Lumacaftor + Ivacaftor

Indications

Lumacaftor + Ivacaftor is used for: Cystic Fibrosis

Adult Dose

Cystic Fibrosis 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 Hepatic impairment Mild (Child-Pugh A): Dosage adjustment not required Moderate (Child-Pugh B): Reduce dose to 2 tablets in the morning and 1 tablet in the evening (ie, lumacaftor 600 mg/ivacaftor 375 mg per day) Severe (Child-Pugh C) Not studied, but exposure is systemic and expected to be higher than moderate impairment Use with caution at a maximum dose of 1 tablet in the morning and 1 tablet in the evening (ie, lumacaftor 400 mg/ivacaftor 250 mg per day), or less, after weighing the risks and benefits of treatment

Child Dose

Cystic Fibrosis <2 years: Safety and efficacy not established 2-5 years 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])

Renal Dose

Administration

Oral Administration Take with fat containing food (eg, eggs, avocados, nuts, butter, peanut butter, cheese pizza, whole-milk dairy products [eg, whole milk, cheese, yogurt]) Oral granules The entire content of each packet of oral granules should be mixed with 1 teaspoon (5 mL) of age-appropriate soft food or liquid and the mixture completely consumed Soft foods examples include puréed fruits, flavored yogurt or pudding, and milk or juice Food should be at or below room temperature or below Each packet is for single use only Once mixed, consume within 1 hr; mixture is stable for up to 1 hr

Contra Indications

Hypersensitivity

Precautions

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 (see Dosage Modifications) 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 Lactation Excretion of lumacaftor or ivacaftor into human milk is probable; caution advised Both lumacaftor and ivacaftor are excreted into the milk of lactating female rats

Pregnancy-Lactation

Pregnancy Pregnancy Category: B There are no adequate and well-controlled trials in pregnant women; use only if clearly needed during pregnancy Embryofetal development studies in rats and rabbits were conducted with the individual components Lactation Excretion of lumacaftor or ivacaftor into human milk is probable; caution advised Both lumacaftor and ivacaftor are excreted into the milk of lactating female rats

Interactions

Decreased serum concentration w/ strong CYP3A inducers (e.g. rifampicin).

Adverse Effects

Side effects of Lumacaftor + Ivacaftor : >10% Dyspnea (13%) Nasopharyngitis (13%) Nausea (13%) Diarrhea (12%) 1-10% Menstrual abnormalities (10%) Upper respiratory tract infection (10%) Fatigue (9%) Abnormal respiration (9%) Increased blood CPK (7%) Rash (7%) Flatulence (7%) Rhinorrhea (6%) <1% Increased ALT or AST Increased bilirubin Hepatic encephalopathy

Mechanism of Action

Lumacaftor CFTR corrector Corrects the processing and trafficking defect of the F508del-CFTR protein to enable it to reach the cell surface where the CFTR potentiator, ivacaftor, can further enhance the ion channel function of the CFTR protein Ivacaftor CFTR potentiator 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