced sweat chloride, increased weight gain, and improvements in CF symptoms and quality of life.
This combination was not found to increase the QTc interval to any clinically relevant extent
Fat-containing food: When lumacaftor/ivacaftor was administered with fat-containing foods, lumacaftor exposure was ~2 times higher and ivacaftor exposure was ~3 times higher than when taken in a fasting state
Peak plasma concentration
- Lumacaftor: 25 mcg/mL
- Ivacaftor: 0.502 mcg/mL
- Lumacaftor: 198 mcg·hr/mL
- Ivacaftor: 3.66 mcg·hr/mL
Vd: 86 L (lumacaftor)
- Lumacaftor: 99%; primarily to albumin
- Ivacaftor: 99%; primarily to alpha 1-acid glycoprotein and albumin
Lumacaftor: Not extensively metabolized
Ivacaftor: Extensively metabolized, primarily by CYP3A to M1 and M6 (major metabolites)
- Lumacaftor: 25.2 hr
- Ivacaftor: 9.34 hr
- Lumacaftor: 2.38 L/hr
- Ivacaftor: 25.1 L/hr
- Lumacaftor: 51% (unchanged) in feces; 8.6% urine
- Ivacaftor: 87.8% (as metabolites) in feces; 6.6% urine
Indicated specifically for individuals 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
Drug indicationscystic fibrosis patients
Indicated for cystic fibrosis (CF) in patients who are homozygous for the F508del mutation in the CFTR gene
2 tablets PO q12hr (each tablet containing 200 mg/125 mg [ie, 400 mg/250 mg per dose]); take with fat-containing food
Indicated for cystic fibrosis (CF) in patients aged ≥2 yr who are homozygous for the F508del mutation in the CFTR gene
<2 years: Safety and efficacy not established
- Weight <14 kg: 100 mg/125 mg oral granule packet PO q12hr
- Weight ≥14 kg: 150 mg/188 mg oral granule packet PO q12hr
6-11 years: 2 tablets PO q12hr (each tablet containing 100 mg/125 mg [ie, 200 mg/250 mg per dose])
≥12 years: 2 tablets PO q12hr (each tablet containing 200 mg/125 mg [ie, 400 mg/250 mg per dose])
Side effectsDiarrhea , nausea , rash , flatulence , tiredness , shortness of breath , Rhinorrhea , Irregular periods
InteractionsMedroxyprogesterone , Ethosuximide , Erythromycin , Everolimus , Oxecarbazepin , Itraconazole , Bosentan , Venetoclax , norethindrone , neratinib , nafcillin , st. john's wort , Eslicarbazepine acetate , stiripentol , Doravirine , trabectedine , Sonidegib , Cabozantinib , Cariprazine , Cobimetinib , Copanlisib , Etravirine , Dabrafenib , Acalabrutinib , Fostamatinib , Ixazomib , Ribociclib , chlorpropamide , Fosphenytoin , brigatinib , Triazolam , Efavirenz , Tolbutamide , glyburide , Tolazamide , Alfentanil , Osimertinib , Quinine , Quinidine , Pentobarbital , Ethinyl Estradiol , nevirapine , mitotane , valbenazine , ledipasvir and sofosbuvir , ergotamine , fentanyl , Rifabutin , Rifapentine , Glipizide , Ketoconazole , Clarithromycin , Colchicine , Clonidine , Enzalutamide , Daclatasvir , Phenobarbital , Phenytoin , Glimepiride , Levonorgestrol , Midazolam , Carbamazepine , Dihydroergotamine , Disopyramide , Repaglinide , Rifampin , Sirolimus , Cyclosporine , Primidone , Posaconazole , Pimozide , Tacrolimus , Deflazacort , Dexamethasone , Maraviroc , Halofantrine , Nintedanib , Sofosbuvir and velpatasvir , Dexlansoprazole , Abemaciclib , Triphasic , Naltrexone and Bupropion , Cannabidiol , Dronabinol
Worsening liver function, including hepatic encephalopathy, in patients with advanced liver disease reported
Liver function decompensation, including liver failure leading to death, has been reported in cystic fibrosis patients with pre-existing cirrhosis with portal hypertension
Respiratory events (e.g., chest discomfort, dyspnea, and respiration abnormal) were observed more commonly in patients during initiation of therapy compared to those who received placebo; these events have led to drug discontinuation and can be serious, particularly in patients with advanced lung disease (percent predicted FEV1 <40); clinical experience in patients with ppFEV1 <40 is limited, and additional monitoring of these patients is recommended
Elevated transaminases associated with elevated bilirubin in some patients; measure transaminases and bilirubin before initiating therapy, every 3 months during first year of treatment, and annually thereafter; elevated transaminases may require therapy interruption
Chest discomfort, including dyspnea, and abnormal respiration reported during initiation; clinical experience in patients with percent predicted FEV1 <40 is limited; additional monitoring recommended during initiation of therapy
Increase in blood pressure reported in some patients; monitor blood pressure periodically
Cases of noncongenital lens opacities have been reported in pediatric patients treated with ivacaftor
Lumacaftor is a strong inducer of CYP3A; coadministration with sensitive CYP3A substrates or those with a narrow therapeutic index is not recommended
Ivacaftor is a substrate of CYP3A4 and CYP3A5; coadministration with strong inducers is not recommended because of significantly reduced systemic exposure of ivacaftor
Use in transplanted patients not recommended due to potential drug-drug interactions
Safety and efficacy in patients < 12 years, with cystic fibrosis, not established
Points of recommendation
Follow all directions on your prescription label and read all medication guides or instruction sheets. Use the medicine exactly as directed.
Take this medicine with food that contains fat, such as butter, peanut butter, eggs, avocados, nuts, whole milk, cheese, yogurt, or cheese pizza. Follow your doctor's dosing instructions very carefully.
To use the oral granules: Mix the granules with 1 teaspoon of milk, juice, or soft food such as applesauce, yogurt, or pudding. Mix only 1 dose at a time, and use the mixture within 1 hour after mixing. Feed the child a high-fat food just before or just after giving the granule mixture.
Take your doses at regular intervals, 12 hours apart. This will keep a steady amount of the drug in your body at all times.
Ivacaftor and lumacaftor doses are based on age and weight in children. Children from 2 to 5 years old should take oral granules. Children 6 and older should take tablets.
You will need frequent blood tests to check your liver function. Your blood pressure may also need to be checked often.
A child using this medicine may need frequent eye exams.
Store at room temperature away from moisture and heat.
What happens if I miss a dose?
Take the medicine as soon as you can, but skip the missed dose if you are more than 6 hours late for the dose. Do not take two doses at one time.
Be sure to take a missed dose with a food that contains fat.
If you miss doses or stop taking ivacaftor and lumacaftor for more than 1 week, call your doctor before you start taking the medicine again. You may need a different dose.